Chapter 11: Hematology and Oncology (Part 7)

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This is the Crush Step 1 podcast based on the second edition of our best-selling book. The goal is to provide you high yield and high quality audio content of the book to help you study on the go and reclaim some of the time in your day. This is Nick Nissen narrating part 7 of the hematology oncology chapter. Myeloproliferative disorders. Myeloproliferative disorders or MPDs are a group of neoplasic disorders that involve the proliferation of myeloid stem cells. This category of neoplasms includes polycythemia vera, thrombocythemia, CML and myeloid metaplasia with myelofybrosis. With the exception of CML, these disorders are associated with mutation in the Jack II gene and can be treated with hydroxyurea. Polycythemia vera. Polycythemia vera or PV is a myeloproliferative disorder that leads to the unregulated production by myeloid stem cells of increased levels of RBCs and may also produce WBCs and platelets. The term polycythemia refers to a state of increased hemoglobin and manicure values above the normal range. Polycythemia vera is a true polycythemia and the first step in its diagnosis is to distinguish it from a relative polycythemia, EG1 caused by plasma volume contraction, or a secondary true polycythemia. True polycythemias are category into primary and secondary polycythemias. In primary polycythemia, the production of red blood cells results from an EPO independent pathway, as in PV. In secondary polycythemia, the increased production of RBCs results from the excess secretion of EPO that is physiologically appropriate or pathologic. In relative polycythemia, the most common polycythemia, a loss in plasma volume or dehydration results in hemoconcentration of the blood. In other words, the amount of solute, the RBCs and other blood products suspended in the plasma, stays the same while the amount of solution, which is a plasma volume in which blood products are suspended, is decreased, leading to a higher concentration of solute, and not an absolute increase in RBC amount. RBC mass is used to distinguish relative from true polycythemias. RBC mass is always elevated and true polycythemias. Relative polycythemia laboratory findings. Normal oxygen saturation or SAO2, so no physiologic stimulus for EPO release. There's a normal EPO. There's an increased RBC count with concentration of RBCs that has been increased. Remember that the RBC count is a measure of the concentration of RBCs in the blood, so the number of RBCs per microliter of blood. Normal RBC mass, the amount of RBCs has not changed because there is no EPO stimulus to create more RBCs. Remember, RBC mass is a measure of the number of RBCs in the blood. There's also decreased plasma volume. Tissue hypoxia of any cause, e.g. high altitude, pulmonary disorders, decreased hemoglobin, oxygen carrying capacity, results in increased EPO secretion that leads to physiologically appropriate secondary polycythemia. The body is attempting to overcome the hypoxic state by upregulating the production of hemoglobin and RBCs thereby increasing the oxygen carrying capacity of the blood. Physiologically appropriate secondary polycythemia laboratory findings. Decreased oxygen saturation or SAO2 acts as a stimulus for EPO release. RBC count, RBC mass and EPO will be increased with EPO causing bone marrow to increase the production of RBCs resulting in an increase in the RBC count and RBC mass. Plasma volume will be normal. The amount of solute has increased by bone marrow production of RBCs, not the amount of solution. Certain cancers, e.g. renal cell carcinoma, hepatocelular carcinoma, secrete EPO in an autonomous fashion and lead to physiologically inappropriate or pathologic secondary polycythemia. Pathologic secondary polycythemia laboratory findings. Oxygen saturation or SAO2 is normal, so there's no physiologic stimulus for EPO release. However, a topic release of EPO from tumor cells results in increased EPO levels. RBC count and mass are increased. Polycythemia vera, similarly to other MPDs, is associated with the mutation in the JEC2 kinest gene. PV is an insidious disorder that is usually diagnosed in older adults greater than 60 years old, but can occur in any age group. PV patients may enter a spent phase after many years, after diagnosis, develop anemia and have fibiotic bone marrow. Most symptoms of PV are caused by the hyperviscosity of the blood from increased RBCs and it's effects on organs such as headaches, vertigo, mental status and visual changes, congestion of the retinal vein, and spinal megalithrom congestion or acrimedular hematopuesis. As a result, individuals will be at increased risk of thrombotic events, causing significant morbidity and mortality, such as cerebral vascular accidents, strokes, MIs, deep venous thrombosis, sponic infarction and bud-kiyari syndrome, or hepatic vein thrombosis. A subset of patients may be largely