Category Archives: Hematology and Oncology

Moffitt Pearls 12.15.17 + Intern Pearls

Hey Moffitt!

Sorry for delay…better late than never! Thank you to Jill and Emily for presenting a fascinating case of middle aged man with hx of chronic wounds and HCV s/p presenting with foamy urine found to have nephrotic Syndrome, possibly membranous nephropathy based on tempo, demographics and history. Unfortunately patient left the hospital AMA prior to renal biopsy.

HH’s CRANKLES Nephrotic Syndrome Mneumonic: Blast from the past!!!

C –Cardiac/pericarditis

R – renal vein thrombosis

A – Amylodosis and paraproteinemias

N – MCG, FSGS, Membranous (unusual, but possible to have MPGN or IgA Nephropathy)

K – Kimmelesteil and Wilson nodular intercapillary lesions (Diabetes – most common cause world wide)

L – Lupus

E – Eclampsia

S – Secondary syphilis

Nephrotic Syndrome

Definition: > 3.5 g urine protein/day, hypoalbuminemia (< 3 g/dL), peripheral edema. Associated HLD and thrombosis can be present. Hypertension is more common in nephrotic syndromes. 

Differential Diagnosis – see above 

Other associated findings: acute kidney injury (not always), thromboembolism (renal vein thrombosis is found disproportionately in patients with membranous nephropathy), infection (due to urinary loss of immunoglobulins), proximal tubular dysfunction

Biopsy is often necessary to reveal the definitive diagnosis. (note this is in contrast to nephritic syndrome, which can be diagnosed with examination of the urine sediment and blood work: serologies). Interestingly, Richards, et al* found that in 28 patients with nephrotic range proteinuria, histologic information obtained via biopsy altered management in 24/28 cases (86%!!!)

Treatment: Diuretics (treat edema), Ace-inhibitor (proteinuria), statin (hyperlipidemia), anticoagulation (hypercoagulability)

Membranous Nephropathy 

Epidemiology

In non-diabetics this accounts for up to 1/3 of cases of Nephrotic Syndrome. Especially common among white men.

Breakdown in primary vs secondary causes:

MN is most often primary (idiopathic), associated with the presence of anti-PLA2R antibodies (can be measured in serum); although, it has been associated with a variety of conditions, including hepatitis B antigenemia; autoimmune diseases (eg, lupus); malignancy; and the use of certain drugs such as gold and nonsteroidal antiinflammatory drugs (NSAIDs). MN may also be seen in conjunction with other glomerular diseases such as diabetic nephropathy and crescentic glomerulonephritis.

First pass work-up (per up-to-date)

  • CMP + Albumin
  • CBC
  • UA with examination of the sediment
  • Protein/Creatinine ratio or 24 urine for protein
  • Tests for hepatitis B & C  & HIV
  • Serum C3 and C4 complement levels
  • In patients older than 50 years – serum free light chains (SFLCs) and serum protein electrophoresis (SPEP) with immunofixation
  • Anti-PLA2R antibody (by enzy

Treatment

  • Based of risk if progression given low risk disease often spontaneously resolves without therapy (see link for more info).
  • First-line immunosuppressive therapy consists of cytotoxic drugs (cyclophosphamide) plus glucocorticoids or a calcineurin inhibitor with low-dose or no glucocorticoid.

Intern Report Pearls

Virchow’s Triad – RF for clotting

  1. Hypercoagulable
  2. Stasis
  3. Endothelial damage

Compartment Syndrome

  1. Pain
  2. Pallor
  3. Pulseless
  4. Poikelothermia
  5. Paralysis
  6. Paresthesias

Phlegmasia cerulea dolens (painful blue edema) is an uncommon severe form of DVT which results from extensive occlusion (blockage by a thrombus) of the major and the collateral veins of an extremity.

Evaluation of Isolated Elevated PTT

  • Contamination
  • Deficiency
  • Inhibitor – factor 8 is the most common inhibitor

When concerned about an inhibitor order a mixing study – does not correct with mixing study.

