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Types: Urothelial Carcinoma (transitional cell) (90%) Risk Factors: occupational exposures (dye manufacturers, rubber aluminum factories), smoking SCC of the bladder (5%) Associated with chronic inflammation (schistosoma, chronic UTI, chronic foley use) Treatment: Surgery Adenocarcinoma of bladder (2%) Treatment: Cystectomy Small Cell Bladder Cancer (1%) Treatment: Cisplatin + Etoposide (like regimen for SCLC) →  RT or cystectomy Plasmacytoid: Associated with CDH1 gene mutation Diagnosis: Cystoscopy with biopsy . Once confirmed, needs TURBT (Transurethral resection of bladder tumor)  Ensure muscle is present in the biopsy specimen. If no muscle: Repeat TURBT PET/CT to ensure no distant metastases Staging: T2 (invades muscularis propria) determines need for neoadjuvant therapies Treatment: Non-Muscle Invasive Bladder Cancer (cTa, cT1, Tis) : Typically treated by urology, not necessarily med onc If muscle is not present in the specimen: repeat TURBT Tx: TURBT followed by single dose intravesical mitomycin C or epirubicin Risk stratification for Non-Muscle Invasive Bladder Cancer: Low risk - Papillary urothelial neoplasm of low malignant potential - Low-grade urothelial carcinoma + (Ta + ≤ 3 cm + Solitary) Intermediate risk - Low-grade urothelial carcinoma + (T1 or  > 3 cm, or  Multifocal or Recurrence within 1 year) - High grade urothelial carcinoma + (Ta + ≤ 3 cm + Solitary) High risk - High-grade urothelial carcinoma + (T1 or  > 3 cm, or  Multifocal or CIS) - Very high-risk features (any of the following): BCG unresponsive Variant histologies Lymphovascular invasion Prostatic urethral invasion Treatment based on risk stratification: Low risk: Followed by surveillance Intermediate Risk: Intravesicular Therapy vs. Surveillance High risk: Very High Risk: Cystectomy preferred over BCG No very high risk features: weekly intravesical BCG x6 doses If CR (negative cytology, no residual cancer): maintenance BCG up to 3 years If no CR (BCG unresponsive/intolerant): Cystectomy (preferred) Pembrolizumab (Keynote-057): if unwilling to undergo surgery Intravesicular chemo: Valrubicin, docetaxel, mitomycin, gemcitabine Nadafaragene firadenovec-vncg Nogapendekin alfa inbakicept-pmln If recurrence of non-invasive bladder tumor: Treatment would be based on new tumor’s AUA risk group Muscle Invasive Bladder Cancer: Stage II (cT2, N0) - Stage IIIA (up to T1-T4a and N1) If cystectomy candidate: Need to ask if the patient is “cisplatin eligible?” Galsky criteria for cisplatin ineligible: CrCl <50-60 NYHA 3-4 ECOG 3-4 Grade 2+ neuropathies Grade 2+ ototoxicity If “cisplatin eligible”: neoadjuvant chemo → cystectomy +/- adjuvant nivolumab Neoadjuvant ddMVAC ( d ose- d ense M ethotrexate, V inblastine, D oxorubicin, C isplatin ) prefered over Cis/Gem, but more toxic (VESPER) Neoadjuvant Cis/Gem + Durva (NIAGARA) Consider adjuvant Nivolumab/Pembro x1 year If upstaged to T3/4, N+ or residual disease If “cisplatin ineligible”: upfront cystectomy If not cystectomy candidate: TMT (Trimodal therapy): Maximal TURBT followed by chemo-RT Can consider chemo-RT if: <T4 “Not next to tubes” (ureters or urethra)- not at UJV or bladder base Not multiple tumors Chemo-RT options: High-Dose Cisplatin 5-FU + Mitomycin Gemcitabine If not candidate for cystectomy or definitive chemoRT RT or TURBT Stage IIIB (T1-T4, N2, N3 and M0) Downstaging systemic therapy: If CR/PR: followed by cystectomy or chemo-RT If no response/progression: treat as metastatic disease Concurrent chemo-RT: If PR: consider BCG, surgical consolidation, treat as metastatic disease If progression: treat as metastatic disease Metastatic Bladder Cancer: Preferred : Pembro + Enfortumab Vedotin (EV) EV side effects: Dermatologic side effects, peripheral neuropathies, hyperglycemia, ocular side effects, pneumonitis/ILD, myelosuppression. EV needs eye exam prior to starting and monitoring for DKA. Other options: Gem + Cis ddMVAC Gem + Cis + Nivo followed by nivolumab maintenance If not cisplatin eligible: Gem Gem + Carbo Gem + Carbo → avelumab Gem + Paclitaxel Pembrolizumab Atezolizumab If SD or CR after chemotherapy: adjuvant avelumab ( JAVELIN Bladder 100) Later Line options: Pembrolizumab: preferred post-platinum Enfortumab vedotin: after IO, if not received previously Chemotherapy: Gem/Cis, Gem/Carbo, ddMVAC Erdafitinib: if FGFR mutation present Side effects: hyperphosphatemia, hyponatremia, and retinal pigment epithelial detachment (needs baseline ophtho evaluation → monthly for first 4 months → q3 months thereafter.  Sacituzumab govitecan (TROPHY-U-01) Disatamab Vedotin (anti-HER2 with MMAE taxane payload) Fam-trastuzumab deruxtecan-nxki (HER2 positive, IHC 3+) Urachal Cancer If localized: Partial or complete cystectomy with en bloc resection of urachal ligament with umbilicus and LN dissection

Background: Risk factor: HPV (high risk) > HIV, smoking Mostl y SCC Work-up: DRE Anoscopy LN biopsy/FNA HIV test Chest/abd CT scan Staging: T1: ≤ 2cm T2: 2-5cm T3: > 5cm T4: Tumor of any size invaded to adjacent organs Perianal SCC Non-metastatic disease (M0): Local excision/surgery: Indications: T1 N0 well/moderately differentiated T2 N0 with no sphincter involvement ChemoRT: Indications: T1 N0 poorly differentiated T2-4 N0 Any T N+ ChemoRT can cure without requiring an abdominoperineal resection (APR) The 5-year survival rate is close to 90% Regimens: 1st line: 5-FU + Mitomycin + RT Capecitabine + Mitomycin + RT Category 2B: 5-FU + Cisplatin + RT If a patient did not achieve CR 6 months after chemoRT → definitive surgery (APR) Metastatic disease: First line:  Carbo/taxol + Retifanlimab (preferred) Carbo/taxel mFOLFOX6 FOLFCIS Leucovorin ( Fol inic acid), 5- F U , Cis platin Category 2B: 5FU/Cisplatin DCF D ocetaxel,  C isplatin, 5- F U Subsequent line:  PD-1 inhibitors (if no prior immunotherapy received) Anal SCC Non-metastatic disease (M0) : ChemoRT (regimens mentioned above) If good response to chemoRT but residual mass: R eassess in a few months (up to 6 months after chemoRT) If progression after chemoRT → t ypically receive APR Metastatic disease: (Regimens mentioned above)

Here are some points that can make your Hem/Onc life easier- The earlier you learn them, the better. Lesson Number 1 Below is a list of anticancer agents for which the category and mechanism of action can be recognized by their names: Chemotherapy: ... rubicin : Anthracycline ...tecan : Topoisomerase I inhibitors ...mustine : Alkylating agents ...carbazine : Alkylating agents ...taxel : Taxens (Microtubule-targeting agent) Vin...stine: Vinca alkaloids ( Microtubule-targeting agent) ...platin: Platinum compounds ...trexed : Antifolates ( Antimetabolites) ...citabine: Pyrimidine analogues ( Antimetabolites) Immunotherapy: ...limab: PD-1 inhibitor ...limumab: CTLA-4 inhibitors ... alidomide: Immunomodulators ... cabtagene ...leucel: CAR T-cell therapy Targeted therapy: ...rafenib: BRAF inhibitors ... metinib: MEK inhibitors ...rolimus : mTOR inhibitor ...tinib : TK inhibitor ... brutinib: BTK inhibitor ... rasib: KRAS inhibitors ...trectinib : NTRK inhibitors ... zomib: Proteasome inhibitors ...lisib: PI3Kδ inhibitors Lesson Number 2 In chemotherapy regimens, the abbreviations are typically derived from the initial letters of the component agents. For example, CMF represents C yclophosphamide, M ethotrexate, and 5- F luorouracil. There are some exceptions: Cis p latin and Carbo p latin may be represented by P ( P latinum compounds). Pacli t axel and Doce t axel may be represented by T ( T axanes). Doxorubicin ( A driamycin) is often represented by A. Lesson Number 3 Route of administration: All TKI agents are administered orally. All immunotherapy medications are administered IV, except for immunomodulatory agents (lenalidomide, thalidomide, pomalidomide) which are given orally. Lesson Number 4 Assessment of treatment efficacy in hematology/oncology: Complete response (CR): Disappearance of all evidence of disease. In lymphomas (Lugano criteria): No abnormal FDG uptake on PET (Deauville score 1-3), regression of all lesions to normal size, and no new lesions. In acute leukemias: No circulating blasts, no extramedullary disease, trilineage hematopoiesis in BM with <5% blasts, and recovery of blood counts (ANC ≥1000, platelets ≥100k) Partial response (PR) : Significant but incomplete reduction in disease burden. In lymphomas: ≥50% decrease in the sum of the product of diameters of target lesions, with no new lesions and reduced FDG uptake compared to baseline (Deauville score 4-5 with decreased avidity). In leukemias: PR is less commonly used, but may refer to a substantial reduction in blast percentage or disease burden without meeting all CR criteria. Progressive disease (PD) : Worsening or growth of disease. In lymphomas: >50% increase in the size of existing lesions, appearance of new lesions, or increased FDG uptake (Deauville score 5). In leukemias: Increase of at least 25% in the absolute number of circulating or BM blasts, or development of new extramedullary disease. Lesson Number 5 Castrate-sensitive prostate cancer (CSPC): Also termed "hormone-sensitive" or "androgen-sensitive" prostate cancer. Responds to androgen deprivation therapy (ADT), with tumor growth suppressed when serum testosterone is reduced to castrate levels (typically <50). Castrate-resistant prostate cancer (CRPC): Prostate cancer that progresses clinically, radiographically, or biochemically (rising PSA) despite ongoing ADT and maintenance of castrate levels of serum testosterone (<50). This resistance can occur in both non-metastatic (M0 CRPC) and metastatic (M1 CRPC) disease. Confirm castrate testosterone levels before diagnosing CRPC, and continue ADT even after resistance develops. Lesson Number 6 Measurable Residual Disease (MRD): Residual malignant cells that persist after treatment but are undetectable by standard microscopy.  After a patient achieves complete remission by standard criteria (no detectable disease by microscopy), more sensitive lab techniques (multiparameter flow cytometry, real-time quantitative PCR, NGS) can identify very low levels of leukemic cells that persisted. Patients who are MRD-positive after induction or consolidation therapy have a significantly higher risk of relapse and worse overall survival compared to those who are MRD-negative (regardless of their initial risk category or disease subtype). MRD positivity at key time points (end of induction, end of consolidation) identifies patients at higher risk for relapse and may prompt consideration of therapy intensification or allo-HSCT. Lesson Number 7 Liver biopsy: Liver mass + Cirrhosis: biopsy is generally not indicated for a patient with cirrhosis who has a liver mass if the lesion meets established imaging criteria for HCC on CT or MRI. In this setting, imaging features (arterial phase hyperenhancement, washout, capsule appearance) has high specificity, and biopsy is not routinely required. Consider biopsy if: Imaging is inconclusive Lesion does not meet criteria for definite HCC (LI-RADS 5) Suspicion for a non-HCC malignancy (cholangiocarcinoma) Atypical risk factors (cirrhosis due to congenital or vascular causes) Tumor markers suggest alternative diagnoses Liver mass, No cirrhosis: Biopsy is recommended to confirm malignancy and guide management Systemic therapy in HCC: Generally indicated for patients with HCC and Child-Pugh class A or ≤B7 , while it is not recommended for Child-Pugh class >B7 or C. Lesson Number 8 Basics of radiotherapy (RT): RT application ranges from definitive therapy in localized disease, to consolidation after chemotherapy, palliation of symptoms, and as part of conditioning regimens for HSCT. NCCN emphasize the use of involved-site radiotherapy (ISRT) to limit exposure to adjacent uninvolved organs, thereby reducing long-term complications such as hypothyroidism, cardiac toxicity, and secondary malignancies. Treatment planning requires CT-based simulation and often incorporates PET and MRI for precise target delineation. NCCN provides specific dose and fractionation recommendations based on histology, disease stage, and treatment intent. For example, follicular lymphoma is typically treated with 24–30 Gy, while DLBCL may require 30–36 Gy for consolidation after chemotherapy. Lesson Number 9 Anticoagulation use in renal and hepatic dysfunction: DOACs (apixaban, rivaroxaban, edoxaban, dabigatran): generally avoided in severe renal (CrCl <30 mL/min) or hepatic dysfunction (Child-Pugh B/C or significant LFT elevation). Apixaban may be used with caution in renal impairment but should be avoided in severe hepatic dysfunction. LMWHs (dalteparin, enoxaparin): preferred in patients with GI malignancy or if DOACs are contraindicated, but require caution and possible anti-Xa monitoring in renal dysfunction. DOACs (especially rivaroxaban and edoxaban) are associated with a higher risk of GI bleeding in patients with GI malignancy. Data  on hepatic dosing adjustments are limited. UFH: preferred in severe renal dysfunction or when rapid reversal is needed. Warfarin: consider if other agents are contraindicated, but requires close INR monitoring, especially in hepatic dysfunction. Lesson Number 10 You can stare at this table to strengthen your visual memory and learn about lymphomas! Black cells: Positive For example: CLL has CD5 + White cells: Negative For example: FL has CD5 – Gray cells: Weak/dim For example: CLL has weak/dim CD20 Black cells with white circles: Positive, occasionally negative For example: FL often has positive CD10, but can be negative as well. Lesson Number 11 Terminal deoxynucleotidyl transferase (TdT): Template-independent DNA polymerase expressed in immature lymphoid cells Normally present in precursor B and T lymphoblasts Hallmark of lymphoblastic neoplasms, including ALL and lymphoblastic lymphoma Occasionally seen in the blast phase of CML (when transformation is lymphoid rather than myeloid) Lesson Number 12 Key distinguishing features of leukemias: CLL:  CD5+ and CD23+ co-expression on B-cells (unique among leukemias). CML: BCR-ABL1 fusion; immunophenotype less diagnostic ALL:  TdT+, lymphoid markers CD10+ in B-ALL CD3+ in T-ALL AML:  TdT−, MPO+, myeloid markers (CD13, CD33, CD117) IN PROGRESS...!