asymptomatic, not displaying symptoms of hyperviscosity or thrombotic events. These patients, only presenting symptom, may be preridous after warm bath, caused by abnormal histamine release by mass cells. Clinical and laboratory findings include the following. Epipato-spinamegly may be present. Left upper quadrant pain can be present from splinamegly or splinic infarct. A radic complexion and congenital plethera can be noted from congestion of blood vessels. Peptic ulcer disease may be present with an unclear cause, possibly increased histamine release seen in this disorder. Gaudier thritis is a result of increased cell turnover caused by cancer. EPO is decreased. Remember, PV is an EPO independent polycythemia. The EPO is low because of I use physiologic response to abnormally high RBC levels is to decrease the production of RBCs by decreasing its secretion of EPO. Lugocytosis or thrombocytosis may be seen in some patients. Bone marrow aspirate may show hyperplasia of all three myeloid cell lines. Patients in the spent phase will have a bibrotic bone marrow. Differentiate from CML by the absence of Philadelphia chromosome and increase LAP score. LAP is decreased in CML. Treatment. This is fatal if left untreated with a 1-3-year survival. With treatment, expected survival can be more than 10 years. Non-myelose-appressive agents include the following. Periodic phlebotomy to keep hematocrit less than 45%. This treatment is effective but chronic lobotomy may result in IDA and reactive thrombocytosis. Patients will have increased risk of thrombotic events in the first few years after this therapy. Myelose-appressive agents such as hydroxyureia with reduced rate of periodic phlebotomy and interferon alpha or IFN alpha may also be used. Myeloid metaplasia with myelofyrosis. Myeloid metaplasia with myelophyrosis or MMM is a myeloproliferative disorder called caused by neoplasic changes in the myeloid stem cells that lead to the pathologic proliferation of fibroblasts causing marrow fibrosis. Neoplasic cells produce ineffective RBCs, WBCs, and platelets. The findings in MMM are similar to those in the spent phase of PV, in which there is a replacement of marrow with collagen fibrosis. MMM is also associated with the mutation of the Jack II gene on chromosome 9. Myeloid metaplesias, another term for extramedular hematoplasis. Metaplesis can occur in almost every tissue in the body. In MMM, the main side of extramedular hematoplasis is a spleen, which is enlarged in more than 90% of patients. The myeloid fibrosis develops early in this disease because of the increased release of platelet-derived growth factor and transforming growth factor beta or TGF beta by the neoplasic mega-caric sites. These growth factors promote the growth of non-neoplasic fibroblasts leading to increased production of collagen and fibrosis of the marrow. MMM occurs primarily in individuals older than 60 years. The typical presentation is one of marrow failure, anemia, thrombocytopenia, and neutropenia, with left upper quadrant pain. Spinomegally and resultant spinic infarction. Plato-spinomegally results from increased spinic hematoplasis, which increases portal blood flow and leads to portal hypertension and spinomegally. Metaplesis of cirrhoso-services can lead to spinic infarction. The platyospinomegally results from increased spinic hematoplasis, which increases portal blood flow and leads to portal hypertension and spinomegally. Metaplesis of cirrhoso-services can lead to a large plural or pericardial effusion. Initially, the bone marrow is hypercellular, but early in the disease progression, it becomes hyposellular and fibrodich with increased collagen and reticulum fibers. Figure 11.37 demonstrates hyposellular, bibrotic bone marrow biopsy from a patient with myeloid metaplesia with myeloid fibrosis. Lucco-erithroblastosis or myeloid pysis is on peripheral blood smear. This is defined as a presence of an immature granulocytic precursors and nucleated RBCs found on the smear. The RBCs will have a characteristic teardrop shape called decrocytes from RBCs being squeezed out of fibrodich marrow. Ciccinemia from lucco-erithroblastosis may occur. WBC and platelet count is variable. Platelets are abnormally large. Per treatment, it's anectomy if complications developed from massive spinomegally, hydroxuria and interferonalpha. Hey everyone, Chris here from MedPrep2Go and I wanted to ask you to please follow us on social. There may be links in the show notes or you can find us at MedPrep2Go on Facebook, Instagram, LinkedIn and now YouTube. We'd greatly appreciate it as we try to spread the word about MedPrep2Go in key apneocal education accessible and affordable. Disorders of hemeproduction. The production of hem is a highly regulated biochemical process, a defect in any step results in the accumulation of pathway intermediates. The accumulation of certain hem intermediates can be toxic leading to the development of a disorder called