pathology

Terminology Adjuvant therapy - given in addition to standard therapy Consolidation therapy - given after induction therapy with multidrug regimens to further reduce tumor burden Induction therapy - initial dose of treatment to rapidly kill tumor cells and send the patient into remission Maintenance therapy - given after induction and consolidation therapies or after the initial standard therapy to kill any residual tumor cells and keep the patient in remission Neoadjuvant therapy - given before the standard therapy for a particular disease Remission - less than 5% tumor burden Salvage therapy - given when standard therapy fails Adjuvant therapies in various cancers Metastasis to bone - bisphosphonates (e.g. zoledronic acid) are given to prevent lytic lesions and pathologic fractures as well as malignant hypercalcemia. Bisphosphonates work by inhibiting osteoclasts and thereby preventing bone breakdown. Breast cancer Tamoxifen , a selective estrogen recep...

Presentation Acute cases present with garlic breath, vomiting, watery diarrhea, and QTc prolongation. If severe, there can be pancytopenia and hepatitis.  Chronic cases present with: sensorimotor neuropathy -- stocking glove distribution with burning sensation, distal weakness, hyporeflexia skin changes -- 1. first there is a change in skin color (hypo/hyperpigmentaiton), 2. later hyperkeratosis (scaling of palms/ soles), 3. Mees lines (horizontal lines on fingernails)  Pathology Arsenic binds to sulfhydryl groups and disrupts cellular respiration and gluconeogenesis.  Sources of arsenic include pesiticides/ insecticides, contaminated water (e.g. well water), and pressure treated wood (e.g. antique furniture).  Diagnosis Urine arsenic levels Treatment Chelation therapy with: Dimercaprol (British anti-Lewisite, BAL) DMSA (meso-2,3-dimercaptosuccinic acid, succimer) Relevant Images Dimercaprol has sulfhydryl groups an...

Presentation 30 to 40 year old patient has episodes of visceral autonomic dysfunction (typically results in abdominal pain ), sensorimotor neuropathy ( tingling, weakness ), and psychiatric symptoms . Episodes can last anywhere from a few days to weeks. For example 40 year old with acute onset of psychosis (delusions, insomnia, irritability), abdominal pain, and peripheral neuropathy (tingling in hands/ feet). There is usually a family history of mental illness e.g. schizophrenia. On physical exam, the abdomen is soft and usually non-tender or only minimally tender, this is because the abdominal pain is neuropathic. Patients may also have constipation, vomiting, anxiety, and mood changes. The onset is usually when patients are in their 30s and 40s . Pathology Partial deficiency of prophobilinogen deaminase , which is required for heme synthesis. Diagnosis  Elevated urinary porphobilinogen (dark red/ brown urine) Management Glucose in high doses can inhibit heme...

Drug-induced photosensitivity reactions Antibiotics - tetracyclines e.g. doxycycline Antipsychotics - chlorpromazine, prochlorperazine Diuretics - furosemide, hydrochlorothiazide Others - amiodarone, promethazine, piroxicam Photo toxic Reaction drug + ultraviolet radiation -> reactive oxygen species (ROS) produced -> damage cell membranes and DNA result is similar to a sunburn - redness, pain, bullae in sun exposed areas, but often worse.  Photo allergic Reaction drug + ultraviolet radiation -> change in drug structure -> delayed hypersensitivty reaction result is similar to eczema and requires sensitization (previous exposure)

Aortic regurgitation Murmur -- early diastolic murmur Exam findings -- hyperdynamic pulse, bounding or "water-hammer" peripheral pulses Detailed explanations blood regurgitates into the LV from the aorta --> even less blood in the aorta --> decreased DBP --> peripheral arteries "collapse". When the LV contracts the next time it has more blood to pump out -> increased stroke volume -> increased SBP -> peripheral arteries must accomodate this increased flow and pressure and they "expand". Net result "bounding" pulse Aortic stenosis Murmur --  Exam findings -- pulsus parvus et tardus (low amplitude and delayed upstroke) Mitral regurgitation Mitral stenosis Apical diastolic rumble Atrial septal defect Murmur -- widening and fixed splitting of S2, may have midsystolic pulmonary flow murmur Exam findings -- if large, tachypnea. Details ASD -> L to R shunting -> more blood in RA then RV ...