Clotting & Bleeding – Causes 

  • APS
  • DIC
  • HIT
  • Liver Disease

Management of Bleeding with Inhibitor 

Give factor back or bypass cascade – PCC or FEIBA, Novo 7

Steroids – Prednisone 1 mg/kg per day

Rituximab or Cyclophosphamide

PLEX

IVIG

Acquired Inhibitor – Causes  • Underlying Cancer

  • Exogenous exposures
  • Autoimmunity
  • Medication related
  • Pregnancy
  • Idiopathic – ~50% cases unknown cause
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Moffitt Pearls – 11.13.17 – Pulmonary Report

Thank you to Dr. Wolters for joining us today and to Tyler for presenting the case of a man w/ hx of SCC on pembrolizumab p/w 2 months of DOE & 1 wk of cough not responsive to levofloxacin. We discussed the role of ABGs > VBGs and the ddx for organizing PNA. The patient ended up having pneumonitis 2/2 to his PD-1 inhibitor which was discontinued and he was then started on steroids.

Key Pearls

  1. There are several toxicities associated with PD-1 inhibitors. See here for prior pearls on these check point inhibitors!
  2. One needs to lose ~ 50% of their lung function to have SOB @ rest!!
  3. Try to obtain an ABG in a patient who is hypercarbic given the variability of a VBG and its estimation of pCO2. Per Dr. Wolter’s the pCO2 from a VBG can be wrong ~ 20% of the time.
  4. Reverse Halo Sign (RHS) on a CT Chest is a patch of normal lung surrounded by abnormal densities . There is a ddx and figure for RHS below!

ABG vs. VBG – Thank you Kenny for sharing!!

Pathophysiology:

  • Arterial: accurate O2 content; nl pH = 7.4 (7.35-7.45), CO2 = 40 (35-45)
  • Venous: carries excess CO2 to be ventilated off in the long. ~3-5 mmHg higher than arterial blood

EvidenceSystemic review and meta analysis

  • Arterial pH ~ 0.03 higher than venous
  • Venous and arterial pCO2 do NOT correlate that well (off in ~ 20% of gases)
  • Good negative predictive value of CO2 if low, but not as helpful if high

Practical application:

  • If you want O2 status, you can use SpO2 as a surrogate marker, but ABG is more accurate
  • If concerned for pH or CO2 status and ABG isn’t easy (ie painful and technically challenging); VBG as 1st pass -> understand limitations
  • If the VBG doesn’t make sense or you want to be totally sure, get an ABG

Organizing PNA

Defined as the lung’s response and subsequent repair to any insult. Often associated with the reverse halo sign (RHS) characterized by a central clearing surrounded by denser air-space consolidation (often ground glass) in the shape of ring/crescent. This happens because in the following situations the lung heals from the center outwards. Was initially described in cryptogenic organizing PNA, however is now part of a wider DDX that includes the following:

  • Autoimmune (Sarcoid, Wegener’s granulomatosis)
  • GVHD
  • Aspiration
  • Malignancy
  • Drug effect – PD-1 Inhibitors à 5% of patient’s will develop pneumonitis @ a mean of 7 months; 85% will respond to discontinuation & steroids.
  • Infectious – endemic fungal infections, PCP PNA,
  • Idiopathic – cryptogenic

Here is a great article and figure on the evaluation of Revere Halo Sign (RHS)RHS--g013

https://www.evernote.com/shard/s307/sh/553ffa9d-b57c-4946-a6ec-8d88fac245ad/9cf66d454abb647c86ed5696e6ee1a42

VA Ambulatory Report 9.13.17 – Vitiligo, Hashimoto’s, and Pernicious Anemia

Thank you to Rabih for presenting this interested case of a young man presenting to clinic with fatigue, weight gain, hypopigmented skin lesions found to have pernicious anemia, hashimoto’s and possible vitiligo.

Key Learning Points

  • For skin hypopigmentation try to determine if there is complete depigmentation vs. hypopigmentation to narrow your differential
  • Decision to treat subclinical hypothyroidism is based on level of TSH elevation, age, CV risk factors, and symptoms
  • Consider pernicious anemia as a cause of B12 deficiency especially in patients with other autoimmune diseases

 

Hypopigmentation of the skin

  • First try to determine if it is complete depigmentation or hypopigmentation.  This can be difficult especially in lighter skin individuals.
    • Degpimentation
      • Vitiligo – most frequent cause of depigmentation
        • Loss of epidermal melanocytes
        • Etiology not known, but associated with autoimmune diseases
        • No racial or ethnic propensity but often causing more impact on darker skin individuals due to is being more disfiguring
      • Consider exposures to chemicals (such as those found in hair dyes, insecticides, adhesives) or meds (topical steroids, imatinib, pegylated interferon)
    • Hypopigmentation
      • Commonly seen after an inflammatory skin process
      • Infections – pityriasis versicolor, leprosy, syphilis, non-syphilis treponema, onchocerciasis
      • Atopic – pityriasis alba
      • Rheumatologic causes – scleroderma, discoid lupus
      • Acquired
        • idiopathic guttate hypomelanosis – seen with aging
        • progressive macular hypomelanosis – unknown cause, possibly related to infection, typically seen in young adults, more common in darker skin individuals
      • Nutritional deficiencies – B12, copper, iron, kwashiorkor
      • Endocrinopathies – hypopituitarism, Cushing syndrome,