porphyria. Porphyrycutanetarda. Porphyrycutanetarda or PCT is a genetic or acquired disorder of hemeproduction and the most common porphyria. PCT develops from decreased activity, the enzyme in the fifth step of hemicynthesis, uroporfinogen, decoboxylase or UROD. This deficiency leads to the accumulation of hemepathway intermediates such as uroporfin and iron. The pathology of this disease is directly associated with the buildup of uroporfin and iron. PCT is characterized by sun-induced blistering and erosion of the skin caused by accumulation of uroporfin deposits in the skin. Patients also may develop hyperpigmentation, hypertricosis or increased hair growth mainly on the face and skin fragility. The accumulation of iron results in citerosis from iron overload. Primarily affecting the liver, resulting in hem hepatic inflammation and cirrhosis. Enherited causes of PCT are mostly sporadic mutations in 80% of the cases and the UROD gene. The remaining 20% of cases of PCT are inherited in an autosomal dominant manner. It is unclear how PCT is acquired but several risk factors have been observed. These included hepatitis C virus or HCV infection, alcohol abuse, excess iron, estrogens and exposure to chlorinated cyclic hydrocarbons. Diagnosis is made by measuring urine, uroporfin, which will be increased. Treatment is aimed at eliminating exposure to precipitants, decreasing iron levels and increasing the excretion rate of porphorins by the liver. Patients are instructed to avoid alcohol consumption, iron supplementation, sunlight exposure, intake of estrogens and exposure to chlorinated cyclic hydrocarbons. Excess iron is managed by routine philbotomy. Odos, antimilarials such as chloroquine or hydroxychloroquine help increase removal porphorins from the liver by increasing the rate of excretion. Patients with HCV should have their infection controlled with antiviral medications for proper control of PCT. Acute Interminate Porphyria Acute Interminate Porphyria or AIP is a rare autosomal dominant disorder of hemeproduction. Individuals with AIP are deficient and porphorbillanogen diaminase or uroporfinagen synthase and enzyme in the hem synthesis pathway, resulting in the accumulation of upstream intermediates inside the cytosol, namely PBG and Delta ALA. Build up of these two intermediates is toxic to cells and can also cause degradation of myelin. The symptoms of AIP are variable with severe poorly localized abdominal pain being the most common. The symptoms can be categorized by the five P's of AIP. The first P is painful abdomen, often confused for acute abdomen leading to a belly full of scars. The second P is port wine for port wine colored urine. The urine is carolous initially, but exposed to light it causes the PBG and urine to oxidize and gives urine its color. Third P is peripheral neuropathy or patchy numbness and parasthesias. The fourth P is psychological disturbances such as anxiety, confusion, psychosis and dementia. And the fifth P is precipitated by drugs. One is that enhanced at a chrome P450 activity, sulfa drugs, barbituates, and some antisecotics and alcohol. A feature that distinguishes AIP from other porphyrys is that it has no sun-induced blistering in the skin or rashes. The diagnosis is obtained by observing the presence of increased urinary excretion of PBG and genetic testing, which can also measure porphyrybilinogen, deaminase activity, but this is less helpful in the diagnosis. The treatment is aimed at decreasing factors that participate attacks and to discontinue any offending drugs and at halting the endogenous hemiproduction pathway. Endogenous hemiproduction can be decreased by inhibiting ALA synthase, the rate limiting step in hem synthesis. ALL synthase is inhibited by hem, the end product of hem synthesis via feedback inhibition and also by glucose. Hemogenes should receive a high carbohydrate or glucose infusion during acute attacks and hematin or hem originate to help resolve severe attacks. Both are hem-like substances. Pharmacologic treatment, antaquagulants, heparin. Heparin is a glycosamine glycan administered parentarily, intravenously or subcutaneously, that binds AT3 with high affinity. This fast-acting antaquagulant within onset of action in seconds works by inducing a conformational change in AT3 that results in a 1000-fold increase in its protease activity. Clinically, it has been used as prophylaxis as well as treatment of venous thrombosis and pulmonary embolism. Heparin also is used as edgment therapy for unstable angina, MI, and stroke. Hemogen can be safely administered for antaquagulation during pregnancy because it does not cross placenta. Tidefacts include bleeding and HIT. Clinical effects are reversed by protamine sulfate, and are followed by measuring the PTT. Controndications include active bleeding, bleeding disorders, history of HIT and aortic dissection. Direct thrombin inhibitors. Lepurudin, Bivalorudin, and Devagatrin. A direct thrombin