Terminology Severe hypertension = blood pressure >/= 180/120 mmHg Hypertensive urgency = severe hypertension without symptoms or acute end-organ damage Hypertensive emergency = severe hypertension with acute, life-threatening, end-organ complications. Malignant hypertension = hypertensive emergency where the end-organ damage presents as retinal hemorrhages, exudates or papilledema Hypertensive encephalopathy = hypertensive emergency where the end-organ damage presents as cerebral edema and non-localizing neurologic symptoms and signs. For example, headaches, nausea, vomiting, restlessness, confusion, agitation, seizures, and even coma. Management Blood pressure should be lowered slowly, 10-20% in the first hour then 5-15% over the next 23 hours. Cerebral ischemia can occur if blood pressure is lowered to fast, resulting in altered mental status and/or generalized seizures.

Positive predictive value = TP/ (TP + FP) Negative predictive value = TN/ (TN + FN) Sensitivity = TP / (TP + FN) Specificity = TN/ (TN + FP)

When there is a confounding factor (something that is associated with both the exposure and outcome).

When there are problems with the collection of information e.g. errors in measurement of exposure and outcome. To minimize, standardization of measurement techniques and training of observers is needed

When the sample population differs from the target population with respect to their exposure and/ or the outcome.

When the people/ subjects in the study are aware that they are being studied they will behave differently and therefore affect the outcome of the study. To minimize this bias, the subjects must not be aware that they are being studied.

Patient will have a ruddy face (facial plethora), high blood pressure, and itching that occurs after exposure to water e.g. after bath/ shower (aquagenic pruritis). Physical exam will show splenomegaly. Some patients may present with burning in hands/ feet (erythromelalgia), transient visual disturbances, bleeding, and gouty arthritis (increased RBC turnover). CBC will show very high hemoglobin and hematocrit, high platelet count and WBC count. Increased blood viscosity is responsible for the visual disturbances, the hypertension, etc. It is important to know the mutation responsible for PV - a JAK2 mutation that results in the gene always being active. The gene produces a JAK2 tyrosine kinase that differentiates myeloid cells into erythrocytes (red blood cells). Normally, the gene is activated by erythropoietin (EPO) released by the kidneys (less so the liver) when there is tissue hypoxia. With the always active gene, erythropoietin isn't needed and the levels are low. This i...

Patient will have a severe infection that may require longer than normal to improve even with antibiotics. On CBC, the WBC count will be markedly elevated (typically >50,000). On peripheral smear, there will be many immature forms of neutrophils (myelocytes, promyelocytes, metamyelocytes, bands). However, most will be further along in maturation (i.e. more bands). Look for a high leukocyte alkaline phosphatase (LAP) score. Differential Dx The LAP score helps differentiate this from CML which can also present with infections as well as immature forms of neutrophils (myelocytes, metamyelocytes) but has a low LAP score. This is because the neutrophil precursors are so immature that they don't function as well. CML also usually has a higher WBC count (typically >100,000). Also unlike CML, leukemoid reaction does not present with increased basophils. Relevant Images More of the mature neutrophil precursors e.g. bands, metamyleocytes as well as mature (segmented) neutrophil...