Chemotherapy Anthracyclines: 💉 Intercalate into DNA, inhibit topoisomerase II, generate free radicals → DNA damage → cell death Doxo rubicin (Adriamycin) Dauno rubicin Epi rubicin Ida rubicin (Idamycin) Topoisomerase inhibitors: 💉 Interfere with DNA unwinding and replication → cell death Topoisomerase I inhibitors: Irin otecan Top otecan Topoisomerase II inhibitors:  Doxorubicin (Adriamycin) (Anthracycline and Tomoisomerase II inh) Etoposide Alkylating agents: DNA cross-linking → inhibits replication → cell death Cyclophosphamide 💊   💉 Ifosfamide   💉 Busulfan 💉 Melphalan 💊 💉 Car mustine   💉 Lo mustine 💊 Temozolomide (Temodar) 💊 Pro carbazine 💊 Da carbazine   💉 Microtubule-targeting agents :   💉 Disrupt mitotic spindle formation → mitotic arrest → cell death Taxanes:  Pacli taxel (Taxol) Doce taxel Cabazi taxel Vinca alkaloids: Vin cri stine (Oncovin) Vin bla stine Platinum compounds:   💉 DNA cross-linking → inhibits replication → cell death Cis platin Carbo platin Oxali platin Antimetabolites:   Hypomethylating agents (DNA hypomethylation →  reactivation of tumor suppressor gene): Acacitidine   -SubQ Decitabine   💉 Decitabine/cedazuridine  (Inqovi) 💊 Antifolates: Methotrexate  💊   💉 Peme trexed  (Alimta) 💉 Ralti trexed   💉 Purine analogues: 6-mercaptopurine  💊 6-thioguanine  💊 Fludarabine   💉 Cladribine  💉 Pyrimidine analogues: Cytarabine 💉 5-fluorouracil (5-FU) 💉 Gem citabine (Gemzar) 💉 Cape citabine (Xeloda)   💊 Floxuridine  💉 Immunotherapy PDL-1 inhibitors:   💉 Atezolizumab Durvalumab (Imfinzi) Avelumab PD-1 inhibitors:   💉 Pembrolizumab (Keytruda) Nivolumab (Opdivo) Tislelizumab Cemip limab Dostar limab Retifan limab Toripa limab CTLA-4 inhibitors:   💉 Ipi limumab Treme limumab Bispecific T-cell engager (BiTE):   💉 Binds two targets simultaneously (CD3 on T cells and Tumor-associated antigen on cancer cells) → directs T cells to the tumor → T-cell mediated cytotoxicity Blinatumomab Teclistamab Immunomodulatory imide drugs (IMiDs): 💊 Len alidomide Th alidomide Pom alidomide Targeted Therapy BRAF inhibitors: 💊 Vemu rafenib Dab rafenib Enco rafenib So rafenib MEK inhibitors: 💊 (Often combined with BRAF inhibitors) Tra metinib Cobi metinib mTOR inhibitors: Si rolimus 💊 Eve rolimus 💊 Temsi rolimus   💉 VEGF inhibitors:   💉 Block VEGF signaling → inhibit tumor angiogenesis → reduce tumor growth Bevacizumab (Avastin) Ramucirumab Aflibercept Small molecule VEGFR (multi-kinase) inhibitors:   💊 Sunitinib Sorafenib (VEGFR and BRAF inhibitor) Pazopanib Axitinib Cabozantinib Lenvatinib KRAS inhibitors:   💊 Soto rasib Adag rasib BCR-ABL inhibitors:   💊 Imatinib Dasatinib Nilotinib Ponatinib EGFR inhibitors:   💊 Erlotinib Gefitinib Osimertinib (Tagrisso) NTRK inhibitors: 💊 Laro trectinib En trectinib Repo trectinib BTK inhibitors: 💊 Ibrutinib Zanu brutinib Pirtobrutinib Remibrutinib ROS1 inhibitors: 💊 Entrectinib (NTRK and ROS1 inh) Repotrectinib (NTRK and ROS1 inh) Crizotinib (ALK and ROS1 inh) Lorlatinib (ALK and ROS1 inh) ALK inhibitors:   💊 Crizotinib Lorlatinib Alectinib Brigatinib RET inhibitors: 💊 Selpercatinib Pralsetinib HER-2 inhibitors: Tyrosine kinase inhibitor:   💊 Lapatinib Neratinib Monoclonal antibody:   💉 Trastuzumab (Herceptin) Pertuzumab (Perjeta) Margetuximab Antibody-drug conjugates:   💉 Ado-trastuzumab emtansine Trastuzumab deruxtecan (Enhertu) Proteasome inhibitors: Borte zomib  (Velcade) 💉 Carfil zomib   💉 Ixa zomib   💊 Phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors: 💊 Idela lisib Umbralisib Zandelisib Linperlisib Leniolisib CD20 inhibitors: 💉 Rituximab Ublituximab Obinutuzumab Ofatumumab Ocrelizumab

Myeloid cells: Granulocytes (neutrophils, eosinophils, basophils) Neutrophils maturation in BM: 7-10 days, circulates in blood: 1 day, duration in tissue: 2-3 days Monocytes Macrophages Gaucher’s Disease:  Autosomal recessive lysosomal storage disorder Caused by a deficiency of the enzyme glucocerebrosidase (GBA gene) Cells accumulate in the liver, spleen, and bone marrow Classic “crumpled tissue paper” appearance (Buzz word) Dendritic cells Mast cells Lymphocytes: B cells T cells NK cells Leukocytosis Mechanism: Demargination (acute)- Changes in production or release from storage (long term) Causes: Infection Stress Drug induced (steroids, beta agonists, lithium) Chronic inflammation Post-splenectomy Non-hematologic malignancy Marrow stimulation Primary hematologic disease CML (BCR/ABL) Hereditary neutrophilia Down’s syndrome Leukocyte adhesion deficiency Defective integrin receptor (LAD1) Loss of expression of LFA1, Mac-1, gp150;95 Inability to ingest and kill microbes opsonized by C3bi Elevated WBC, recurrent infections (cutaneous abscesses), delayed umbilical cord separation Treated with HSCT Neutropenia Mechanism: Defect in WBC production, increased margination, peripheral destruction Drug induced agranulocytosis: Methimazole, Propothiouricil, Cephalosporins, Penicillins, Sulfa drugs, Chloramphenicol, Carbamazapine, Valproic Acid Significant morbidity and mortality Remove offending agent Causes: Benign neutropenia (Duffy null associated neutropenia): Constitutional neutropenia Usually a story of non-white individual with mildly decreased WBC without any problematic symptoms Severe congenital neutropenia (SCN): Severe infections, survival improved with GCSF High incidence of AML ELANE mutation Kostmann’s Syndrome: Autosomal recessive HAX1 mutation → disrupts mitochondrial function → defective neutrophil differentiation Cyclic neutropenia: Usually benign, “cyclic” every 15-35 days Myelocyte arrest on BMBx May require GSCF in certain circumstances Mutation in ELA2  Not associated with AML Autoimmune Neutropenia: Primary (more common in children) Moderate to severe neutropenia, caused by anti neutrophil antibodies Spontaneous remission over 2 years: 95% Treated with ppx abx, GCSF with severe/recurrent infection Secondary (more common in adults) Large granular lymphocytic leukemia (LGL) Treated with MTX Autoimmune diseases Neutropenia can be a marker of disease activity Felty Syndrome: Rheumatoid arthritis, neutropenia, splenomegaly Treated with steroids, IVIG Chediak-Higashi Syndrome: Autosomal recessive Lysosomal trafficking regulator protein  Increased bacterial infections, albinism and neuropathy Blood smear: giant cytoplasmic granules in the leukocytes and platelets Consider HSCT Chronic granulomatous disease: Defects in NADPH oxidase → Cells are unable to produce reactive oxygen compounds Prone to develop infections with catalase producing bacteria Staphylococcus aureus, Serratia, E. Coli, Klebsiella, Nocardia, Burkholderia cepacia, Aspergillus Diagnosis: Nitroblue tetrazolium or dihydrorhodamine 123 (DHR) Treatment: Lifelong antifungal and antibacterial prophylaxis with or without immunomodulatory (interferon gamma) therapy Hemophagocytic Lymphohistiocytosis (HLH) Life threatening syndrome characterized by excessive immune activation and hyperinflammation Primary: More common in children, rare in adults Secondary: Due to infection (frequently EBV), malignancy, autoimmune disease Macrophage activation syndrome (MAS) is a subtype of secondary HLH, triggered by rheumatic or autoimmune diseases. Diagnostic criteria: Fever  Splenomegaly  Bicytopenia  Hypertriglyceridemia or hypofibrinogenemia Hemophagocytosis  Ferritin >500 Low/absent NK cell activity  Soluble CD25 elevation Treatment: HLH-94 protocol: Etoposide + Dexamethasone (taper) Treat underlying cause

Types: Papillary Thyroid Carcinoma Medullary Thyroid Carcinoma Follicular Thyroid Carcinoma Hurthle Cell Carcinoma Anaplastic Thyroid Carcinoma Suspicious features of thyroid nodules on US: Irregular margins Microcalcifications Taller than wide shape Rim calcifications with small extrusive soft tissue component Extrathyroidal extension Central vascularity Treatment: Treatment typically entails surgery (lobectomy vs. thyroidectomy) Indications for thyroidectomy : History of prior radiation exposure (Category 2B) Extrathyroidal extension Poorly differentiated and differentiated high-grade carcinoma Lateral cervical LN metastases or gross central neck LN metastases Tumor >4 cm Bilateral nodularity Known distant metastases Post thyroidectomy Post-operative thyroglobulin should be negative. If positive, concerning for residual disease.  Obtain Radioactive Iodine (RAI) uptake scan if has any high risk features: Largest primary tumor >2 cm in size Detectable anti-Tg antibodies High-risk subtypes (poorly differentiated, tall cell, columnar cell, hobnail variants, diffuse sclerosing, and insular) Lymphatic invasion Cervical LN metastases Macroscopic multifocality (one focus > 1 cm) Postoperative unstimulated thyroglobulin 1 - 10 ng/mL Microscopic positive margins Can defer RAI if all criteria met: Papillary thyroid cancer Small primary tumor (≤ 2 cm) Intrathyroidal Unifocal or multifocal (all foci ≤ 1 cm) No detectable Tg antibodies Postoperative unstimulated thyroglobulin <1 ng/mL or stimulated Tg <2ng/mL Negative postoperative ultrasound, if done RAI is not indicated in the treatment of Medullary thyroid cancers. Levothyroxine To maintain low TSH levels in the treatment of patients with papillary, follicular, or Hurthle cell carcinoma Papillary Thyroid Cancer Highly curable Localized disease is treated with surgery as above In patients who undergo thyroid lobectomy + isthmusectomy and are found to have any of the following features, should undergo a complete thyroidectomy: Tumor >4 cm Gross positive resection margins Confirmed nodal metastasis Vascular invasion Confirmed contralateral disease Gross extra-thyroidal extension Metastatic Disease Responds well to RAI if it takes up radioiodine on scans- can be curative Can use lenvatinib or sorafenib if no other actionable mutations If NTRK gene fusion: Larotrectinib Entrectinib If BRAF mutation: Dabrafenib Trametinib If RET fusion positive: Pralsetinib Selpercatinib Can consider cabozantinib if progressed following prior VEGFR-targeted therapy Medullary Thyroid Cancer Arise from parafollicular C cells of the thyroid Workup: Screening for germline RET proto-oncogene mutations CEA level Calcitonin level Screen for pheochromocytoma Contrast-enhanced CT of Neck/Chest and Liver MRI (or 3-phase CT of liver) or Ga-68 DOTATATE PET-CT scan if there is a high concern of distant metastases.  Systemic imaging is considered for patients who have a high burden of disease, calcitonin level >500 pg/mL, or elevated CEA levels.   Treatment: ≥ 1 cm in diameter OR bilateral thyroid disease: Total thyroidectomy with bilateral central neck dissection . <1 cm in diameter AND unilateral thyroid disease: Total thyroidectomy with consideration of a bilateral central neck dissection. Post-operative levothyroxine to normalize the TSH. RAI is not indicated Calcitonin can be used to monitor for disease recurrence If slightly rising: continue to monitor CEA and calcitonin levels In patients with stable or slowly progressive indolent disease, can be closely monitored and not be started immediately on kinase inhibitor If calcitonin level rises to ≥ 150 pg/mL: CT with contrast of the neck, liver, and chest and possibly a bone scan Metastatic Disease: Treatment includes kinase inhibitors use: Vandetanib Cabozantinib Selpercatinib (if RET mutated) Anaplastic Thyroid Cancer Very aggressive- worst prognosis of all types of thyroid cancer All patients classified as having Stage IV disease Originate from the follicular cells of the thyroid Often invade the surrounding tissues including the trachea, esophagus and larynx They do not have any uptake of iodine nor do they synthesize thyroglobulin.  RAI therapy is ineffective as treatment Should be genomically profiled to see if the tumor harbors a BRAF V600E mutation, RET fusion, or NTRK gene fusion is present Treatment:  Locoregional disease: Consider total thyroidectomy with therapeutic LN dissection.  Can consider adjuvant EBRT/IMRT with radiosensitizing chemotherapy. Locally advanced/unresectable: EBRT/IMRT + chemotherapy (weekly Carboplatin/Taxol).  Reconsider surgery after neoadjuvant therapy depending on the response. Can consider targeted neoadjuvant therapy for patients with borderline resectable disease. Metastatic:  Consider surgery or RT for local palliative control Same: If NTRK gene fusion: Larotrectinib Entrectinib If BRAF mutation: Dabrafenib Trametinib If RET fusion positive: Pralsetinib Selpercatinib