inhibitor, or DTI, as the name implies, acts by directly inhibiting circulating and clot-bound thrombin, also known as factor 2A, and provides antatrombin 3 independent antaquagulation. Lepurudin and Bivalorudin are Herodin adilogs that differ from Devagatrin and how they bind to inactivate the thrombin enzyme as well as route of administration. Devagatrin is given orally. it is used as an alternative antiquity. Immunisturbed intravenously, or IV, for patients with a history of HIT or Heparin allergy. Side effects include bleeding. No therapeutic drug monitoring is widely available for DTIs. Theoretically, may use the thrombin clotting time to monitor, but it is not generally used in clinical practice. Contrindications are similar to those of Heparin. Direct factor 10A inhibitors like a pixaban and re-roxaban. Direct factor 10A inhibitors are another class of antitroman 3 independent anticoagulants that act to directly inhibit circulating and clot-bound factor 10A. Currently these medications are only available clinically in oral formulations and are used as alternatives to Warfarin and Heparin. They are used for stroke prevention and atrial fibrillation, as well as pulmonary embolism or PE, or deep vein thrombosis treatment and prophylaxis. They have a rapid onset and an offset of action, which reduces the need for bridging. Additionally, they do not require frequent monitoring or redocering because they have few drug interactions and no food impairments or food interactions relative to Warfarin. They are contraindicated in severe renal impairment. Warfarin or Committed. Warfarin is an oral anticoagulant that inhibits the normal production of vitamin K dependent clotting factors in the liver. It functions by inhibiting epoxide reductase. The enzyme that helps regenerate vitamin K from its epoxide form to its reduced or active form. Warfarin basically induces a functional vitamin K deficiency state in the body. Cardinal factors 279 and 10 and protein C and S depend on vitamin K as a cofactor for their complete synthesis. Clinically, it is used for the treatment and prophylaxis of venous thrombosis and pulmonary embolism. Additional uses include anticoagulation therapy for atrial fibrillation and patients with mechanical heartbealths. Clinical effects are monitored by following the PT and INR. Effects are reversed immediately with administration of fresh frozen plasma and within a few hours with vitamin K infusion. Controndications include history bleeding disorders and active pregnancy. Warfarin crosses the placenta and is tryogenic. Antipylet agents. Asperin. Asperin is a prototypical non-srotal anti-inflammatory drug or NSAID. The mechanism action of NSAIDs involves the inhibition of cycloxygenase, COX-1 or COX-2 enzymes, thereby preventing the conversion of arachidonic acid to prosaglannins or TX-A2. Asperin differs from other NSAIDs and that it irreversibly inhibits COX enzymes. The inhibition of prosaglannins synthesis results in its anti-inflammatory and analgesic decrease in prosaglannin E2 actions. The inhibition of TX-A2 production leads to decreased platelet aggregation, producing an anti-quagulent effect. Clinically, it is used as an anti-piratic, analgesic, anti-inflammatory and anti-quagulent or anti-platelet drug. Set effects include gastric ulcers and bleeding, central effects like hyperventilation or tinnitus, and rye syndrome. Clinical effects are monitored by measuring the PT, which will be increased. It is indicated in children and adolescents because it can lead to rye syndrome. The anopiridine derivatives like clopidigrel and teclopidine. Clopidigrel and teclopidine are the anopiridine derived anti-platelet medications that act via mechanism other than that of aspirin. Clopidigrel works by irreversibly inhibiting the binding of ADP to its receptor on platelets, thereby reducing platelet aggregation. Clinically, is often used in conjunction with aspirin to decrease ischemic events and patients with a previous history of stroke, coronary artery disease, and peripheral arterial disease. It is also used to reduce thrombosis after cardiac stent placement or in patients who cannot tolerate aspirin therapy. Set effects include bleeding, severe neutropenia, TTP, rashes, and dyspepsia. Clopidine is associated with a worse side effect profile than clopidigrel. It is contrary to catering patients with active bleeding. EBSIXIMAM. EBSIXIMAM is a monoclonal antibody that works as a platelet aggregation inhibitor by binding to the GP2B3A receptor on activated platelets. This blockclade prevents platelets from sticking together and inhibits thrombus formation. Clinically, it is used as an anticoagulant and acute coronary syndrome and also to prevent rostinosis after coronary angioplasty. Side effects include bleeding or GI bleed and thrombusidopenia. It is contraindicated in patients with active bleeding, recent GI bleed within six weeks or thrombusidopenia. Phosphodiostrace 3 inhibitors, like