Quick Review Patient is often older, and can no symptoms or have B symptoms (night sweats, etc), fatigue, and weight loss (caused by early satiety due to enlarged spleen). On physical exam, an enlarged spleen can be palpated. CBC shows very high WBC count (typically >100,000) with elevated basophils on differential. Peripheral smear shows early, immature neutrophil precursors (myelocytes, metamyelocytes) as well as many basophils. It is important for CML to know the details of the genetic abnormality because it relates to the treatment. CML is due to a translocation of BCR and ABL on chromosomes 9 and 22 resulting a fusion BCR-ABL gene that produces a tyrosine kinase that is always active. The treatment of choice is a tyrosine kinase inhibitor e.g. imatinib. They work to suppress the tyrosine kinase and can induce disease remission. Relevant Images Immature neutrophil precursors on peripheral smear BCR-ABL translocation

Quick Review Patient is an adult (usually older, but can also be younger) with fatigue (due to anemia) and bleeding (due to thrombocytopenia) and on CBC there is decreased hemoglobin, decreased platelets, and WBC varies (can be normal, increased or decreased).  LDH will be elevated. The most important form of AML to know is acute promyelocytic leukemia (APML). On peripheral smear, AML presents with myeloblasts with Auer rods. Bone marrow biopsy will show myeloid blasts, for APML this would be atypical promyelocytes. In AML, the bone marrow is crowded with immature myeloid cells ("blasts") preventing development of other cell types (platelets, RBCs, normal WBCs). These myeloblasts are also present in the peripheral blood in large numbers. This is why patients have fatigue (anemia), bleeding/ bruising (thrombocytopenia), increased infections (granulocytopenia). APML can present with DIC (disseminated intravascular coagulation) which results in elevated PT and aPTT and re...

Quick Review Patient will be elderly (>65 y.o), have fatigue (due to anemia) and large firm mobile lymph nodes (supraclavicular, axillary and/or cervical lymph nodes). Splenomegaly on abdominal exam. Some patients may have B symptoms (night sweats, fever, etc). Some may have increased infections or weight loss. Some may be asymptomatic. The key features are elderly patient with abnormal CBC and peripheral smear. CBC will show elevated WBC count, and on differential elevated lymphocytes. Peripheral smear will show increased lymphocytes (lymphocytosis) and they will be mature (small, little cytoplasm); smudge cells may also be seen. Flow cytometry confirms presence of clonal expansion of B lymphocytes by finding CD20, CD19, CD5 etc. Biopsy of the lymph nodes and bone marrow is not usually needed. Key Features most common leukemia in the USA elderly "mature" patients lymphocytosis (elevated WBC count due to lymphocytes, increased lymphocytes on smear) lymphocyte...

Screening Mammography in women over 50 is the screening test that lowers mortality the most. Mammography begins at age 50 and is not routinely done once over 75.  BRCA genetic testing is not routinely done. BRCA gene is likely to be positive if there is a family history of breast cancer or increased risk of ovarian cancer.  Diagnosis A positive mammography is followed by sentinel node biopsy . Sentinel node = the first lymph node that a dye/ tracer injected into the operative field reaches. If biopsy sample is positive for cancer it is tested for markers including ER (estrogen receptor), PR (progesterone receptor), HER2/neu . A positive biopsy result is followed by axillary lymph node dissection .  Prevention Tamoxifen is given if 2 or more first-degree relatives have breast cancer. It reduces risk of breast cancer by 50% and is started at age 40.  Treatment Surgical remova l of the tumor is best done with lumpectomy with ra...

Quick Review Child develops bloody diarrhea (sometimes it's not bloody) and abdominal pain and is given antibiotics which help with the diarrhea. Then about a week later is overly tired with pale skin and petechiae. They also often have reduced urine output (oliguria) and swelling (edema). CBC shows low hemoglobin (anemia), normal MCV (normocytic), low platelets (thrombocytopenia). Serum chemistry shows elevated BUN and Cr (renal damage). Liver function testing shows elevated bilirubin (suggests hemolysis). Peripheral blood smear shows schistocytes. Diagnosis is based on history and above laboratory tests. Treatment is supportive (fluids, electrolytes, blood transfusions, dialysis). The cause is Shiga toxin producing bacteria, usually E. coli O157:H7 which is a strain of enterohemorrhagic E. coli (EHEC). The toxin destroys the epithelial lining of the colon leading to abdominal pain and bloody diarrhea. Once in the blood the toxin damages endothelium leading to platelet microth...