Risk factors: History of cryptorchidism (undescended testis) Family history of testicular cancer Personal history of testicular cancer Initial work up: Testicular ultrasound Tumor markers: AFP, hCG, LDH Do not biopsy testis. Radical inguinal orchiectomy (through inguinal incision, not scrotum) Brain MRI recommended if: Neurologic symptoms Post-orchiectomy beta-hCG > 5000 Extensive lung metastases Non-pulmonary visceral metastases AFP >10000 (non-seminoma) Predominant choriocarcinoma component (non-seminoma) isochromosome 12p is a hallmark cytogenetic abnormality in testicular germ cell tumors It is a somatic genetic abnormality/ Not considered a hereditary predisposition factor Types: Seminoma: More likely to present with localized disease, indolent growth, less likely to be metastatic beyond RP nodes Non seminoma: Embryonal Carcinoma, Choriocarcinoma, Yolk Sac Tumor (endodermal sinus tumor), Teratoma Tumor Markers: AFP: NOT produced by seminomas (if high, assume non-seminoma) Half life ~7 days May be elevated due to liver disease/toxicity.  Generally ignore if <20-25 ng/mL B-HCG: Can be made by any germ cell tumor.  Half life ~3 days.  Can have false positives from hyperthyroidism, marijuana consumption or in hypogonadism from pituitary HCG production (can test this by administering testosterone. if coming down, then not from cancer). LDH: Very non-specific. used for staging purposes, but not very important in response to treatment or relapse. Risk Stratificatio n: Risk Status Nonseminoma Seminoma Good Risk Testicular or retroperitoneal primary tumor + No nonpulmonary visceral metastases + Post-orchiectomy markers (all): AFP <1000, hCG <5,000, LDH < 1.5 ×ULN Any primary site + No nonpulmonary visceral metastases + Normal AFP, any hCG, any LDH Intermediate Risk Testicular or retroperitoneal primary tumor + No nonpulmonary visceral metastases + Post-orchiectomy markers (any): AFP 1,000–10,000, hCG 5,000–50,000, LDH 1.5–10 ×ULN Any primary site + Nonpulmonary visceral metastases + Normal AFP, any hCG, any LDH Poor Risk Mediastinal primary tumor OR Nonpulmonary visceral metastases OR Post-orchiectomy markers (any): AFP >10,000, hCG >50,000, LDH >10 ×ULN No patients classified as poor prognosis Seminoma Testicular Cancer AFP is normal in seminomas. Treatment: Stage IA, IB (limited to testes): Radical inguinal orchiectomy followed by:   Surveillance - preferred approach Adjuvant Carboplatin (AUC/Area Under Curve 7) x1-2 cycles Adjuvant radiation to retroperitoneum (consider risk of secondary cancers in younger patients) Consider adjuvant treatment if “high risk” features for recurrence, specifically rete testis invasion or tumor size > 4cm. Monitor tumor markers to ensure downtrended Stage IS (limited to testis but have persistent elevation of tumor markers after orchiectomy) Tumor marker elevation after orchiectomy generally indicates presence of metastatic disease despite radiographic evidence of disease, thus treat like stage III (see below) Treat as good/intermediate risk based of how high tumor markers are CAP CT with contrast Stage IIA Seminoma (spread to RP nodes, <3cm) RT to para-aortic and ipsilateral LNs BEP x 3, or EP x 4 BEP: B leomycin + E toposide + Cis p latin Nerve sparing RPLND Stage IIB Seminoma (spread to RP nodes, >3 cm) BEP x3, or EP x 4 Stage IV: Treatment is same for seminomas and nonseminomas Chemo regimen based on risk stratification (Table above): Good risk: BEP x3 cycles, or EP x4 cycles Intermediate/Poor risk: BEP x4 cycles, or VIP x4 cycles (if contraindication to Bleomycin) Residual Masses >3 cm: PET CT and resect if FDG avid If residual mass is present after completion of treatment: perform PET/CT and likely surgery (if FDG avid). The mass may be teratoma vs fibrosis/necrosis. About 10-15% of resected residual masses harbor viable germ cell tumor Late relapse (> 2 years after completion of chemo) Consider surgery if resectable Consider VeIP or TIP x 4 Consider high dose chemotherapy Non-Seminoma Testicular Cancer Stage I: Radical inguinal orchiectomy followed by:   Surveillance (preferred) BEP x 1 RPLND RT is NOT an option for non-seminoma. Consider adjuvant treatment if “high risk” features for recurrence, specifically lymphovascular invasion, predominant embryonal carcinoma >50%, histology, Invasion of spermatic cord or scrotum Monitor tumor markers to ensure downtrended Stage II: RPLND → if malignant nodes, consider adjuvant EP x2 BEP x3 or EP x4 Stage IV: Treatment is same for seminomas and nonseminomas Chemo based on risk stratification (Table above): Good risk: BEP x3 cycles, or EP x4 cycles Intermediate/Poor risk: BEP x4 cycles, or VIP x4 cycles (if contraindication to Bleomycin) Later Line therapies: TIP: Pacli t axel, I fosfamide, Cis p latin VeIP: V inblastine , E toposide, I fosfamide, Cis p latin High-Dose chemo: Carboplatin/Etoposide x2 cycles Paclitaxel/Ifosfamide/Carboplatin/Etoposide x3 cycles Pembrolizumab (MSI-high, dMMR, TMB high) HSCT Residual Masses >3 cm: Resect RPLND: all NSGCT residual masses MUST be resected. Clinical Pearls Check tumor markers immediately prior to initiation of treatment for risk stratification. It is unlikely to be a seminoma if AFP is elevated, regardless of what pathology says. Beta-hCG can be mildly elevated in hypogonadism, hyperthyroidism, marijuana use. Avoid bleomycin in patients with underlying lung disease, elderly, reduced GFR If bleomycin toxicity develops: complete course with EP or change to VIP Bleomycin does not cause neutropenia. Typically G-CSF is not needed and would treat through myelosuppression Testicular cancer is associated with cryptorchidism

Introduction: Non-Hodgkin lymphoma is categorized into two groups of B-cell lymphomas and T-Cell lymphomas, B-cell lymphomas (85–90%): (discussed in a separate post B-Cell Non-Hodgkin lymphoma ) Low-grade B-cell lymphomas (LGBL): DLBCL: The most common, aggressive Follicular lymphoma (FL): Indolent, arising from germinal center B cells Marginal zone lymphoma (MZL): Extranodal, Nodal, Splenic Mantel cell lymphoma (MCL): More aggressive, Derived from mantle zone B cells Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) Lymphoplasmacytic lymphoma (LPL) Hairy cell leukemia High-grade B-cell lymphoma (HGBL): Burkit lymphoma (BL): Highly aggressive, germinal center origin HGBL with MYC and BCL2 ("double-hit" lymphoma) HGBL with MYC and BCL2 and BCL6 rearrangements ("triple-hit" lymphomas) HGBL-not otherwise specified (HGBL-NOS) T-cell lymphomas (10-15%): Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS): The most common subtype of mature T-cell lymphomas A of aggressive lymphoproliferative disorders arising from mature T cells that do not fit into other defined T-cell lymphoma categories Cutaneous T-cell lymphoma (CTCL): Mycosis Fungoides Sézary Syndrome Anaplastic large cell lymphoma (ALCL): Can be ALK-positive or ALK-negative Enteropathy-associated T-cell lymphoma (EATL): Rare, aggressive peripheral T-cell lymphoma of the small intestine Strongly associated with celiac disease Hepatosplenic T-cell lymphoma (HSTCL) Adult T-cell leukemia/lymphoma (ATLL) Extranodal NK/T-cell lymphoma (ENKTL) T-cell large granular lymphocytic leukemia (T-LGLL): Less common, often with extranodal involvement T-Cell Non-Hodgkin Lymphomas Adult T-Cell Leukemia/Lymphoma (ATLL) Background: Immunophenotype: Positive CD2, CD3, CD4, CD5, CD25, CCR4 Negative CD7, CD8, cytotoxic markers (TIA-1, granzyme B, perforin) Variable CD30 CD30 is a marker of activated/mature lymphocytes Presence of > 5% T lymphocytes with abnormal immunophenotype is required for diagnosis Associated with HTLV-1 Can have skin lesions or osteolytic bone lesions (which leads to hypercalcemia) Peripheral smear shows atypical lymphocytes with multilobulated “flower” cells Treatment: BV-CHP B rentuximab V edotin + C yclophosphamide, H ydroxydaunorubicin (Doxorubicin) , P rednisone First-line treatment of CD30-positive peripheral T-cell lymphomas Dose adjusted EPOCH Zidovudine + interferon Anaplastic Large-Cell Lymphoma (ALCL) Background: Positive CD30 Subtypes: ALK-positive ALCL: Systemic, often younger patients, better prognosis ALK-negative ALCL: Systemic, older patients, worse prognosis Primary cutaneous ALCL: Localized to skin, excellent prognosis Breast implant–associated ALCL: Localized to capsule/implant, distinct management Treatment: Localized disease be cured with complete excision Consider RT +/- systemic therapy if residual disease Systemic therapy: First Line: BV-CHP First-line for systemic CD30+ ALCL Brentuximab Brentuximab + Cytoxan, Doxorubicin, Prednisone CHOP EPOCH Subsequent Lines: Brentuximab or clinical trial preferred Bendamustine Bortezomib Cyclophosphamide ALK inhibitors (alectinib, crizotinib, brigatinib, ceritinib, lorlatinib) Only for relapsed/refractory ALK-positive ALCL Mycosis Fungoides (MF) /Sezary Syndrome (SS) Background: Primary cutaneous Lymphoma that involves T cells MF generally affects the skin but may progress to affect the internal organs over time. SS is defined by blood involvement and having clonal rearrangement of TCR in the blood Requires systemic treatment Treatment: Skin directed therapies: Local RT Phototherapy Topical corticosteroids Topical Imiquimod Topical Nitrogen Mustard Topical Retinoids Topical Mechlorethamine Systemic Therapies: Mogalizumab Romidepsin Interferon alfa Retinoids Bexarotene Brentuximab vedotin Gemcitabine Methotrexate Extranodal NK/T-Cell Lymphoma (ENKTL) Background: Very aggressive Typically difficult to diagnose due to necrosis Typical phenotype of NK cell: CD2+, CD7+, surface CD3- ( may express cytoplasmic CD3ε) , CD56+ ( characteristic NK cell marker), CD4 and CD8 are usually absent. Typical phenotype of T-Cell: CD2+, CD7+, surface CD3+ (defining factor), EBER-, CD56 variable, rearranged TCR T Helper: CD3+, CD4+, CD8- T cytotoxic: CD3+, CD4-, CD8+ EBV-encoded RNA (EBER) in situ hybridization is characteristically positive in ENKTL. May present with major GI bleed if involved Subtypes: Nasal ENKTL Extranasal ENKTL Aggressive NK-cell leukemia Treatment: ChemoRT: RT concurrently with 3 cycles of DeVIC DeVIC: De xamethasone, Etoposide ( V P-16), I fosfamide, C arboplatin SMILE x 2-4 cycles → RT SMILE: S teroid (Dexa), M ethotrexate, I fosfamide, L -asparaginase, E toposide P-GEMOX x2 cycles → RT → P-GEMOX P-GEMOX: P egaspargase, Gem citabine, Ox aliplatin GELAD x2 cycles → RT → GELAD x 2 cycles GELAD: G emcitabine, E toposide, Pegaspargase ( a form of L - a sparaginase ), D examethasone If treated with chemo alone: Modified SMILE → allo-HSCT consolidation P-GEMOX → allo-HSCT consolidation DDGP → allo-HSCT consolidation DDGP: D examethasone, Cisplatin ( D DP), G emcitabine, P egaspargase

Cutaneous Melanoma The BRAF V600 mutation is a frequent somatic/acquired driver mutation in cutaneous melanoma. Cyclin-dependent kinase inhibitor 2A (CDKN2A) is the most frequently mutated high-risk gene associated with familial cutaneous melanoma. Staging: Any N+ disease is Stage IIIA and up Memorize staging: Stage Thickness Ulceration T1a < 0.8 mm No T1b < 0.8 mm Yes T1b 0.8–1 mm with or without T2a 1–2 mm No T2b 1–2 mm Yes T3a 2–4 mm No T3b 2–4 mm Yes T4a > 4 mm No T4b > 4 mm Yes Stage T N M Stage 0 Tis N0 M0 Stage IA T1a N0 M0 Stage IB T1b, T2a N0 M0 Stage IIA T2b, T3a N0 M0 Stage IIB T3b, T4a N0 M0 Stage IIC T4b N0 M0 Stage III Any T, Tis ≥N1 M0 Stage IV Any T Any N M1 Localized Melanoma:  Surgical Margins are based on the Breslow thickness: Thickness: Surgical margin: In situ 0.5-1 cm ≤ 1 mm 1 cm > 1 mm - 2 mm 1-2 cm >2 mm 2 cm Adjuvant radiation : Consider for desmoplastic melanoma with risk factors for local recurrence: Location on the head and neck Extensive neurotropism Pure desmoplastic melanoma subtype Close margins where re-resection in not feasible, or locally recurrent disease Extracapsular extension of melanoma in clinically (macroscopic) involved lymph node ≥1 involved parotid node ≥ 2 involved cervical or axillary nodes ≥ 3 involved inguinofemoral nodes ≥3 cm cervical or axillary node ≥ 4 cm inguinofemoral node Routine imaging: NOT recommended for stage IA-IIA melanoma with no evidence of disease (only if concerning sign/symptom). Routine SLN biopsy : NOT recommended for patients with Stage IA (T1a N0 M0) Consider SLN biopsy for Stage IB (T1b/T2a N0 M0) If clinically negative node but SLN+ → complete LN dissection + ultrasounds q3 months For in-transit metastasis (Stage III): If resectable: Resection followed by adjuvant therapy If unresectable: Systemic therapy Local treatment options (TVEC, IL2, imiquimod, RT) Adjuvant therapies: For stage IIB/C : Adjuvant Nivolumab (Checkmate-76K) Adjuvant Pembro x1 year (Keynote-716) For stage IIIA: Better outcomes than Stage IIB/C, consider against adjuvant therapies (great prognosis) For stage IIIB/C/D: Adjuvant Nivolumab x1 year (Checkmate-238) Adjuvant Pembro x1 year (Keynote-054: d id not include stage IIIA with SNL+ and <1 mm tumor burden) Perioperative pembro (3 doses prior and 15 doses after) for stage IIIB-IVC (SWOG 1801) Adjuvant Dabrafenib/Trametinib if actionable BRAF mutation: only BRAF/MEK combination approved (COMBI-AD) Metastatic Melanoma: First line treatment Ipilimumab + Nivolumab Checkmate-067 (Nivo 1 + ipi 3) - combo more side effects Checkmate-511: flip dosing (Nivo 3 + Ipi 1) - improved AE’s Nivolumab/relatlimab-rmbw (Opdualag)- preferred in metastatic disease Nivolumab Pembrolizumab  If BRAF V600E or V600K:  Still use IO in 1L setting DREAMSeq Trial: Ipi + Nivo followed by Dabrafenib+Trametinib (BRAF/MEK inhibitor) after PD showed OS benefit in patients with BRAF V600E (compared to the opposite) BRAF/MEK inhibitor provides a rapid response rate compared to immune-based therapy. However, responses can sometimes be short-lived. Consider using first in patients with visceral crisis who have BRAF V600E/V600K mutation Associated with increased risk of hemorrhage, cardiomyopathy, and ocular toxicities Treatment options with BRAF/MEK inhibitors: Dabrafenib/Trametinib Best CNS penetration- Associated with fevers Cobimetinib/Vemurafenib Vemurafenib causes more SCC and rash/photosensitivity Encorafenib/Binimetinib If progression with above options: Consider tumor-infiltrating lymphocyte therapy (TILs) with Lifileucel If oligometastatic disease: Can do resection followed by “peri-adjuvant” therapy Uveal Melanoma Associated with BAP1 (familial uveal melanoma) or GNAQ/GNA11 mutation They like to metastasize to liver (Buzz word) Treatments for advanced disease: Pembrolizumab Nivolumab Ipi/Nivo Tebentafusp (ImmTAC) T cell receptor targeting gp100  MHC-A/class 1 molecule Preferred over immunotherapy in patients with HLA-A*01:01-positive disease Ipilimumab Chemotherapy Trametinib HEPZATO KIT (melphalan for injection/hepatic delivery system) Acral/Mucosal Melanoma Acral melanoma: Distinct type of melanoma found on palms of hands or feet Mucosal Melanoma: Markers are S-100 and HMB-45 and Melan-A If KIT mutation is present: Can treat with imatinib, dasatinib, nilotinib, ripretinib Basal Cell Carcinoma (BCC) Associated with abnormalities in the sonic hedgehog pathway Rarely Metastasizes  Local Disease: Low risk disease : Location in trunk/extremity <2cm in size Well defined borders Primary disease No sites of prior RT No immunosuppression Nodular and superficial subtypes No perineurial invasion High risk disease : Poorly defined borders Larger than 2cm on trunk/extremities Any lesions located on head, neck, hands, feet, anogenital area Recurrent disease Site of prior RT With perineural invasion Aggressive growth pattern Treatment: If low-risk disease: Resection If high-risk disease: Mohs, standard excision with wider margins, radiation (avoid in patients with predisposition to develop neoplasm), systemic therapy Metastatic/Locally Advanced: First line: Sonidegib For patients with recurrence following surgery or radiation therapy For patients who are not candidate for surgery or radiation therapy Not approved for metastatic disease Vismodegib For metastatic disease (SHH pathway) Subsequent lines: Cemiplimab upon progression Squamous Cell Carcinoma (SCC) Risk factors:  Sun exposure, advanced age, sensitivity to UV radiation, immunosuppression use. Local disease: Treatment: Surgical resection Consider neoadjuvant cemiplimab if: Locally advanced disease/surgery would be too morbid Very rapid growth Positive lymphovascular invasion) For high-risk localized disease ( same criteria as BCC ): Consider adjuvant radiation, standard excision with wider margins, Mohs, PDEMA Metastatic disease: First line: Cemiplimab Pembrolizumab Second line: Carboplatin/paclitaxel/cetuximab (also consider if contraindication to immunotherapy) Merkel Cell Carcinoma Background: Cutaneous neuroendocrine cancers Highly aggressive Associated with polyomavirus CK20 is highly positive marker Local disease: Surgery with SLNB +/- radiation in high risk patients (HIV, CLL, Head and Neck Primary site, +LVI, >1cm) Metastatic disease: First line: Pembrolizumab (Keynote-017) Avelumab (JAVELIN Merkel 200) Nivolumab Ipi + Nivo Retifanlimab Subsequent lines: platinum/etoposide, topoitecan, cyclophosphamide, doxorubicin, and vincristine, TVEC, Ipi/nivo, pazopanib, somatostatin analogues (if positive) Kaposi Sarcoma Typically associated with HIV Limited disease: If asymptomatic: Consider observation or treating HIV If symptomatic: Consider local therapies, RT, or systemic therapies Advanced disease: In patients with untreated HIV → start HAART In patients with treated HIV: First line: Doxil (preferred), Paclitaxel Subsequent lines: Nivolumab, Pembro, Pomalidomide, Abraxane (if paclitaxel intolerant), Bortezomib, Etoposide, Gemcitabine, Imatinib, Ipi/Nivo, Lenalidomide, Sirolimus (for transplant associated KS), Thalidomide (for patients with IRIS), Vinorelbine