cylistaseol and diperamidol. Phosphodiostrace 3 or PDE3 inhibitors stop clot formation by blocking the enzymes that normally inactivate cyclic AMP or CAMP, leading to increased levels of CAMP and platelets. As you may remember, CAMP is an important mediator of platelet activity and increased levels lead to inhibition of platelet aggregation. These medications also act as direct arterial vasodilators by inhibiting the cellular reuptake of adenosine, leading to an increased level of extracellular adenosine. Increased adenosine levels then act as local vasodilators. Clinical uses include angina-prophylaxis, intermittent clotication, prevention of stroke or transgenic ischemic attack when combined with aspirin. Side effects are related to its function as a vasodilator, including headache, nausea, hypotension, palpations, arrhythmias, GI upset, and thrombocytopenia. Controndications include heart failure, especially New York Heart Association Class 3 or 4 failure, tachycardia, and hypovolemia. Thrombolytics, Altaplace or TPA, Ridaplace or RPA, Tenectaplace TNKase, and Streptocainase. Thrombolytics are medications that can help dissolve blood clots by a process referred to as thrombolysis. These adorns catalyze the formation of endogenous plasma, the protease that removes clots or thrombi from plasma ingen. Plasma cleaves fibrin as well as thrombin clots. You will see elevated PT and PTT without any change in platelet count. Clinically, this class medication are used for treatment of MI ischemic stroke or massive PE side effects include bleeding, spasucly hemorrhagic stroke. It's contraindicated in patients with a history of hemorrhagic stroke, known intracranial malignancy, non-stereobolascular lesion or arteriovenous malformation. Recent ischemic stroke within the last three months, known bleeding disorder, or active bleeding suspected aortic dissection or significant closed head or facial trauma within three months. Relative contraindications include severe hypertension, recent major surgery or pregnancy. Antenneoplastics. Antimetabularites. Methotrexate or MTX. Methotrexate is an antimetabular medication as an analog for full ac acid. Full ac acid is required to carry out one carbon transfer reactions in various synthetic pathways, specifically the synthesis of purine nucleotides like thymidylate and semimedal acid, serine and methionine. Methotrexate inhibits dihydrofolate reductase or DHFR and prevents the regeneration of folate for continued use in DNA synthesis. This antifolate agent is not selective for tumor DHFR versus normal DHFR. Therefore it can affect the DNA synthesis and cell growth, normal and tumor cells. However, it does not have a greater toxic effect in the DNA synthesis or S phase of cells that are rapidly dividing. Clinically it is used as an antineoplastic agent used with other chemotherapy agents to treat leukemias and HL and other malignancies. It is also used as an immunosuppressant in the treatment of rheumatoid arthritis. Methotrexate is used in the medical management of ectopic pregnancy. Side effects commonly include bone marrow suppression, liver damage and neurotoxicity. Civic effects can be damaged with the administration of lukewarm or philinic acid, which is taken up in disproportionate amounts by normal cells versus tumor cells. Five fluoroyorocell or five FU. Five FU is a pyrimidine analog that acts during the S phase of the cell cycle. Similarly to MTX, they work synergistically by inhibiting different enzymes in the DNA synthesis pathway. Five FU halts DNA and protein synthesis. Five FU is an anti-metabolite that irreversibly inhibits thymidolate synthetase, thereby blocking the synthesis of thymidine. It is enzymatically converted to its active form, five fluorodeoxiuridine or five FDUMP, which in turn inhibits the middle late synthase and halts DNA synthesis. leads to an imbalance in cell development and a thymineless death. of the cell. Thymineless death occurs when bacterial yeast or human cells are deprived of thymidine triphosphate or DTP and essential precursor for DNA synthesis, thereby initiating irreversible cell death. Clinically, it is used in the treatment of colon cancer and superficial tumors like basal cell carcinoma. Side effects include myelose suppression, GI amucocytis, and photosensitivity. Side effects cannot be reversed by lukewarm. As a thioprene and six-mercaptopurine or six-MP, as a thioprene is a pro-drug that is non-anzomatically cleaved to create six-MP, six-MP, the analogue of adenine is an antimatablet that works by inhibiting many enzymes involved in denovopurine synthesis in the ass face. This immunosuppressive medication must first be converted by hypoxanthine, guanine, phosphorybosinal transferase or HGPRT to exert its clinical effects. Clinically, these medications are used for the treatment of leukemias and lymphomas. They are also immunosuppressants used to treat certain autoimmune disorders, including rheumatoid arthritis, SLE, and