Quick Review A 2 year old boy is brought to the clinic because of a swollen painful knee after injury during play or a fall. On exam the knee is very swollen, there is limited range of motion, and there is ecchymoses and swelling around the areas of the leg that were injured (e.g. thigh, shin, hip). There may be a family history of a male relative dying of a deep brain bleed or a male relative with similar problems with joint swelling, easy bruising or delayed bleeding after dental procedure (e.g. tooth extraction). Only male family members are affected (x-linked recessive). Physical exam will show limited mobility and pain on movement. X-ray of the joint will show a large effusion (hemarthrosis). CBC will be normal. Coagulation studies will show elevated aPTT, and either reduced factor VIII (hemophilia A) or factor IX (hemophilia B) activity. Treatment is to replace the missing coagulation factor. Desmopressin may be given for mild hemophilia A. Years later the boy has injured t...

Approach to Anemia Macrocytic Anemias Macrocytic anemia refers to anemia in which red blood cells are large i.e. with a mean corpuscular volume (MCV) > 100 fL. Macrocytic anemias are divided into 2 groups: megaloblastic and non-megaloblastic. Megaloblastic Anemias Vitamin B12 (Cobalamin) deficiency Folate deficiency Non-megaloblastic anemias Alcoholism Hypothyroidism Liver disease Medications - e.g. chemotherapy, zidovudine, hydroxyurea Acute myeloid leukemia Myelodysplastic syndrome Megaloblastic anemias have not only large red blood cells, but also hypersegmented (usually >5 lobes) neutrophils. This is because with megaloblastic anemias there is impaired DNA synthesis. Folate and Cobalamin (B12) deficiency Folate and Cobalamin deficiency can both cause megaloblastic anemia. To understand how these two are differentiated during diagnostic lab work, it is important to understand the biochemistry of a few reactions. Both folate and cobalamin are requi...

Deep Venous Thromboembolism Proximal DVTs have a higher risk of PE than distal DVTs. Proximal DVTs are those that affect the popliteal or femoral veins. Treatment of DVT Oral direct factor Xa inhibitors (e.g. rivaroxaban, apixaban) are a better choice than the traditional warfarin heparin combination. The factor Xa inhibitors work quickly, do not require monitoring of INR, and avoid the adverse effects and restrictions associated with warfarin use. Patients who are not candidates for factor Xa inhibitors include those with poor renal function and those with malignancy associated thrombosis. Warfarin and heparin are the traditional anticoagulants used to treat DVTs. Unfractioned heparin or low molecular weight heparin (enoxaparin) must be given first as it acts quickly and works to combat the initial pro-coagulant effect of warfarin (due to the fact that warfarin first reduces protein C & S production before affecting other vitamin K-dependent factors). With this combinati...

Thrombolysis Plasminogen is converted to plasmin, and this step can be enhanced using thrombolytics/ fibrinolytics (e.g. streptokinase, tPA, and urokinase). Plasmin then acts to promote fibrinogen degradation as well as degradation of the fibrin clot into fibrin split products. The formation of plasmin from plasminogen is inhibited by antithrombolytics/ antifibrinolytics (e.g. aminocaproic acid, tranexamic acid). Thrombolytics Tissue plasminogen activator (tPA) derivatives including reteplase, alteplase and tenecteplase are fibrin-specific and act only on fibrin that is part of a recently formed clot. Because they do not act systemically, these are drugs are associated with a smaller risk of bleeding. Streptokinase and urokinase are non-fibrin specific thrombolytics that act more systemically. Contraindications to Thrombolytic Use