Background: Genetic Risks: Li-Fraumeni syndrome (p53) NF1 (malignant peripheral nerve sheath tumors) Familial Rb Gardeners/FAP (APC) Desmoid tumors Most are sporadic tumors Risk factors: Prior radiation is the #1 risk factor (esp within 10-30 years) HIV or HHV-8 (Kaposi Sarcoma) Chronic Lymphedema (Angiosarcoma) Most common types: Gastrointestinal stromal tumor (GIST) Characterized by c-KIT or PDGFRA mutations Liposarcoma Well-differentiated/Dedifferentiated liposarcoma MDM2 and CDK4 are highly sensitive and specific Myxoid round cell liposarcoma Associated with t(12;16) translocation involving DDIT3 Leiomyosarcoma Synovial sarcoma Associated with SYT-SSX Undifferentiated pleomorphic sarcoma malignant peripheral nerve sheath tumor (MPNST) Diagnosis : Needle or excisional biopsy Staging: Require MRI if in extremity or trunk TNM Staging: T is variable based on the tumor location CT chest: Tumors tend to metastasize to lungs SCARE ( higher propensity for lymphatic/LN metastasis ): S ynovial sarcoma C lear cell sarcoma A ngio sarcoma R habdomyo sarcoma E pithelioid  sarcoma Treatment: Localized disease: Surgery Consider pre-op vs post-op radiation Post-op: larger volume of radiation, less wound healing complication Benefit of chemotherapy is not very clear with soft tissue sarcoma Consider use of adjuvant pembrolizumab in high grade/stage III sarcomas Local recurrence: Re-excision +/- radiation is the preferred treatment Systemic therapy is controversial Consider for high-grade, rapidly growing, or multifocal recurrences Metastatic disease: Resection for oligometastatic disease (potentially curative)  Systemic Therapy: Doxorubicin AIM: Doxorubicin ( A driamycine), I fosfamide, M esna Doubles response rates, but no change in OS AD: Doxorubicin ( A driamycine), D acarbazine Used in leiomyosarcoma Doxorubicin + Trabectidin Gemicitabine +/- Docetaxel Trabectidin Liposarcoma and leiomyosarcoma Associated with muscle injury Eribulin liposarcoma Paclitaxel Angiosarcoma and kaposi sarcoma Pazopanib Soft tissue sarcoma but not liposarcoma Pembrolizumab (if TMB >10) Palbociclib Well/de-diff liposarcomas Imatinib Dermatofibrosaroma pertuburans  Nabsirolimus Pecoma Tazametostat Epithelioid sarcoma Benign but locally aggressive tumors Synovial giant cell tumor: High recurrence rate Treatment: Surgery Medication: Paxidartinib (liver toxicity) Vimsultinib (ORR 40%, no serious liver injury) Desmoid tumor: Associated with FAP/Gardner syndrome Treatment: Observation is preferred approach Can be asymptomatic or spontaneously regress Surgery Ablation: Cryo or Radiofrequency ablation (RFA) Nirogasestat  Ovarian toxicity (early menopause) Other TKIs such as sorafenib (off label) Kaposi Sarcoma: Associated with HIV and HHV8 Treatment: HAART: if associated with HIV Pomalidomide If failure of HAART therapy HIV negative patients Paclitaxel Doxorubicin Local excision or radiation

Major components of hemostasis: Primary hemostasis (platelet plug) Defects lead to mucosal bleeding (petechiae, purpura, epistaxis) Secondary hemostasis (blood clot) Defects lead to larger bleeds related to surgery/trauma (joint bleeds, muscle bleeds) Coagulation Cascade: Intrinsic pathway Initiated by Factor XII → activates prekallikrein to kallikrein and high-molecular-weight kininogen → activation of factor XI and IX and VIII Extrinsic pathway Initiated by tissue factor → activate factor 7 Common pathway Factor X, V, II and I (symmetrical roman numerals) Vitamin K dependent factors: Factor II, VII, IX, X, protein C and S Inhibited by warfarin All produced in liver Natural anticoagulants: Antithrombin Protein C and Protein S Tissue factor pathway inhibitor (TFPI) Individual factor clinical pearls: Factor XIII deficiency: Does not affect INR and PTT Factor XII deficiency: May affect PTT in vitro but no clinical bleeding, does not require treatment Factor XI deficiency: Mild to no bleeding- May present late in life Factor VIII, IX deficiency: Hemophilia A & B May require recombinant/activated factor VIII, IX or downstream product Factor VII deficiency: Rare autosomal recessive Affects PT/INR, not PTT Treated with recombinant factor VIIa q6-8h or FFP If both INR and PTT affected: think something in the common pathway X, V, II, I, or fibrinogen Acquired factor X deficiency is associated with AL amyloidosis If acquired inhibitor present: Most likely would require some type of immune suppression such as corticosteroids, IVIG, Rituximab, cyclosporine, PLEX, etc.  Fibrinolysis & clot degradation: Plasminogen activators Convert plasminogen to plasmin, which degrades fibrin clots Mechanism of action of tPA (tissue plasminogen activator) Antithrombotic/Anticoagulants Vitamin K antagonist Warfarin: Competitively inhibits vitamin K oxide reductase Prevents carboxylation of Gla residues on their amino terminus Hepatic clearance Main indications: anticoagulation for mechanical heart valves Antiphospholipid syndrome (APLS) Administration requires close monitoring of INR Rare side effect is warfarin skin necrosis Due to hypercoagulable state within 24 hours of warfarin treatment Due to shorter half life of protein C which leads to thrombotic state Deficiency of protein C and S, Factor V Leiden, antithrombin III, hyperhomocysteinemia, and antiphospholipid antibodies are common risk factors Reversible with: Hold medication If INR < 10, no bleeding Vitamin K If INR > 10, no bleeding FFP is technically an option PCC (preferred in emergent situations) Antithrombin activation Heparin Hepatic clearance Reversible with protamine sulfate Lovenox More specific to target factor Xa activity Renal clearance Reversible with protamine sulfate Fondaparinux More specific to target factor Xa activity  Renal clearance NOT reversible with protamine sulfate Factor Xa inhibitor Apixaban, Edoxaban, Betrixaban Antidote: Andexanet Alpha Direct Thrombin inhibitors Argatroban Hepatic clearance Non-peptide  Parenteral  Bivalirudin Renal clearance Peptide (20 aa) Parenteral  Dabigatran (Pradaxa) Oral  Renal clearance Antidote: Idarucizumab  Antiplatelets COX inhibitor Aspirin Irreversible platelet inhibitor Acetylates cyclooxygenase 1 & 2 Commonly used in cardiac/stent patients P2Y12 Antagonists (ADP receptor) Ticlopidine, clopidogrel, prasugrel, ticagrelor Commonly used in cardiac/stent patients GPIIB/IIIa antagonists Has indication in ACS with PCI but not widely used Can cause rapid thrombocytopenia (drug/platelet complex leads to ab formation) Abciximab Half life 14 days Eptifibatide  Cyclic heptapeptide Very short half life <1 hour Tirofiban Protease activated receptor 1 (PAR1) Vorapaxar Irreversible  Used to reduce thrombotic cardiovascular events in MI and PAD (secondary prevention) Cleared in feces and renally Von Willebrand Disease (VWD) Von Willebrand Factor: Found in endothelial surface Binds with GP1b on platelets Subtypes of vWD: Type 1 and Type 3: Quantitative disorders Function proportional to level of enzyme/protein present Type 1C: Associated with increased clearance/shorter half life of vWF Type 2: Functional disorder/ Function is disproportion to level of enzyme/protein present Type 2A: Reduction/absence of high-molecular-weight vWF multimers → decreased platelet-dependent vWF activity Heyde syndrome: Aortic stenosis + intestinal angiodysplasia + Type 2A vWD Type 2B: Gain-of-function mutation in vWF → increases its affinity for platelets → enhanced platelet binding and clearance → thrombocytopenia The only one wit h elevated Ristocetin-Induced Platelet Aggregation (RIPA) Autosomal dominant Never give ddAVP Type 2M: Decreased vWF interactions with platelets/collagen but with a preserved multimer pattern Type 2N: Reduced binding of vWF to factor VIII → low factor VIII levels Like hemophilia (may have a female patient to delineate from hemophilia) The presence of a female patient with a hemophilia-like bleeding phenotype should prompt consideration of vWD rather than hemophilia. FVIII:C vWF:Ag vWF: RCoF RIPA Type 1 (most common) ↓ ↓ ↓ ↓ or normal Type 2A ↓ ↓ ↓↓ ↓↓ Type 2B ↓ ↓ ↓↓ ↑ Type 2N (recessive) ↓↓ normal normal normal Type 3 (rare, recessive) ↓↓↓ ↓↓↓ ↓↓↓ ↓↓↓ Treatment: Depends on type of vWD Desmopressin (ddAVP) Transiently increases vWF and FVIII in plasma Used in: Type 1 and Type 2A (minor procedures) Administered nasally or IV Ideally can perform a challenge to document response (pre, 1hr, 4 hr levels) Hyponatremia can occur (from SIADH) Development of tachyphylaxis after a few doses Intermediate-purity factor concentrates Humate-P Alphanate Wilate Recombinant vWF Does NOT contain factor 8, therefore not for acute bleed in Type 3 Indications: Moderate/severe Type 1 for major procedures Type 2A for major procedures Type 2B for most procedures Antifibrinolytics Tranexamic acid Aminocaproic acid Pregnancy: Normally one can expect physiologic increase in vWF during pregnancy that exceeds 50IU/dL Should be above 50IU/dL for epidural to be placed or surgery/delivery (and for 3-5 days after delivery) vWF levels also decline over 2-3 weeks postpartum Acquired von Willebrand disease: Associated with certain lymphoproliferative disorders, plasma cell dyscrasias, neoplasms, severe thrombosis, hypothyroidism, ECMO/LVAD Treatment: Desmopressin, factor VIII/vWF concentrates, IVIG, plasmapheresis, plateletpheresis, corticosteroids, rituximab, other types of immunosuppression Hemophilia X-linked recessive Deficiency of factor VIII (type A) and factor IX (type B) Levels correlate with bleeding severity Severe: <1% Spontaneous bleeding, risk of intracranial bleeding, risk of developing inhibitors Moderate: 1-5% Fewer spontaneous bleeds, but can become severe once bleed starts Mild: 5-50% Bleeding with certain procedures (surgery/trauma), catastrophic bleeding is rare Lead to larger bleeds related to surgery/trauma (joint bleeds, muscle bleeds), intracranial Can lead to compartment syndrome Long term sequelae: Hemophilic arthropathy Decreased joint space Bony erosion Treatment: Factor therapy Raise levels to normal for severe bleeds or treat minor bleeds Goal: above 50% Factor VIII 1 unit/kg body weight raises factor level 2% Example: 50 U/kg raises level to 100%, followed by maintenance 25 U/kg in 12 hours Factor IX 1 unit/kg body weight raises factor level 1% Ex: 100 U/Kg raises level to 100%, followed by maintenance 50 U/Kg Use Aminocaproic acid (Amicar) or TXA for mucosal/oral cavity bleeding Consider DDAVP for mild hemophilia A Emicizumab: (factor 8 mimetic) approved for prophylaxis of bleeding in congenital hemophilia A Associated with thrombotic complications when used with FEIBA Gene therapy is also an option for hemophilia A and B Bypassing agents are useful in factor deficiencies, particularly with inhibitors Be suspicious of an inhibitor if bleeding does not resolve with factor replacement Hypercoagulability Who needs a work up? DVT/PE with intermediate risk of recurrence Unprovoked VTE in unusual locations Cerebral vein/sinus, retinal vein/artery, splanchnic veins, renal veins, gonadal vein, skin Arterial thrombus (if unexplained) Timing of testing should be at least 1 month after being off of anticoagulation Do not test during acute clot as it can skew test results/difficult to interpret Thrombophilias: Antiphospholipid syndrome Needs history of thrombosis and/or pregnancy morbidity Labs tested need to be down 2 times > 12 weeks apart Anti-cardiolipin (IgG/IgM) Anti-beta2-glycoprotein (IgG/IgM) Lupus anticoagulant Strongest independent factor Can be falsely positive if drawn while on anticoagulation Treatment: Warfarin Antithrombin deficiency Protein C & S deficiency Homozygous Factor V Leiden (most common) Homozygous Prothrombin gene mutation (factor II) Heterozygous for both F5L and prothrombin gene Hemolytic diseases