inflammatory bowel disease. Side effects include bone marrow suppression, GI amucocytis, and liver damage. Six-MP is metabolized by zanthioxidase. It may result in increased toxicity in patients taking L-peurinal. Sixtheoguanine or six-TG. Six-TG is a guanine analog antimatablet that works similarly to six-MP. It blocks the synthesis of guanine nucleotides and results in the arrest of DNA and RNA synthesis in the ass face. Unlike six-MP, it is metabolized by the opurine methyl transferase and is safe to give with L-peurinal. Clinically, it is used in the treatment of acute leukemias and chronic myelol leukemia. Side effects are similar to six-MP except that it can be given with L-peurinal. Side terabene. Side terabene is an S-phase specific antimatallolite, an analog of deoxyscytidine, a deoxyribonucleoside resembles cytidine with one oxygen atom removed. That block DNA synthesis by incorporating itself into the inter-nucleotide linkages in DNA. Clinically, it is used in the treatment of acute leukemias, like AML or ALL, and in lymphomas for induction therapy. Side effects include bone marrow suppression and GI mucocytis. Cladrabene or 2CDA. Cladrabene is a synthetic purine analog that is used in the treatment of harrysell leukemia. It is an immunosuppressant that inhibits DNA processing by cells. It is an adenosine-daminase inhibitor clinically used for treatment of harrysell leukemia. It's side effects include bone marrow suppression, neurotoxicity, and renal toxicity. Antitumor antibiotics. Dectinomycin. Dectinomycin or actinomycin-D is an antibiotic used as a chemotherapy medication which disrupts the cell cycle by inhibiting transcription. It works by binding double-stranded DNA and blocking elongation of the chain by RNA polymerase. Clinically, it is used to treat wellms tumor and children, which may be curative if combined with surgery and radiation. Rabdo-myosarcoma, Ewing sarcoma, and choreocarsinoma. Decterubicin. Decterubicin or adriamisin is an antibiotic. It is the A part of the ABVD chemotherapy regimen. It works by integrating with DNA to disrupt replication and transcription. Decterubicin inserts itself into DNA leading to breaks in the chain. Clinically, it is used in the treatment of multiple myeloma leukemias, HL sarcomas, and solid tumors, breast ovary bladder and lung. Side effects include significant cardiotoxicity, leading to dilated cardiomyopathy, bone marrow suppression, and ellipesia. Bliomisin. Bliomisin is a G2 phase specific drug and is the B part of the ABVD chemotherapy regimen. This agent is a mixture of glycoproteins that produce free radicals on binding DNA. The free radicals create breaks in DNA which accumulate in lead to cell death. Clinically, it is used in the treatment of HL, to stickular carcinoma, and sclamous cell carcinomas. Side effects include skin changes or hyperpigmentation ulcers, ellipesia, and life threatening pulmonary fibrosis. Pulmonary function must be monitored. It produces minimal bone marrow suppression. Alcalating agents. Cyclophosphamide and if-phosphamide. Cyclophosphamide is an alcalating mustard agent. Like other alcalating agents, it exerts its effect by alcalating DNA, which is lethal to cells, and is most toxic to rapidly dividing cells. It is the most commonly used alcalating agent. Cyclophosphamide is unique in that it can be administered orally. Both cyclophosphamide and if-phosphamide require activation by the liver's P450 system to function properly. Clinically, it is used to treat NHL, breast carcinoma, and ovarian carcinomas. It also acts as an amyosuppressant. Side effects include hemorrhagic cystitis, leading to bladder fibrosis. This side effect is decreased by aggressive hydration and administration of mesna and myelus suppression. Nitrosuureas. Nitrosuureas, e.g. carmustine, low-mustine, semustine, and streptozosin, are DNA alcalating agents using chemotherapy. Nitrosuureas are a subgroup of medications that work by alcalating the cross-linked strands of DNA to create breaks and inhibit its replication, also leading to inhibition of RNA and protein synthesis. These medications must be metabolized into their active products. Carmustine or BCNU and low-mustine or CCNU are too closely related nitrosuureas that are highly lipophilic and readily cross the blood-brain barrier. They are used in the treatment of many brain tumors. Side effects include myelus suppression, brinotoxicity, and pulmonary fibrosis after prolonged use. Pusulfin. Pusulfin is an alkyl sulfonate that acts as a non-specific alcalating agent. It acts similarly to other alkylating agents and forms or active intermediates that alkylate DNA bases, mostly purines, leading to cross-linking of bases, abnormalities in base pairing, and DNA strand breakage. Clinically, it was used as the main treatment for CML until a metanib, the gold standard treatment of CML was discovered. Though it continues to play a role in the treatment of CML, Pusulfin is also used