 

Subclinical Hypothyroidism

  • Definition: Elevated TSH with Normal T4
    • Always recheck after 2-3 months given these are numbers are dynamic to confirm subclinical hypothyroidism
  • When should we treat subclinical hypothyroidism? Based on TSH level, age, symptoms, TPO antibody status, and CV risk factors
    • TSH >10
      • Treat all patients <70
      • For patients >70 only treat if symptoms are present or have +TPO antibody
    • TSH 7-10
      • If symptoms are present
      • If patient is <70 and has cardiac risk factors or has +TPO
        • Patients who are younger and have +TPO antibodies are more likely to progress to overt hypothyroidism
    • TSH 4-7 AND
      • Symptoms of hypothyroidism: consider 6 month trial of treatment but stop therapy is symptoms do not improve with treatment
  • See this discussion in NEJM for more review of subclinical hypothyroidism
  • Recent study in NEJM showed no benefit to treating subclinical hypothyroidism in adult s> 65 years

 

Pernicious Anemia Fun Facts

  • What is pernicious anemia? Anemia due to autoimmune atrophic gastritis.
    • Autoanitbodies to intrinsic factor and parietal cells –> Loss of parietal cell mass –> hypochlorhydria and inadequate production of intrinsic factor –> B12 malabsorption –> anemia
  • It is called pernicious anemia because when it was described patients symptoms would progress gradually over time without available treatment
  • Diagnosis
    • Macrocytic anemia, low B12
    • Autoantibodies to parietal cells and intrinsic factor
      • Antibodies to IF are specific but not sensitive
      • Antibodies to parietal cells have better sensitivity, but only ~80%
      • If high enough concern and negative antibodies, may need EGD with biopsy demonstrating atrophic gastritis in the gastric body
    • Can also check serum gastrin which will be elevated
  • 40% of patients will have autoimmune thyroid disease
  • There is a theory that H. pylori infection may trigger the autoimmune destruction of parietal cells. However patients with pernicious anemia are less likely than age matched controls to have h. pylori. Associated with H. pylori infection thought possibly due to active infection gradually replaced by an autoimmune process
  • Increased risk of gastric neuroendocrine tumors and adenocarcinoma

Moffitt Pearls 7.10.17 – PD-1 Inhibitors & PCP Pneumonia

Pulmonary Report 7.10.17

Thank you to Ugo for presenting the case of an elderly male with widely metastatic melanoma refractory to PD1 inhibitors presenting with 1-2 weeks of fatigue, FTT, DOE found to have PCP pneumonia!

Top Pearls:

  • PD1 inhibitors are considered first-line therapy for metastatic melanoma.
  • Common toxicities of immune check point inhibitors include immune-mediated inflammation of virtually any organ system. See below for more details on PD1 inhibitors.
  • The risk for opportunistic infections w/ checkpoint inhibitors is related to the steroids that are generally given to treat the checkpoint inhibitor toxicities. A case report & paper (https://www.ncbi.nlm.nih.gov/pubmed/27501841) illustrating this risk.
  • Remember! For patients on steroids if > 20 mg/day of prednisone for > 2 weeks –> give PCP prophylaxis. (per expert opinion -> the rule of Dr. Jen B!)

Which patient that are immunocompromised get PCP?

  • HIV-positive patients (CD4 < 200)
  • Cancer, solid organ transplant, BMT – related to type & chemo intensity
  • Rheumatologic (GPA has intrinsic risk)
  • Chronic steroids (see Jen rule above)

Steroids for Rx of PCP in HIV-Negative patients??

  • Not well studied in HIV-negative patients, only a few retrospective studies
  • No mortality benefit, but may expidite recovery
  • Steroids are recommended in the AJT guidelines
  • 40-60 mg Prednisone BID x 5-7 days with 7-14 day taper

 

Table Comparing PCP in HIV Positive and Negative Patients (thanks Jen!)

table PCP

 

PD-1 Inhibitors (blast from the past)

pd1

Emerging data show that 20% of patients with melanoma treated with ipilimumab achieve long-term survival! See this associated review.