Hemoglobinopathy Sickle Cell Disease (discussed below) Thalassemia (discussed below) Hemoglobin C Substitution of lysine for glutamic acid in 6th position of the beta globin chain Subtypes: Hb AC (Hb C trait): No symptoms Hb CC (Hb C disease): Causes HbC crystals Symptoms: anemia, mild hemolytic anemia (prone to gallstone), splenomegaly Hb SC: less sickling and vaso-occlusive events compared to Hb SS More retinopathy, priapism and ischemic necrosis of bones Hemoglobin E Substitution of lysine for glutamic acid in 26th position of the beta globin chain Common in India, Southeast Asia, Bangladesh Heterozygous: No anemia but microcytosis Homozygous: microcytic anemia with large target cells Hemoglobin Lepore Hemoglobin M Genetic cause of methemoglobinemia Can cause cyanosis, otherwise asymptomatic Can be due to mutations in alpha, beta or gamma globin genes, but normal methemoglobin reductase level Heme iron is locked in ferric state Methemoglobin level is 15-30% Life expectancy is unaffected Sickle Cell Disease (SCD) Due to 6th amino acid in beta chain changed from glutamate (charged) to valine (hydrophobic) Less soluble in hypoxic conditions → sickling in affected individuals Less common in individuals with Sickle Cell Trait (heterozygous) Electrophoresis for trait: ~40% Hb S, ~60% Hb A2 Associated with medullary RCC Protects against malaria, hence its geographic distribution Other variants: Hgb SC disease Sickle trait with HbC disease Slightly worse phenotype than sickle cell trait alone, less anemic than Hgb S More retinopathy, priapism and ischemic necrosis of bones 50% HgbS, 50% HbC (runs like Hgb A2) Sickle Beta Thalassemia Heterozygous state involving one sickle cell gene (HbS) and one beta thalassemia gene Types: Sickle beta zero thalassemia (S-β⁰) : No beta globin production from the thalassemia allele, so no HbA is produced. The clinical presentation is indistinguishable from sickle cell anemia (HbSS). Sickle beta plus thalassemia (S-β⁺) : Some beta globin is produced, resulting in variable amounts of HbA. Clinical severity is generally milder than S-β⁰ or HbSS. Electrophoresis: ~60% Hb S, 4-30% Hb A2, <20% Hb A Clinical features include: Chronic Pain Pain Crises Infection Encapsulated organisms (due to splenic dysfunction) S. pneumoniae , H. influenzae  type b and N. meningitidis Salmonella osteomyelitis Most probably due to Salmonella Long term sequelae affecting multiple organ systems Long term hemolysis → free Hb binds NO → Pulmonary hypertension, leg ulceration, priapism, stroke No role for sildenafil in patients → more pain crises Vaso-occlusion → pain crises, acute chest syndrome, osteonecrosis, retinal vessel occlusion/neovascularization Thrombosis risk (more PE than DVT) Aplastic crisis Associated with parvovirus infection Binds P antigen Hyperhemolysis Almost immediately after transfusion Avoid further transfusions if possible Splenic sequestration crisis Extensive trapping of RBCs in spleen → rapid anemia, hypovolemic shock The size of spleen regress after patient receives blood transfusion Helps to differentiate it from hypersplenism which size of spleen does not regress after blood transfusion. Splenectomy should be considered due to risk of recurrent sequestration Acute chest syndrome Fever, cough, chest pain, hypoxia, infiltrate on XR chest Caused by acute stressors: infection, hypoxia, PEs, etc.  Treated with O2, antibiotics, transfusion (simple vs. exchange), and incentive spirometry Stroke Treat with exchange transfusion in acute setting Recommended to perform chronic transfusion therapy for prevention (goal Hb S <30%) Renal papillary necrosis Can cause hematuria and flank pain Vaccination: S. pneumonia, N. meningitides, Haemophilus influenzae Seasonal flu Hepatitis B Treatments: Hydroxyurea Decreased vaso-occlusive pain, ACS, transfusion needs, priapism Improved survival and quality of life For all patients regardless of age and history of vaso-occlusive episodes. Can start during infancy Exceptions: pregnancy and time of conception (both males and females) Increases fetal hemoglobin (goal Hb F >20%) and therefore less Hgb S Complications: bone marrow suppression (most common), GI upset L-glutamine (Endari) Oral Amino acid leads to decreased oxidative stress → less acute pain episodes Indication: If patient has ≥ 2 pain episodes per year despite hydroxyurea Crizanlizumab Monoclonal antibody against p-selectin Reduces frequencies of vaso-occlusive crises IV given at 0, 2, and 4 weeks Indication: If patient has ≥ 2 pain episodes per year despite hydroxyurea (or if they cannot receive hydroxyurea) Voxelotor Oral  Binds Hb S and stabilizes the oxygenated form → reducing sickling Increases hemoglobin values, reduces hemolysis Can’t be stopped suddenly Transfusions: Simple:  Any acute need for increased O2 carrying capacity Symptomatic anemia Hb goal around 10 Beta4 tetramers present Forms Heinz bodies, which cause “bite cells” Acute chest syndrome Prior to/during major surgery (if needed) Exchange:  Goal is to reduce Hb S% quickly: Goal Hb S is 30% (STOP trial) Used for stroke treatment/prevention, life/organ threatening vaso-occlusive event (severe acute chest syndrome), acute severe cholestasis/RUQ syndrome NOT for pain crisis Possibly helps prevent iron accumulation Avoid transfusing blood with C, E, and Kell antigens Transfusion is NOT indicated for: Anemia, uncomplicated pain, infections, minor surgery, avascular necrosis, uncomplicated pregnancies Excess transfusion can lead to alloimmunization and iron overload Gene therapy Casgevy: Exagamglogene autotemcel Lyfgenia: Ovotibeglogene autotemcel ACE inhibitor/ARB Reduce proteinuria Pain management Morphine, hydromorphone and fentanyl Avoid meperidine (increases risk of seizure) and ketorolac  Thalassemia Normal Hgb Electrophoresis: Hb A (95-98%), Hb A2 (2-3%), HbF (~1%) Hgb A: alpha2, beta2 Hgb A2: alpha2, delta2 Hgb F: alpha2, gamma2 Also provides protection against malaria, hence its geographic distribution Typically we can find full deletions of alpha genes and point mutations in beta genes Alpha thalassemia Hb F and Hb A2 are usually normal Normally 4 alleles (2 on each chromosome) One alpha deletion  (silent carrier): Phenotypically silent, normal electrophoresis Two alpha deletions  (Alpha thal trait): Microcytic, mild anemia Three alpha deletions ( Hemoglobin H): More anemic, variable severity (some transfusion dependent) Beta4 tetramers present Forms Heinz bodies, which cause “bite cells” Four alpha deletions  (Hydrops fetalis): Causes gamma tetramers (in utero): Hemoglobin Barts Typically causes intrauterine death Can be treated by in utero exchange transfusions followed by HSCT Constant spring mutation:  “Non-deletional” type of alpha thal mutation (caused by a point mutation) leads to more severe phenotype in Hgb H MCV is near normal  Concurrent alpha thalassemia and sickle cell has milder SS phenotype due to unbalanced globin chain synthesis leading to deficiency in Hb per cell (less sickling) Also associated with ATRX (alpha thalassemia/mental retardation syndrome) Regulates expression of HBA1 and HBA2 (alpha genes) Craniofacial features, genital anomalies, severe developmental delays, alpha thalassemia Beta thalassemia Multiple types of mutations:  B0 = absent beta globin synthesis for that allele B+ = decreased, but still present beta globin synthesis Beta thalassemia major (Cooley’s Anemia): B0, B0 Much more severe phenotype Beta thalassemia intermedia: contains at least 1 B+ allele Likely not transfusion dependent B+/B+ might require occasional transfusions Associated with osteoporosis  Infants are typically okay at birth due to Hb F but starts to become evident around age 1 Electrophoresis will show alpha tetramers Symptoms: Microcytic anemia Splenomegaly Bony deformities (bossing) Iron overload (due to transfusions, increased absorption from gut) Extramedullary hematopoiesis due to ineffective erythropoiesis/hemolysis Treatments: Luspatercept (BELIEVE) Decreases blood transfusion requirement Gene therapy:  Betibeglogene autotemcel Exagamglogene autotemcel (CRISPR/Cas9 gene-edited cell therapy) Erythrocytosis/Polycythemia Generally defined as: Males: Hb >16.5 and HCT >49 Females: Hb >16 and HCT >48 Work up: First check EPO level If EPO high/inappropriately normal → secondary polycythemia Due to physiological stressor (smoking, obesity, sleep apnea, living in high elevations) or EPO secreting tumor If patient with history of renal transplant, consider post transplant erythrocytosis (PTE) Treat with ACE/ARB If unable to tolerate higher doses, then consider phlebotomy If EPO low → primary polycythemia Consider polycythemia vera (PV) or another myeloproliferative neoplasm (MPN) PV is associated with headache, dizziness, pruritus (after shower), early satiety Related mutations: JAK2 V617F mutation : If positive, consider BMBx MPL, CALR: Also associated with essential thrombocythemia/myelofibrosis BCR/ABL: Associated with Chronic Myeloid Leukemia VHL gene (Chuvash): mutations in EPO receptor Methemoglobinemia Congenital/Acquired Due to deficiency of cytochrome b5 reductase Type 1: only affects RBCs Type 2: affects all cells Associated with development abnormalities, most infants die in the first year of life Methemoglobin level: If >20%: patient will develop clinical symptoms (respiratory depression, confusion) If >40%: life threatening Prevention: Avoid agents that may induce methemoglobinemia (nitrates, dapsone, benzocaine) Treatment:  Methylene blue 1% with dose 1-2 mg/kg IV in 5 min Allows iron in Hb to become ferrous (2+) Ascorbic acid Blood transfusion or exchange transfusion if symptoms are severe

Early detection: Individualized informed decision-making for prostate cancer screening (DRE and PSA) Discuss risks and benefits: Age 45–75 at average risk Age 40–75 at high risk (Black/African American, family history, germline mutations) Definitive diagnosis: Requires prostate biopsy, Gleason grading, and TNM staging. Clinical Pearls: Think of Prostate Cancer treatment on a "spectrum": Localized Disease → Biochemical recurrence (BCR) → Non-metastatic castrate resistant prostate cancer (NMCRPC) or Metastatic Castrate Sensitive Prostate Cancer (MCSPC) → Metastatic Castrate Resistant Prostate Cancer (MCRPC) Post- radical prostatectomy (RP) PSA should be undetectable. Post-radiation PSA should not, monitor for the nadir to determine BCR.  BCR is defined as: After RP: PSA ≥ 0.2 after RP or 2 rising PSA’s from nadir after RP (should be 0 after RP) After RT: : PSA increase by ≥2 above nadir PSA after radiation (Phoenix Criteria) Consider PSA doubling time of ~ 6-10 months. Androgen Deprivation therapy (ADT):  LHRH agonist (goserelin, leuprolide, triptorelin) Causes initial testosterone surge (typically start bicalutamide before Lupron to prevent tumor flare) GnRH antagonists (degarelix, relugolix) Consider relugolix if patient has cardiovascular comorbidities Side effects: “manopause” with night sweats, hot flashes, weight gain, sexual dysfunction, mood changes, cardiovascular side effects, DVT, hypertension, osteoporosis. Monitor DEXA scans q2 years Neoadjucant Hormonal Therapy (NHT): Abiraterone + Prednisone If taken without prednisone, can cause HTN and hypokalemia due to hyperaldosteronism Side effects: hepatotoxicity, HTN, hypokalemia and fluid retention (from mineralocorticoid excess), hyperglycemia (due to prednisone), cardiovascular adverse events, adrenal insufficiency Need to monitor LFT Enzalutamide Can cause falls and lower seizure threshold Darolutamide Apalutamide Localized prostate cancer: Risk stratification based on NCCN guideline: Very low risk T1c + Grade Group 1 + PSA <10 + Fewer than 3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core + PSA density <0.15 Low risk T1–T2a + Grade Group 1 + PSA <10 Intermediate risk No high- or very-high-risk features + one or more intermediate risk factors: T2b–T2c Grade Group 2 or 3 PSA 10–20 Favorable intermediate: intermediate risk factors and Grade Group 1-2 and <50% biopsy cores positive Unfavorable intermediate: 2-3 intermediate risk factors and/or Grade Group 3 and/or ≥ 50% biopsy cores positive High risk T3a OR Grade Group 4 or Grade Group 5 OR PSA > 20 Very high risk T3b–T4 OR Primary Gleason pattern 5 OR 4 cores with Grade Group 4-5 Treatment: If undergoing radical prostatectomy: Check if any adverse features are present on final pathology. Positive margins Seminal vesicle involvement Extracapsular extension Detectable PSA If any adverse feature is seen can either monitor or EBRT +/- ADT Expect PSA to become undetectable after radial prostatectomy. Very low risk localized prostate cancer: Active surveillance (in patients with >10 years anticipated survival) Observation (in patients with <10 years anticipated survival) Low risk localized prostate cancer: Active surveillance RT Radical prostatectomy Observation (in patients with <10 years anticipated survival) Intermediate risk localized prostate cancer: Favorable: Active surveillance RT Radical prostatectomy + PLND (in patients with >10 years survival) Unfavorable: Baseline bone and soft tissue imaging Radical prostatectomy + PLND (in patients with >10 years survival) RT + 4-6 months ADT (5-10 years survival) Observation (5-10 years survival) High Risk/Very High Risk localized prostate cancer: Baseline bone and soft tissue imaging needed >5 years survival or symptomatic: RT + ADT x2 years + Abiraterone/Prednisone (if very-high risk) x2 years Radical prostatectomy + PLND <5 years survival and asymptomatic: Observation ADT EBRT Node positive, M0: >5 years survival or symptomatic: EBRT + ADT + Abiraterone (preferred) < 5 years survival and asymptomatic: Observation or ADT Biochemical Recurrence: Obtain imaging to rule out local recurrence or distant metastasis: If negative: Salvage RT + ADT x2 years If positive for pelvic recurrence: RT + ADT + Abiraterone/Prednisone x2 years If distant metastasis: treat as M1 disease Non-metastatic castrate resistant prostate cancer (nmCRPC): Definition of castrate resistance: elevated PSA despite testosterone <50 ADT + Neoadjuvant Hormonal Therapy (Apalutamide, Enzalutamide, Darolutamide) Metastatic prostate cancer: Treatment: Metastatic castrate sensitive prostate cancer (mCSPC): mCSPC low volume: ADT + NHT (Abiraterone, Enzalutamide, Apalutamide) Consider addition of SABR ( Stereotactic Ablative Body Radiotherapy ) mCSPC high volume: presence of visceral mets or 4+ bony mets with at least 1 beyond vertebra or pelvis (CHAARTED) Docetaxel + ADT + Abiraterone (PEACE-1) Docetaxel + ADT + Darolutamide (ARASENS) If poor PS (not able to tolerate triplet therapy) can use ADT + NHT Metastatic castrate resistance prostate cancer (mCRPC): Cabazitaxel if progressed on Docetaxel (TROPIC) Olaparib (if BRCA positive) Rucaparib (if BRCA positive) PARP inhibitor + NHT Olaparib + Abiraterone Talazoparib + Enzalutamide Pembrolizumab (If MSI-high/MMRd) Radium-223 (Xofigo, for bone only disease) Lutetium-PSMA  (if fails Docetaxel)  Radioligand delivers beta-particle radiation to PSMA-expressing cells (VISION) Approved for patients with symptomatic bone metastases but no signs of visceral disease Causes bone marrow toxicity Sipuleucel-T recommended if: Asymptomatic/minimally symptomatic No liver metastases Life expectancy > 6 months ECOG 0-1 Clinical Pearls If patient has rapid progression of disease discordant from PSA, consider neuroendocrine differentiation Treat with with cisplatin/etoposide Bisphosphonate decreases skeletal related events in patients with castration-resistant prostate cancer and bone mets No clear benefit to using bisphosphonate in patients with castration sensitive disease as it has not shown to reduce skeletal related events Germline testing may be considered in patients with: Intermediate risk prostate cancer with intraductal/cribriform histology History of prostate cancer + history of pancreatic, colon, gastric, melanoma, urothelial, GBM, bile duct, small intestinal cancer High risk/very high risk/node positive/metastatic prostate cancer