in bone marrow transplantation and kills bone marrow cells in preparation for the procedure. Side effects include pulmonary fibrosis, which is the main side effect, and hyperpigmentation. Micro tubule inhibitors. Vincristine and finblasting. Vincristine or ankyvorn is a vinc alkyloid used in the O part of the MOPP chemotherapy regimen. Vincristine is an M phase inhibitor of the cell cycle and works by binding to tubule. Thereby, preventing polymerization of microtubules and spinal formation. Inhibition of microtubule formation leads to a rest of the cell cycle at metaphase and stops mitosis. Finblasting is a similar medication that is the v part in the ABVD chemotherapeutic regimen. Clinically, it is used in the treatment of HL, leukemias, lums tumor, and choreocarsinomas. Side effects include peripheral neuropathy and constipation. Vincristine causes minimal myelosuppression. Finblasting, on the other hand, produces significant myelosuppression. Packletaxel. Packletaxel or taxel is the first of the taxing family of chemotherapeutic agents. It is an M phase agent that prevents the breakdown of the metatotic spindle and inhibits completion of anaphase. Packletaxel, a derivative from the U tree, acts by binding tubule and in promoting polymerization and stabilization of microtubules unlike the vincula alkaloids, which inhibit polymerization. The microtubules created are highly stable but dysfunctional, leading to mitotic arrests and cell death. Clinically, it is used against ovarian carcinomas, breast cancers, claims cancers of the head and neck and other cancers. Side effects include serious hypersensitivity reactions like dysmnea, urticaria, and hypotension, peripheral neuropathy and bone marrow suppression. Topoisomerase inhibitors. Potophyletoxins like etoposide and tiniposide. Etoposide and tiniposide are potophyletoxin-dryochemotherapeutic medications. Members of the potophyletoxin drug class are G2 phase-specific and act by inhibiting tubuleisomerase 2. They form a three-part complex with DNA and tubuleisomerase 2, leading to the inhibition of tubuleisomerase 2, and an accumulation of breaks in the DNA. Since tubuleisomerase 2 normally Receals double strand. DNA breaks. The accumulation of breaks leads to degradation of DNA and cell death. Clinically, etoposide and tinniposide are used to treat lung and prostate carcinomas, small slow carcinomas, to circular cancers, lymphoma, ALL, and AML. Side effects include bone marrow suppression and possible high rate of secondary leukemias and children treated with etoposide with characteristic 11Q23 translocation due to DNA breaks induced by medication. Tinniposide also inhibits tuboysomerase 2 and is mainly used in the treatment of ALL. Side effects include severe myelose suppression, gastrointestinal toxicity, hypersensitivity reactions, and alopecia. Tipoysomere is an enzyme that changes DNA structure by facilitating the relaxation of DNA superquiling during the process of replication and transcription. Clinical uses include colon cancer for eirino tcan, ovarian cancer, and small cell lung cancer. Side effects include diarrhea and severe bone marrow suppression. Steroid hormones and their antagonists. Prednisone. Prednisone is a strong synthetic glucocorticoid that is the last P in the MOPP regimen. It has many actions on the body. Prednisone must be metabolized to prednisolone is active form, after which it binds to a cytosol receptor and is transported into the nucleus activating specific corticosteroid response genes. Prednisone acts as an anti-inflammatory and immunosuppressant agent by blocking proliferation of activated T cells and inhibits production of inflammatory mediators and also inhibits the antibody production. It may trigger apoptosis of immune cells, especially lymphocytes. Prednisone also produces neutrophilia without pandemia via demarcination of neutrophils in the circulation. It helps maintain blood glucose levels by increasing gluconeogenesis. It increases muscle catabolism and increases lipolusys. It also acts as a weak mineralocorticoid. Clinically, it is used in the treatment of autoimmune diseases such as rheumatoid arthritis and asthma, but is also used in leukemias like CLL and HL. Side effects include hypocortisolism like cushing syndrome, hyperglycemia, and increased risk of infections, osteoporosis, muscle wasting, skin thinning, fat deposition, and psychosis. Tamaxifen and Reloxifen. Tamaxifen is a selective estrogen receptor modulator or SEM that acts primarily as an anti-estrogen but has weak estrogenic activity. It competes with the estrogen for the estrogen receptor. Tamaxifen is not effective in pre-menopausal women because they produce enough estrogen to out-compete Tamaxifen for the estrogen receptor and creates a non-productive complex with its receptor, failing to induce estrogen-responsive genes and RNA synthesis. This results in suppression of growth in estrogen-responsive tissues. As a result of the partial