Aspirin Aspirin works by irreversibly acetylating platelet cyclooxygenase 1 (COX-1) resulting in decreased production of thromboxane A2. Aspirin also irreversibly acetylates COX-2 when given at high doses which results in an anti-inflammatory effect. P2Y12 Inhibitors Examples include clopidogrel , prasugrel and ticagrelor as well as ticlodipine . They work by binding to the P2Y12 component of ADP  receptors on platelets resulting in inhibition of platelet aggregation. Phosphodiesterase inhibitors Dipyridamole and Cilostazol also cause inhibition of platelet aggregation and they work by inhibiting phosphodiesterase activity which leads to elevated cAMP. Glycoprotein IIb/IIIa inhibitors Examples include abciximab , eptifibatide , and t irofiban . These work by inhibiting binding of platelet glycoprotein IIb/IIIa with fibrinogen and fibronectin. Quizlet Flash Cards

For more about  heparin  (enhances antithrombin activity) and  warfarin  (inhibits production of vitamin-K dependent clotting factors and anticoagulant proteins C & S), see their individual posts. Factor Xa Inhibitors Fondaparinux is a synthetic pentasaccharide that inhibits factor Xa. The other factor Xa inhibitors end in "xaban" and include rivaroxaban , apixaban , and edoxaban . Thrombin Inhibitors Direct thrombin inhibitors include argatroban, hirudin, and lepirudin.

Mechanism Unfractioned heparin (UFH) has a pentasacharide sequence that binds to antithrombin to form a complex. The UFH-antithrombin complex is better at inactivating factor Xa then antithrombin alone. This is because once bound to UFH, antithrombin undergoes a conformational change. The UFH-antithrombin complex can also inactivate thrombin by binding to it. Low moleculer weight heparin (LMWH) also has a pentasaccharide sequence that binds to antithrombin to form a complex. The LMWH-antithrombin complex also inactivates factor Xa, however, it doesn't work on thrombin. This is because the pentasaccharide sequence on LMWH is too short to both complex with antithrombin and bind thrombin. LMWHs typically end in "parin", examples include enoxaparin and dalteparin . Adverse effect:  Heparin-Induced Thrombocytopenia (HIT) Heparin is a common cause of thrombocytopenia. LMWH (e.g. enoxaparin) is less likely than unfractioned heparin to cause HIT.   There are two m...

Coagulation Cascade To understand the coagulation disorders, an understanding of the coagulation cascade is necessary. The coagulation cascade consists of an extrinsic and intrinsic pathway both of which end in a common pathway. The extrinsic pathway begins when damaged tissue releases thromboplastin. Thromboplastin activates factor VII and the activated factor VII then activates factors IX and X. The intrinsic pathway begins when exposure to subendothelial collagen or exposure to high molecular weight kininogen (HMWK) activates factor XII which is also known as Hageman factor. The activated factor XII then activates factor XI which goes on to activate factor X. Activated factor IX needs to be in a complex with activated factor VIII, platelet factor 3 (PF3) and calcium. Calcium is needed to bind the activated coagulation factor. The common pathway begins with activated factor X which can be arrived at by either the intrinsic or extrinsic pathways. Activated factor X forms a comp...

Mechanism Warfarin is a commonly used anticoagulant that works by inhibiting synthesis of vitamin K dependent clotting factors (II, VII, IX, and X) and proteins C and S by the liver. Specifically, warfarin inhibits the enzyme vitamin K reductase resulting in inhibition of vitamin-K dependent gamma-carboxylation of glutamic acid residues on clotting factors II, VII, IX and X. Warfarin takes a few days to start working and it first affects protein C and S production. Because proteins C and S have anticoagulant properties, warfarin, initially results in a temporary increase in the risk of thrombus formation. Therefore, before starting warfarin patients are generally given another anticoagulant such as heparin. Metabolism Warfarin is metabolized by cytochrome P450, a microsomal enzyme in the liver. Reversing the effects of Warfarin Fresh frozen plasma (FFP) restores vitamin-K dependent clotting factors, making it the quickest way to normalize prothrombin time (PT). Vitami...