Monoclonal Gammopathies IgG >> IgM > IgA SLiM-CRAB: S: ≥ 60% BM Plasmacytosis Li: K/L ratio ≥ 100 or ≤0.01 M: MRI >1 focal lesion (>5 mm size) C: Calcium >11 or >1 ULN R: Renal Cr >2 or CrCl <40  A: Anemia Hb <10 or 2< LLN B: ≥ 1 lytic lesions MGUS:  M protein <3                                           Plasma cell in BM <10%          No SLiM-CRAB SMM:    M protein ≥ 3 or ≥ 500 mg/24hr urine     Plasma cell in BM 10-60%       No SLiM-CRAB MM:      Plasma cell proliferative disorder + ≥ 1 of SLiM-CRAB Monoclonal Gammopathy of Undetermined Significance ( MGUS) Mayo risk stratification (progression to MM) based on: M protein size Ig subtype K/L ratio Low risk:                       0 factors (M protein ≤1.5,  IgG isotype, K/L ratio normal) Risk of progression in 20 years: %5 Repeat CBC, Cr and SPEP q6 months, no additional testing is required Low intermediate risk:  1 factor Risk of progression in 20 years: %21 High intermediate risk:  2 factors Risk of progression in 20 years: %37 High risk:                      3 factors Risk of progression in 20 years: %58 Smoldering Multiple Myeloma Treatment: Standard of care: observation PETHEMA-GEM study: OS benefit of treatment for high risk Smoldering MM with lenalidomide/Dexamethasone High risk SMM: if 2 out of 3 criteria: >20% BM plasmacytosis >20 K/L ratio >2 g/dl M protein Multiple Myeloma (MM) High risk MM: High risk cytogenetics: t(4;14), t(14;16), t(14;20), del 17p/monosomy17/TP53 mutation, 1q21 gain, MYC translocation, karyotype del 13 R-ISS III Extramedullary disease Standard risk MM: Favorable cytogenetics: t(6;14), t(11;14), Hyperdiploid karyotype International Staging System: Stage I:   B2 microglobulin <3.5 or Alb >3.5 Stage II:  Not stage I or III Stage III: B2 microglobulin ≥ 5.5 Revised- International Staging System: Stage I:   ISS stage I + no high-risk chromosomal abnormality AND  normal LDH Stage II:  Not stage I or III Stage III: ISS stage III + high-risk chromosomal abnormality OR  high LDH Revised 2- International Staging System: Low risk: 0 point Not stage II or III AND  normal LDH AND  no high risk chromosomal abnormality Low intermediate: 0.5-1 points Stage II OR  high LDH OR  high risk chromosomal abnormality High intermediate risk: 1.5-2.5 points  Any combination of high risk features which equals a score of 1.5-2.5 High risk: 3-5 points Any combination of high risk features which equals a score of 3-5 Medications: Lenalidomide:  If CrCl >60: No adjustment If CrCl 30-60: 10-15 mg daily If CrCl <30: 15 mg every other day If patient is on HD: 5 mg daily Multiple myeloma and (Lenalidomide + Dexa): increases risk of thrombotic events → patients may need Aspirin or AC based on IMPEDE or SAVED scoring system. (You can search and memorize them or simply ignore them as I did) Bortezomib: Does not need dose adjustment in renal failure Causes peripheral neuropathy              - SQ causes less neuropathy compared to IV Particularly effective in patients with high risk chromosomal abnormalities If T.bili >1.5 xULN: dose  0.7 mg/m2 per injection Needs prophylaxis for shingles: Valacyclovir 500 mg po BID Daratumumab: CD 38 antibody Pomalidomide: For patients who: received at least one prior therapies including lenalidomide and Bortezomib disease progressed within 60 days after the last treatment Should not be given to patient if T.bili >2 and AST/ALT >3 xULN  Reduce the dose 25% in patients on HD Ixazomib: For patients who received at least one prior therapies 46% improvement in PFS in patients with high risk cytogenetics Elotuzumab: Targets SLAMF7 (on myeloma and NK cells) Talquetamab: Targets CD3 and GPRC5D Zoledronic acid: Side effects: myalgia, hypocalcemia, jaw osteonecrosis and renal failure Dose if: - CrCl >60: 4.0 mg daily - CrCl 50-60: 3.5 mg daily - CrCl 40-50: 3.3 mg daily - CrCl 30-40: 3.0 mg daily - CrCl <30: Zoledronic acid is contraindicated Denosumab: Can be offered to patients with kidney failure Treatment regimens: Non-transplant candidates: Lenalidomide + Dexa Lenalidomide + Dexa + Bortezomib (RVD)        - SWOG S0777 study: Adding Bortezomib to RD improves OS and PFS Lenalidomide + Dexa + Daratumumab        - MAIA study: Adding Daratumumab to RD improves PFS  Bortezomib + Melphalan + Prednisone (VMP) Transplant eligible patients: RVD RVD + Daratumumab (GRIFFIN study) Carfilzomib + Lenalidomide + Dexa Avoid myelotoxic agents like Melphalan Patients with myeloma kidney/renal failure: Cyclophosphamide + Bortezomib + Dexa (CyBorD)  These patients should not be treated with Lenalidomide initially. When the kidney function improves, treatment can be transitioned from CyBorD to RVD ± Daratumumab . Refractory multiple myeloma (failed at least two prior treatments): Pomalidomide + Dexa Ixazomib + Lenalidomide + Dexa (TOURMALINE-MM1) Elotuzumab + Lenalidomide + Dexa  Elotuzumab + Pomalidomide + Dexa Patients with significant neuropathy at baseline: Daratumumab Melphalan + Dexa (transplant ineligible) Systemic Amyloidosis: CyBorD + Daratumumab and hyaluronidase  CyBorD Daratumumab Bortezomib + Melphalan + Dexa (transplant ineligible) Waldenstrom Macroglobulinemia (WM) Malignancy of mature plasmacytoid lymphocytes that secrete IgM Categorized as a lymphoplasmacytic lymphoma No treatment if patient is asymptomatic Indications for treatment:  Disease related Hb <10 and plt <100, hepatosplenomegaly, bulky LAP, Hyperviscosity syndrome, neuropathy, amyloidosis, B symptoms, cold agglutinin hemolytic anemia Treatment: Preferred regimens: Bendamustine + Rituximab Dexa + Rituximab + Bortezomib Dexa + Rituximab + Cyclophosphamide Ibrutinib ± Rituximab  Zanubrutinib Patients with hyperviscosity syndrome and patients undergoing treatment with Rituximab-containing regimen, plasmapheresis should be considered to lower IgM level to <4000 mg/dl (Rituximab can cause flare in the level of IgM) Plasmacytoma Solitary or multiple osseous or soft tissue plasma cell tumors They may have M spikes Treatment: Radiation  They may progress to multiple myeloma Plasma cell Leukemia Highly aggressive, OS <12 months Immunophenotype is different from myeloma ≥ 5% plasma cells in peripheral blood POEMS Syndrome Paraneoplastic syndrome of plasma cell disorder P: demyelinating Polyneuropathy (Major criteria) O: Organomegaly E: Endocrinopathy M: Monoclonal gammopathy (Major criteria) S: Skin changes