estrogen agonist activity, Tamaxifen reduces the severity of osteoporosis and postmenopausal women, but it can stimulate endometrial growth and increases the risk of endometrial cancer. It also increases high density like protein or HCL levels protecting against atherosclerosis and cardiovascular disease. Reloxifen and endometrial estrogen antagonist is a drug similar to Tamaxifen, but does not stimulate endometrial growth and therefore does not increase the risk of endometrial cancer. It also protects against osteoporosis. Clinically, it is used in the treatment of estrogen receptor, positive breast cancer, and to prevent osteoporosis in postmenopausal women. These are the two types of endometrial cancer, which include nausea, vomiting, hot flashes, and increased risk of endometrial cancer in Tamaxifen only. Other agents. Cisplatin and carboplatin. Cisplatin is a platinum containing compound that is a member of the platinum coordination complex class of anti-cancer medications. Cisplatin X similarly to the Eucolating Agents. It enters a cell and creates interest and interest and DNA crosslinks. These crosslinks result in DNA instability and cell death. Clinically, it is used in the treatment of testicular and lung carcinomas. Cytifex include significant nephrotoxicity, ototoxicity, brinil nerve, or CN8 damage, and mild myelosuppression. Carpoplatin is a similar agent with less toxicity, but greater bone marrow suppression. Hydroxyluria. Hydroxyluria is an S-phase specific medication that inhibits DNA synthesis by blocking ribonucleotide reductase, stopping the conversion of ribonucleotides to deoxyribonucleotides. Hydroxyluria also acts by increasing the circulating levels of fetal hemoglobin. Clinically, it is used in the management of sickle cell, anemia, and various myeloid cancers, like CML. Cytifex include bone marrow suppression, nausea, vomiting, and diarrhea at high doses. Cytifex is a monoclonal antibody that binds and inhibits the ERB-B2, or HER2 receptor, a family of tyrosine kinases, expressed in some breast cancers. The HER2 pathway promotes cell survival, growth, and division. Clinically, it is used in the treatment of the metastatic breast cancer. Cytifex include cardiomyopathy. The metanibber glyvec is a monoclonal antibody that acts by binding and inhibiting the tyrosine kinase produced by the ABL and C-K-IT genes. There are a large number of tyrosine kinase enzymes in the body. The Philadelphia chromosome in CML is produced by fusion of the BCR ABL genes, including in constantly active tyrosine kinase. The C-K-IT gene, or C-Kit gene, also produces a tyrosine kinase whose active site can be inhibited by metanibber. Gastrointestinal stromal tumors often arise from mutations in the C-Kit gene. Clinically, it is used as a first-line treatment for CML. It is also used to treat gastrointestinal stromal tumors. Cytifex include weight gain, which is the most common edema bone marrow suppression, and possibly congestive heart failure. Rutuxemab. Rutuxemab is an anti-CD-20 monoclonal antibody that is used clinically to treat malignancies, like NHL and CLL, and autoimmune diseases like rheumatoid arthritis or ITP. Many BCL neoplasms are CD-20 positive. However, CD-20 is also found in normal BCLs and Rutuxemab to destroy both. Cytifex include fatal infusion reaction within 24 hours of infusion, reactivation of hepatitis B and other viral infections, like JC virus infection leading to PML, and mucusutaneous reactions in diarrhea. Arlottinib. Arlottinib or Tarsiva is a reversible epidermal growth factor receptor in EGFR Tarsine kinase inhibitor, used clinically to treat non-small cell lung cancer. It's main side effect is rash that resembles acne, and primarily involves the face as well as the neck. B-Vasusemab. Arvastin. B-Vasusemab is a medication that inhibits angiogenesis, the growth of new blood vessels. It is a monoclonal antibody against vascular and ethereal growth factor A, or Vegef A. Vegef A is a chemical signal that promotes angiogenesis. Clinical uses include many solid tumors such as colon cancer, renal cancer, ovarian cancer, lung cancer, and glioblastoma multiformy. Cytifex include GI perforations, impaired wound hailing, because it blocks growth of new blood vessels, and hemorrhage. Vmurafenib. Vmurafenib is a B-Raff enzyme inhibitor that is used clinically for the treatment of advanced melanoma. Most common side effects include arthralgia and rash. Cytoxemab. Cytoxemab is an EGFR inhibitor used clinically to treat metastatic colon cancer of the K-RAS wild type. Non-small cell lung cancer as well as head and neck cancer. This most common side effect is an acne-like rash. With that, we wrap up today's episode of the Crush Step 1 podcast. A big thank you to Elsevere Incorporated, the publishing company behind Crush Step 1, as well as all of my other books, for allowing us to put out this book in podcast format. Thank you for joining us, and please check out our other chapters.