Qualitative: Defects in membrane glycoproteins Bernard-Soulier Syndrome (GPIb/IX/V) Glanzmann Thrombasthenia (GPIIB/IIIa) Collagen Defects (GPVI and GPIa/IIa) Defect in platelet granules Storage Pool Deficiency Gray Platelet Syndrome Quebec Platelet Disorder Hermanksy Pudlak syndrome Defects in platelet secretion and signaling Defects in platelet coagulant activity Defects of transcription factors RUNX1 Defects of cytoskeletal/structural proteins Wiskott-Aldrich Syndrome B1-Tubulin Deficiency Kindlin Defect Acquired (iatrogenic) Medications Uremia Cardiopulmonary Bypass Quantitative: Thrombocytosis Essential Thrombocythemia (ET) Thrombocytopenia Decreased bone marrow production Sequestration Hemodilution Increased consumption Increased clearance Alloimmune Pseudothrombocytopenia Platelet Function Tests: Arachidonic acid: Tests the thromboxane pathway Epinephrine: Tests receptor binding leading to ADP release Ristocetin: Tests for the functional vWF receptor/GP1b/IX complex Thrombin: Tests full platelet aggregation independent of both the ADP and prostaglandin pathway Aggregation studies: Primary wave/aggregation: Initial and reversible clumping of platelets stimulated by exogenous agonists like ADP/epinephrine/collagen Secondary wave/aggregation: subsequent often irreversible aggregation caused by the release of internal platelet agonists, such as ADP/ epinephrine Defects in membrane glycoproteins: Bernard-Soulier Syndrome (GPIb/IX/V: receptor for vWF): Autosomal recessive Platelets are unable to bind to vWF on endothelial surface → no platelet adhesion to the vessel walls Platelets increased in size Prolonged bleeding time No aggregation in response to ristocetin  Normal response (with primary and secondary wave) to ADP/epinephrine/collagen Treatment for acute bleeding: platelet transfusion Glanzmann Thrombasthenia (GPIIB/IIIa): Autosomal recessive Heterozygotes without bleeding Platelets are unable to bind with fibrinogen and aggregate with other platelets Impaired clot retraction Normal platelet appearance Normal aggregation with ristocetin No primary or secondary wave with ADP/epinephrine/collagen Treatment: platelet transfusion If refractory to platelet transfusion: use recombinant factor VIIa (NovoSeven) Collagen Defects (GPVI and GPIa/IIa) Defects in platelet granules Storage Pool Deficiency Deficiency of dense or alpha granules Normal aggregation  with ristocetin No secondary wave  with ADP/epinephrine/collagen Robust aggregation to primary ADP but much less with secondary ADP Gray Platelet Syndrome Deficiency of alpha granules VWF, factor V, multimerin, fibrinogen, fibronectin, thrombospondin Gray appearance of platelets on PBS No significant abnormality in aggregation studies Mutations in NBEAL2 (responsible for vesicle trafficking) Predisposed to myelofibrosis and elevated Vit B12 Quebec Platelet Disorder Autosomal dominant Normal to reduced platelet counts Decreased alpha granule proteins due to abnormal proteolysis due to increased urokinase plasminogen activator (PLAU) Platelet transfusion does not provide benefit. Hermanksy Pudlak syndrome Autosomal recessive Defect in dense granules Presents with mild bleeding diathesis (avoid anticoagulants), oculocutaneous albinism, and pulmonary fibrosis Defects in platelet secretion and signaling Defects in receptors and signaling Abnormalities in arachidonic acid pathways and TXA synthesis Normal aggregation with ristocetin Reduced secondary wave with ADP/epinephrine Defects in platelet coagulant activity Defects of transcription factors RUNX1: familial platelet defect  Autosomal dominant Impaired megakaryopoiesis Predisposed to AML Defects of cytoskeletal/structural proteins Wiskott-Aldrich Syndrome X-linked Deficiency of dense granules Immunodeficiency, eczema, and thrombocytopenia B1-Tubulin Deficiency Kindlin Defects Acquired (iatrogenic) Medications Uremia Leads to platelet dysfunction through increased nitric oxide production Treated with hemodialysis and DDAVP Cardiopulmonary Bypass Platelets being exposed to different surfaces/substances can activate them and lose their function Should recover in a few days after surgery Thrombocytosis Reactive Essential Thrombocythemia (ET): Associated with increased risk of thrombosis Very high levels of platelets can be associated with acquired vWD → bleeding Small percentage will progress to post-ET myelofibrosis or leukemic transformation Risk criteria: Very low risk:   age <60 + no JAK2 mutation + no history of thrombosis Low risk : age <60 + JAK2 mutation + no history of thrombosis Treatment: Aspirin Intermediate risk:   age >60 + no JAK2 mutation + no history of thrombosis Treatment: Aspirin +/- Hydroxyurea High risk: (age >60 + JAK2 mutation) or (History of thrombosis) Treatment: Aspirin + Hydroxyurea Consider addition of anticoagulation if history of DVT/PE Thrombocytopenia Platelet type bleeding involves skin or mucous membranes Petechiae, ecchymoses, epistaxis, menorrhagia, GI hemorrhage Usually when platelet count less than 20,000 Decreased bone marrow production Congenital disorders: MYH9 thrombocytopenias (May-Hegglin anomaly) Large platelets, thrombocytopenia, nephropathy, deafness Mediterranean macrothrombocytopenia RUNX1 mutation Paris-Trousseau thrombocytopenia DiGeorge Syndrome Congenital amegakaryocytic thrombocytopenia MPL mutation which encodes TPO receptor Wiskott-Aldrich Syndrome GATA-1 mutation Bernard-Soulier Syndrome Acquired disorders: Leukemias, lymphoma, myeloma Aplastic anemia Fanconi anemia Medications Hemodilution Pregnancy: Blood volume increased by up to 30% Sequestration Hypersplenism Kasabach-Merritt syndrome Linked to giant cavernous hemangioma- when hemangioma grows rapidly, trapping platelets causes thrombocytopenia (platelet sequestration) Also associated with DIC (plt consumption) Increased consumption DIC Treat underlying cause: Pancreatitis, trauma/shock, infection, hepatic necrosis Sepsis Cardiovascular disease (ECMO, artificial heart valves) Vasculitis SLE Wegener's disease (Granulomatosis with polyangiitis) Thrombotic microangiopathy Thrombotic thrombocytopenic purpura (TTP) Hemolytic Uremic Syndrome (HUS) Typically patient has diarrhea (from E.coli strains produce Shiga toxin) and renal failure Shiga toxin PCR in stool helps diagnosis Triad of MAHA, thrombocytopenia, AKI Treat infection, plasmapheresis, supportive care 25% mortality without PLEX 50% of patients with permanent renal failure on HD aHUS Complement mediated, leads to renal failure Diagnosis of exclusion Rule out HUS and TTP Treat with anti-C5 therapy (eculizumab, ravulizumab) Pregnancy complications Pre-eclampsia HELLP syndrome Medications Gemcitabine, ticlopidine, clopidogrel, zosyn, sulfa drugs, vancomycin Heparin induced thrombocytopenia (HIT) Vaccine induced thrombocytopenia (VITT) Similar mechanism to HIT without heparin Treat with: DOAC (could also use bivalirudin, argatroban, fondaparinux), IVIG, Steroids, PLEX can be considered Increased clearance Immune thrombocytopenia purpura (ITP) Alloimmune Neonatal alloimmune thrombocytopenia (NAIT) Fetal platelet antigen leads to material antibodies that transfer the placenta and induce thrombocytopenia in fetus Post-transfusion purpura Parous females form high titer anti-HPA-1a (anti Gp2b3a) alloantibodies that destroy autologous platelets Passive alloimmune thrombocytopenia Transfused platelets contain Ab against recipient platelets Transplantation associated alloimmune thrombocytopenia Patient is refractory to platelet transfusion due to residual host lymphocytes Platelet transfusion refractoriness Alloimmunization due to heavy transfusion history Pseudothrombocytopenia EDTA in the collecting blood tubes can cause platelet clumping Repeat the lab but collect the blood sample in a heparin or citrated tube Conditions with giant platelets: Bernard-Soulier Syndrome (GPIb/IX/V) Gray platelet syndrome ITP May-Hegglin anomaly Montreal platelet syndrome (Type IIb vWD) Heparin Induced Thrombocytopenia (HIT) Heparin binds to platelets and releases PF4 eventually causes heparin-PF4 complexes. Heparin-dependent Ab attaches to complex which activates platelets. Usually cause 50% drop in platelet count between 3-30 days after heparin exposure Median plt count is 60K Not associated with plt count <10K Spontaneous HIT: No prior heparin exposure Happens after orthopedic surgeries (usually knee replacement surgery) Also associated with monoclonal gammopathies Should know 4T score: Degree of thrombocytopenia Timing of thrombocytopenia Presence of thromboses Any other cause of thrombocytopenia? Lab tests: Serotonin release assay, Heparin-PF4 antibody Management: Stop heparin and start anticoagulant with direct thrombin inhibitor Bivalirudin is preferred in abnormal hepatic function Argatroban is preferred in abnormal renal function Transition to warfarin, fondaparinux, or DOAC at discharge Plt count should increase to >150K before transitioning to warfarin (bridging). Also, there should be at least 5 days of overlap between direct thrombin inhibitor and warfarin before the former medication is discontinued. Target INR is 2-3. Fondaparinux is contraindicated if CrCl<30 Duration of AC dependent on if clot present If present: 3-6 months If NOT present: unknown (4 weeks usually offered) Platelet transfusion is associated with higher odds of arterial thrombosis and mortality in patients with HIT and TTP. Immune Thrombocytopenia Purpura (ITP) Ab bind to platelet surface (GP2b3a or GP1ba) → splenic/hepatic clearance Peak incidence in childhood (2-10 years) and adult Causes sudden onset bruising and petechiae and sometimes mucosal bleeding Sometimes preceded by viral illness or immunization/vaccination, also associated with H.pylori infection Smear shows normal RBCs but no platelets Could also see giant platelets Bone marrow biopsy should show megakaryocytes Treat only if plt <20K and/or major bleeding and/or preoperative management Treatment : Acute setting: Dexamethasone vs. prednisone IVIG Secondary Treatment (long term):  Rituximab TPO agonists (Eltrombopag) Splenectomy Tertiary Treatment: Cyclophosphamide, azathioprine, prednisone, anti-D antigen therapy (WinRho), danazol. Vyvgart  Fostamitinib (spleen tyrosine kinase, Syk inhibitor) Splenectomy (if unresponsive to steroids and IVIG) Pregnancy : Treatment is the same as in non-pregnant patients. Steroids are preferred in the first trimester but IVIG is recommended if the patient is close to delivery (IVIG acts more quickly) Thrombotic Thrombocytopenic Purpura ( TTP) Mechanism: Lack of ADAMTS13 (normally cleaves vWF multimers) usually due to inhibitor → vWF multimers persist → adhesion/aggregation of platelets → Shearing/clotting Classic pentad: Microangiopathic hemolytic anemia (Jaundice, purpura) Thrombocytopenia Renal insufficiency Neurologic abnormalities Fever Treatment : Initially treated with PLEX + prednisone If refractory: PLEX (daily) + prednisone + Rituximab ± Caplacizumab Some medications can cause TTP-HUS in rare cases: Quetiapine Oxaliplatine Gemcitabine Bactrim Quinine Congenital TTP is called Upshaw-Schulman syndrome Autosomal recessive Can give regular plasma infusion or recombinant ADAMTS13 since disease is characterized by lack of ADAMTS13 protein

Work up: EUS/ERCP for biopsy and stent placement Consult GI for ERCP if bilirubin high (prior to giving chemotherapy) CT Chest/Abdomen/Pelvis CA 19-9 (baseline) CA19-9 is a good marker but should not be used to determine need for treatment alone Elevated CA 19-9 prompts further evaluation/imaging Consider screening in patients with strong family history of pancreatic cancer and genes associated with pancreatic adenocarcinoma: ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, EPCAM, PALB2, STK11, TP53 If high risk features present (listed below), consider staging laparoscopy to rule out occult metastatic disease. Markedly elevated CA19-9 Large primary tumor Large regional LNs Excessive weight loss Extreme pain Indeterminate/equivocal imaging findings Treatment: Pain control: Opioids Consider celiac plexus block Localized/Resectable Pancreatic Cancer: If tumor located at head or uncinate process: Whipple surgery which removes the pancreatic head, duodenum, distal common bile duct, and sometimes the gastric antrum or pylorus) If tumor located in tail: Distal pancreatectomy + en bloc splenectomy If entire pancreas involved: Total pancreatectomy Unresectable pancreatic cancer is defined by: locally advanced disease: Arterial involvement: Solid tumor contact >180° with the SMA or CA, or aortic involvement. Venous involvement: Complete occlusion of the SMV or portal vein without a suitable vessel for reconstruction. Distant metastasis including non-regional LNs Neoadjuvant therapy: If high risk features present Regimens: mFOLFIRINOX +/- subsequent chemoRT Gem/Abraxane +/- subsequent chemoRT If BRCA or PALB2 mutation: mFOLFIRINOX +/- subsequent chemoRT Gemcitabine/Cisplatin +/- subsequent chemoRT Adjuvant therapy: mFOLFIRINOX 5FU Gemcitabine Gemcitabine/Capecitabine Gemcitabine/Cisplatin Borderline Resectable Pancreatic Cancer: Always needs neoadjuvant chemotherapy. Typically given at least 6 months followed by serial CT scans to monitor resectability Reconsider for surgery after neoadjuvant therapy if: Vascular reconstruction is feasible No distant metastasis Patients who have response/stable disease after 4-6 months of chemotherapy may undergo a chemotherapy holiday or maintenance therapy Metastatic Pancreatic Cancer: First line: mFOLFIRINOX Gem/Abraxane NALIRIFOX: Na no L iposomal Iri notecan + 5- F U + Ox aliplatin NAPOLI-3 Trial: NALIRIFOX > Gem/Abraxane. OS 11.1 months vs 9.2 months, respectively. Plus less side effects Gemcitabine monotherapy (if poor PS) if BRCA or PALB2 mutation: (m)FOLFIRINOX Gemcitabine/Cisplatin Maintenance after induction chemo Maintenance Olaparib if germline BRCA/PALB2 mutated (POLO trial) Subsequent Lines: NALIRI ( Na no l iposomal Iri notecan) + 5-FU + leucovorin NAPOLI-1 Trial: consider if previously received gemcitabine monotherapy or gem/abraxane in first line setting Rucaparib if germline or somatic BRCA or PALB2 mutated Gemcitabine +/- erlotinib Capecitabine (if poor PS) If NTRK gene fusion positive: Entrectinib, larotrectinib, Repotrectinib If RET gene fusion positive: Selpercatinib If TMB >10, dMMR/MSI-high: Pembrolizumab If BRAF V600E mutated: Dabrafenib, trametinib If progressed more than 6 months after completion of initial therapy: Clinical trial (preferred) Rechallenge with initial systemic therapy If progressed less than 6 months after completion of initial therapy: Clinical trial (preferred) Changing to treatment different from the initial systemic therapy Use gemcitabine based regimen if 5FU used previously and vice-versa If MSI-high or dMMR: Dostarlimab If TMB >10: Ipilimumab/nivolumab If KRAS G12C mutation: Adagrasib or Sotorasib If HER2 positive: Enhertu If NRG1 gene fusion: Zenocutuzumab

Diffuse large B-cell lymphoma (DLBCL) Anti-CD19 ADC: Loncatuximab Tesirine Anti-CD19 CAR T cell: Preferred for relapsed/refractory DLBCL if relapsed <1 year. Tisag enlecleucel (tisa-cel) Axicabtagene ciloleucel (axi-cel) Lisocabtagene maraleucel (liso-cel) Brexucabtagene autoleucel (bre xu-cel) Anti-CD19 mAb: Tafasitamab Anti-CD79b ADC ( Antibody–Drug Conjugate ): Polatuzumab vedotin CD20 x CD3 Bispecific Ab: Engineered antibody that simultaneously binds to CD20 on B cells and CD3 on T cells → redirecting T cells to recognize and kill malignant B cells Epcoritimab Glofitamab Mosenetuzumab XPO1 inhibitor (nuclear exporter protein): Selinexor   Follicular Lymphoma/ Nodal Marginal Zone Lymphoma Anti-CD19 CAR T cell: Tisagenlecleucel (tisa-cel) Axicabtagene ciloleucel (axi-cel) Anti-CD20 mAb: Obinatuzumab Rituximab CD20 x CD3 Bispecific Ab: Epcoritimab Mosenetuzumab EZH2 inhibitor: Tazametostat For relapsed/refractory FL who have received at least two prior systemic therapies, regardless of EZH2 mutation status (better response in EZH2 mutated, but still derived benefit in wild type) PI3K inhibitor: Copanlisib   Hodgkin Lymphoma Anti-CD30 ADC: Brentuximab Vedotin PD1 inhibitor: Nivolumab Pembrolizumab   Multiple Myeloma (MM) Anti-CD38 mAb: Daratumumab Isatuximab BCL-2 inhibitor: Venetoclax B-cell mat uration antigen (BCMA) CAR T-cell: Idecabtagene vicleucel (ide-cel) Ciltacabtagene autoleucel (cilta-cel) BCMA x CD3 Bispecific Ab: Engineered T-cell engaging antibody that binds CD3 on T cells and BCMA on MM cells. Teclistamab Elranatamab GPRC5D x CD3 Bispecific Ab: Engineered T-cell engaging antibody that binds CD3 on T cells and GPRC5D on MM cells. Talquetamab SLAMF7 mAb: Elotuzumab   Acute Lymphoblastic Leukemia (ALL) Anti-CD19 mAb: Blinatumumab Anti-CD22 ADC: Inotuzumab ozagomicin   Acute Myeloid Leukemia (AML) Anti-CD33 ADC: Gemtuzumab ozogamicin BCL-2 inhibitor: Venetoclax FLT3 inhibitor: Midostaurin Quizartinib Hedgehog inhibitor: Glasdesgib IDH1 inhibitor: Ivosidenib Olutasidenib IDH2 inhibitor: Enasidenib Sezary Syndrome Anti-CCR4 mAb: Mogalizumab Anti-CD30 ADC: Brentuximab Vedotin Anti-CD52 mAb: Alemtuzumab HDAC inhibitor: Romidepsin IN PROGRESS...

Background: Diagnosis is based on morphological evidence of dysplasia in BMBx Additional studies: karyotyping, flow cytometry, molecular genetics Pearl: Regardless of blast percentage, if a characteristic AML cytogenetic abnormality is seen on BMBx, then should treat as AML. Can be associated with previous drug exposures Example: alkylating chemotherapy or topoisomerase inhibitors Associated with del 5, del 7, or complex chromosomal abnormalities Risk Stratification: Based on the IPSS-R or IPSS-M (newer scoring system includes gene mutations) Classified as Low, Intermediate, High Risk Favorable risk: Cytogenetics: t(8;21), t(15;17), and inv(16) Confer a favorable prognosis regardless of blast percentage Gene mutations: NPM1 (without FLT3-ITD), in-frame bZIP CEBPA Poor risk Cytogenetics: Monosomy 7, inv(3), del(3q), del(7q), complex (2-3 abnormalities) Gene mutations : ASXL1, EZH2, SRSF2, U2AF1, ZRSR2, RUNX1, TP53, IDH2, STAG2, NRAS, ETV6, GATA2, BCOR, FLT3, WT1, NPM1 Very Poor Cytogenetics: Complex (>3 abnormalities) Treatment: Low/Intermediate Risk MDS (IPSS-R 1-4) Erythropoiesis-Stimulating Agents (ESA): Consider first line treatment for symptomatic anemia if serum EPO <500 Goal: Hb 10-12 Hypomethylating Agents (HMA): Acacitidine Decitabine Oral decitabine/cedazuridine Lenalidomide: Treatment of choice for Deletion 5q Luspatercept: “Ringed Sideroblasts” or “MDS-SF3B1” There is now an expanded indication to include in first-line setting regardless of ringed sideroblast status Imetelstat Newer telomerase inhibitor Immunosuppressive Therapy (cyclosporine/ATG) For hypoplastic MDS Ivosidenib/olutasidenib IDH1 mutated Supportive Care Transfusion and Iron Chelation Therapy High Risk MDS (IPSS 5 or more): Hypomethylating Agents (HMA): Acacitidine Decitabine Oral decitabine/cedazuridine AlloSCT: Potentially curative for appropriate population Intensive chemotherapy Chronic Myelomonocytic Leukemia (CMML) Subtype of MDS, not CML! CMML-1 : <10% bone marrow blasts/equivalents CMML-2: <20% bone marrow blasts/equivalents Associated with absolute monocyte >500 PDGFR rearranged associated with eosinophilia Sensitive to imatinib MDS with increased blasts  IB1: 5-9% blasts, no auer rods IB2: 10-19% blasts, auer rods Treat as high risk MDS, consider alloSCT MDS/MPN overlap Atypical CML Associated with SETBP1, CSF3R, ETNK1 mutations Idiopathic Cytopenia of Undetermined Significance (ICUS) Persistent unexplained cytopenia(s) that remain unexplained despite an appropriate evaluation including BMBx. Without evidence of clonality (no somatic mutations or clonal cytogenetic abnormalities) and no morphologic dysplasia. ICUS is a heterogeneous entity; some cases resolve spontaneously, while others may progress to myeloid neoplasms, but the overall risk is lower than CCUS or CHIP. Typically observed Clonal Hematopoiesis of Indeterminate Potential (CHIP) Presence of clonal mutations in leukemia-associated genes, but without cytopenia or morphologic dysplasia ( does not yet meet criteria for diagnosis of a hematologic neoplasm). Common in older adults and confers a low but definite risk of progression to hematologic malignancy (1% per year) and increased risk of cardiovascular disease and all-cause mortality. Typically observed Clonal Cytopenia of Undetermined Significance (CCUS) Persistent cytopenia(s) with evidence of clonality but without morphologic dysplasia or diagnostic criteria for MDS. Higher risk of progression to MDS or AML compared to ICUS or CHIP, especially with high-risk mutations (spliceosome genes, RUNX1, JAK2) or multiple mutations. CCUS is considered a direct precursor to myeloid neoplasms. Typically observed/supportive care Condition Cytopenia Clonality Dysplasia ICUS Yes No No CHIP No Yes No CCUS Yes Yes No MDS   Yes Yes Yes

Non-Small Cell Lung Cancer (NSCLC) T1  T2: 3 cm T3: 5 cm T4: 7 cm N1: Hilar nodes N2: Ipsilateral N3: Contralateral or supraclavicular Stage I:  N0 Stage Ia: T1  (<3 cm, No NGS) Stage Ib: T2a (3-4 cm):              Alectinib if ALK mutated              Osimertinib if EGFR exon 19 deletion or L858R Stage II:  >N1 If unresectable:              Radiation If resectable: Alectinib if ALK mutated Osimertinib if EGFR exon 19 deletion or L858R Chemotherapy: Platinum/Taxol x4 Platinum/Pemetrexed x4 Immunotherapy: (No adjuvant IO if EGFR+) Pembrolizumab x1 year (regardless of PD-L1) Atezolizumab x1 year if PD-L1 1% or higher Stage III: If resectable: same as stage II If unresectable:          Definitive concurrent chemo-RT followed by consolidation Durvalumab x1 year            If EGFR+ after definitive chemo-RT: Adjuvant Osimertinib 80 mg PO once daily Neoadjuvant Therapies for Resectable NSCLC: Nivo + Chemo x3 cycles → surgery → option chemotherapy Nivo + Chemo x3 cycles → surgery → Nivo (if R0) x6 months Pembro + Chemo           → surgery → Pembro Durvalumab + Chemo     → surgery → Durvalumab Stage IV: NGS, Check for driver mutations and PD-L1  Chemo + IO: if no driver mutations/ large burden of disease and need for quick robust response Carboplatin + Pemetrexed + Pembro Carboplatin + Taxol + Pembro Pembrolizumab: if PD-L1 >50% Second Line agents: Docetaxel + Ramucirumab, Pemetrexed, Gemcitabine, Abraxane, Vinorelbine EGFR Exon 21 L858R or Exon del 19  Osimertinib monotherapy Osimertinib + Chemotherapy Amivantamab + Lazertinib EGFR Exon 20 mutation Amivantamab ALK fusion Alectinib, Brigatinib, Crizontinib, Lorlatinib RET fusion Selpercatinib ROS1 fusion  Repotrectinib, Entrectinib, Crizontinib, Lorlatinib KRAS G12C Sotorasib and Adagrasib for 2L MET Exon 14 Skipping Mutation Capmatinib, Crizotinib, Tepotinib BRAF V600E Dabrafenib/Trametinib HER2 Fam-trastuzumab deruxtecan (Enhertu) NTRK Repotrectinib Larotrectinib Entrectinib NRG1 Zenocutuzumab Small Cell Lung Cancer (SCLC) Limited stage-SCLC: T1-2 only: Surgery →  adjuvant chemo (Cisplatin and etoposide) > T2:         ChemoRT Consider:  ChemoRT → consolidation Durvalumab  Consider PCI in LS-SCLC Extended stage-SCLC: No radiation or surgery MRI brain: If brain mets: WBRT + steroids Chemo (carboplatin/cisplatin + etoposide x4 cycles) + IO (Atezolizumab or Durvalumab) Relapsed SCLC If relapse >6 months: re-challenge with Carboplatin + etoposide If relapse < 6 months: Lurbinectedin and Topotecan Talratamab (bispecific Ab) May present with SVC Syndrome IR consult to get tissue and Rad-Onc for chemoRT Mesothelioma Types: Epithelioid Mesothelioma (better prognosis) Non-Epithelioid Mesothelioma (Sarcomatoid or Biphasic) For 1L:  Ipilimumab + Nivo  (prefered for sarcomatoid) Cisplatin + Pemetrexed Cisplatin + Pemetrexed + bevacizumab For 2L:  If immunotherapy used in first line: use chemo If chemo used in first line: use ipi/nivo

Non-Small Cell Lung Cancer (NSCLC) Background: NSCLC (85%): Adenocarcinoma (60%), Squamous (30-35%), other Neuroendocrine (5%) SCLC (15%) Staging: Recommend to memorize TNM staging (questions will not always state what stage but may provide size, nodal involvement, etc) T2 starts at 3 cm and each T goes up by 2 cm → T2 (3 cm), T3 (5cm), T4 (7cm) N1 is hilar nodes, N2 is ipsilateral mediastinal nodes, N3 is contralateral OR supraclavicular nodes Stage I NSCLC Curative intent: Surgical resection (preferred) or radiation (if inoperable) If positive margins, consider RT or re-resection Typically no adjuvant chemotherapy for stage I Stage IB: Obtain NGS  for Stage IB (T2 and up) and above Adjuvant osimertinib if EGFR exon 19 deletion or L858R (ADAURA) Adjuvant Alectinib if ALK mutated (ALINA) Stage II NSCLC Curative intent: Surgical resection or radiation (if unresectable) Can give adjuvant chemotherapy for stage IIA with high risk features and stage IIB High-risk features: poorly differentiated tumors, lymphovascular invasion, wedge resection, visceral pleural involvement, and unknown lymph node status.  Regimens: Platinum/Taxol x4 Platinum/Pemetrexed x4 Adjuvant immunotherapy after chemotherapy (if tumor above 4cm) If EGFR+: No adjuvant IO (concern for pneumonitis) Options for adjuvant IO: Atezolizumab x1 year for Stage II-IIIA with PD-L1% or higher (IMPower-010) Pembrolizumab x1 year for stage IB-IIIA regardless of PDL-1 (Keynote-091) Adjuvant osimertinib x3 years if EGFR Exon 19 deletion or L858R ADAURA Trial: Stage II-IIIA EGFR-mutated NSCLC after complete tumor resection randomized to adjuvant osimertinib 80 mg daily vs placebo until disease recurrence At 2-years: DFS was 90% (osimertinib) vs 44% (placebo). OS was 98% (osimertinib) vs. 85% (placebo). At 5 years: OS was 85% (osimertinib) vs. 73% (placebo). Adjuvant alectinib if ALK mutated in resected stage IB-IIIA (ALINA) Stage III NSCLC Curative intent: Surgical resection or radiation (if unresectable) Adjuvant chemotherapy Platinum/Taxol x4 Platinum/Pemetrexed x4 Adjuvant immunotherapy after chemotherapy No adjuvant IO if EGFR+ Atezolizumab x1 year if PD-L1 1% or higher (IMPower-010) Pembrolizumab x1 year regardless of PD-L1 (Keynote-091) Adjuvant Osimertinib x3 years if EGFR Exon 19 deletion or L858R (ADAURA) Adjuvant Alectinib if ALK mutated in resected stage IB-IIIA (ALINA) If residual disease: R1 (microscopic disease): Sequential or concurrent chemoRT R2 (macroscopic disease): Concurrent chemoRT If unresectable: Concurrent chemo-RT followed by consolidation Durvalumab x1 year PACIFIC trial → PFS was 16.8 months (Durvalumab) vs 5 months (placebo). OS was 83% 1 year and 63% 2 years. If EGFR+: chemo-RT + djuvant Osimertinib 80 mg PO once daily until progression LAURA Trial → PFS significantly improved (39.1 mo with osimertinib vs 5.6 mo with placebo) If resectable: Neoadjuvant therapies: Nivolumab + chemo x3 cycles → surgery → adjuvant chemo (no adjuvant IO) Checkmate 816: median event free survival 31.6 months Vs 20.8 months (chemo alone). pCR rate was 24% vs 2.2% (chemo alone). Nivolumab + chemo x3 cycles → surgery → adjuvant nivo (if R0) x6 months (NADIM) Pembro + chemo→ surgery → Adjuvant Pembro (Keynote-671) Durvalumab + chemo → surgery → Adjuvant Durvalumab (AEGEAN) Stage IV NSCLC  NGS: check for driver mutations and PD-L1 TPS, EGFR (20-25%), ALK (5-7%), ROS1, RET, MET, BRAF V600E, KRAS G12C (13%), HER2 (ERBB2) If waiting for NGS, can start with chemo backbone and add in IO during C2 Chemo + IO (if no driver mutations): Consider if large burden of disease or end organ damage/visceral crisis Carboplatin + Pemetrexed + Pembrolizumab Keynote-189: Platinum + Pemetrexed + Pembrolizumab vs no pembro in adenocarcinomas. The survival benefit for pembrolizumab + chemo was observed across all categories of PD-L1 expression. Carboplatin + Taxol + Pembrolizumab Keynote-407:  Platinum + Taxol + Pembrolizumab vs no pembro in SCC. The survival benefit for pembrolizumab + chemo was observed across all categories of PD-L1 expression. The addition of pembrolizumab resulted in significantly longer OS and PFS than chemotherapy alone.  Pembrolizumab monotherapy Keynote-024: Pembrolizumab monotherapy can be used if PD-L1 >50%.  Keynote-042: Pembrolizumab monotherapy can be extended as first-line therapy even with low PDL-1 TPS (1-49%).  Other second line agents: Nivolumab Atezolizumab Docetaxel + Ramucirumab/Pemetrexed/Gemcitabine/Abraxane/ Vinorelbine Enhertu Telisotuzumab (cMET/MET >/= 50% IHC 3+ and EGFR wild type) Datopotamab deruxtecan: Trop-2 directed ADC (TROPION-Lung-01) EGFR exon 19 or L858R Targeted therapies: EGFR Exon 21 L858R or Exon del 19:  Osimertinib (FLAURA) Osimertinib + chemo (FLAURA-2) Amivantamab + Lazertinib Afatinib Dacomitinib Erlotinib +/- Bev Erlotinib +/- Ramicurumab Gefitinib EGFR Exon 20 insertion mutation: Amivantamab (CHRYSALIS) Amivantamab + chemo (PAPILLON) ALK fusion 5-7%: Can pre-screen with ALK IHC and confirm with FISH or PCR ALK TK inhibitors (Alectinib, Brigatinib, Crizontinib, Lorlatinib) are category 1 for first line therapy. They are superior to chemo in 1L and 2L setting 1G ALK TKI: Crizotinib 2G ALK TKI: Ceritinib, Alectinib, Brigatinib, Ensartinib 3G ALK TKI: Lorlatinib (CROWN trial) 4G ALK TKI: NVL-655 RET fusion:  Selpercatinib ROS1 fusion:  Repotrectinib, Entrectinib, Crizontinib, Lorlatinib KRAS G12C: Sotorasib, Adagrasib Both approved for 2L after 1+ systemic therapy MET Exon 14 Skipping Mutation: Capmatinib, Crizotinib, Tepotinib BRAF V600E: Dabrafenib/Trametinib HER2: Fam-trastuzumab deruxtecan (Enhertu) NTRK Repotrectinib Larotrectinib Entrectinib Small Cell Lung Cancer (SCLC) Background:  Poor prognosis. Median OS ~ 12-14 month Limited-Stage SCLC: confined to the ipsilateral hemithorax, which can be safely encompassed within a radiation field Extensive-Stage SCLC: metastatic, beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion May present with SVC Syndrome IR consult - Ideally could still get tissue diagnosis before treating Rad Onc consult for Emergent treatment with concurrent chemoRT LS-SCLC Treatment Stage I-IIA (T1-2 only): lobectomy + adjuvant chemotherapy (Cisplatin and etoposide) Stage IIB-III: Concurrent chemo-RT Consider post-chemo-RT consolidation Durvalumab (ADRIATIC) → OS was 55.9 months (durvalumab) vs 33.4 months (placebo). PFS was 16.6 months (durvalumab) vs 9.2 months (placebo). Consider prophylactic cranial irradiation (decreases brain metastases and increases OS) ES-SCLC Treatment No radiation or surgery Consider MRI brain Combination chemo+ IO (IMPOWER-133, CASPIAN) (carboplatin/cisplatin + etoposide x4 cycles) + (Atezolizumab/Durvalumab) For brain metastases: start with WBRT + steroids Relapsed SCLC Treatment Consider if platinum-resistant. Can re-challenge with Carboplatin + etoposide if relapse > 6 months after platinum exposure Lurbinectedin and Topotecan can be used in 2nd line if relapse < 6 months (chemo-refractory) Talratamab: bispecific Ab (DeLLphi-301) Clinical Trial Mesothelioma Background:  Types: Epithelioid Mesothelioma: better prognosis Non-Epithelioid Mesothelioma (Sarcomatoid or Biphasic) Highly aggressive cancer, typically unresectable at diagnosis.  Less than 10% of patients survive 5 years or beyond.  Treatment: Ipilimumab + Nivolumab (Checkmate-743): prefered for sarcomatoid Chemo: Cisplatin + Pemetrexed, Cisplatin + Pemetrexed + Bevacizumab Second line:  If immunotherapy used in first line: use chemo If chemo used in first line: use ipi/nivo