PD-1 (programmed cell death 1) and its association with the ligand (PD-L1) is a necessary step in stimulating apoptosis of T-cells, serving as an immune checkpoint. PD-L1 is generally expressed by native cells, signaling to the T-cell “I’m one of you! Don’t hurt me”.  Some tumors have been found to also express PD-L1, enabling them to evade destruction by T-cells.  In order to treat these malignancies, PD-1 inhibitors (pembrolizumab, nivolumab) serve to block the interaction between PD-1 and PD-L1, enabling T-cells to stay “programmed on”, and thus enable immune-mediated destruction of tumor.

Because of this mechanism of action, a common consequence is the upregulation of cell-mediated immunity and, unfortunately, inhibition of native tissues to turn off T-cells. As a result, we commonly see autoimmune-mediated inflammation manifested as new rash, diabetes, thyroid disease, pneumonitis, hepatitis, colitis, etc.

Common Immune-Mediated Toxicities Seen with Check-point Inhibition:

Organ System Manifestation Management
Skin & Mucosa Pruritic rash (most common!)

Alopecia

Vitiligo

Mucositis

Topical corticosteroids

Oral antipruritics

Consider oral steroids

GI Tract Diarrhea/colitis – presents ~6wks into treatment R/O infxn

Anti-motility agents

Steroids if severe

Liver Hepatitis (rate <5%, severe toxicity very rare) Stop therapy if moderate-severe.

Steroids + mycophenolate given rarely.

Lung Pneumonitis – (rate <5%, but occasionally fatal) Steroids common. Infliximab, cyclophosphamide also used, though patients requiring therapy beyond steroids have nearly 100% mortality.
Endocrine Hypophysitis

Autoimmune thyroid disease

Adrenal Insufficiency T1 DM

Hormonal replacement

Steroids

Less commonly reported immune-mediated adverse events include the following: acute renal injury, pancreatitis, neurotoxicity (GBS, myasthenia gravis, PRES, aseptic meningitis, autoimmune encephalitis), cardiotoxicity (myocarditis), hematologic (cytopenias), and ocular inflammation.

Many of the adverse events described above can be managed with continued use of PD-1 inhibitors if mild. However, for severe adverse reactions, PD-1 inhibitors are withheld and potential discontinued permanently.

Moffitt Pearls 7.5.17 – Wilson’s Disease & Hemolytic Anemia

Thank you to Vincent for presenting a challenging case of a young woman with anxiety and depression presenting with unexplained jaundice and cirrhosis, later representing with a severe, hemolytic anemia. Although similar to a prior case presented last month then this was a second presentation of possible Wilson’s disease

 Top Pearls:

  1. Acute alcoholic hepatitis is a chronic disease (despite the name!). Presentation is based on predominantly cumulative burden – a single binge in a patient with otherwise minimal alcohol intake is unlikely to cause severe alcoholic hepatitis.
  2. In a young patient (< 35 yo) with new diagnosis of cirrhosis, consider genetic causes including Wilson’s, hemochromatosis, alpha-1 antitrypsin disease, autoimmune hepatitis, PBC, PSC. Vascular disease and infectious hepatitis should also be considered.
  3. The combination of liver disease and hemolysis raises concern for Wilsonian Crisis, which can herald impending acute liver failure.

Laboratory Diagnosis of Tumor Lysis Syndrome

Alcoholic Hepatitis

The clinical syndrome of acute alcoholic hepatitis includes the following compilation of laboratory and clinical features:

  • Moderately elevated transaminases in a 2:1 ratio of AST/ALT
  • Typically less than 300, rarely greater than 500
  • Elevated bilirubin and Jaundice
  • Jaundice generally develops within 3 months prior to presentation
  • Fever & Neutrophilic Leukocytosis
  • Both should only be ascribed to alcoholic hepatitis after ruling out infection!
  • Right upper quadrant pain – can often palpate tender hepatomegaly
  • Clinical history of chronic drinking with or without recent bing
  • It’s not uncommon that patients have actually decreased their drinking in the weeks-months preceding acute alc hep due to the onset of symptoms with alcohol intake.

See this RCT from NEJM regarding pentoxifylline vs. prednisolone for the treatment of alcoholic hepatitis. Bottom line:  Acute alcoholic hepatitis is a profoundly morbid disease with very high mortality (30-40% in 6 months).  Prednisolone was associated with a reduction in 28-day mortality, but did not reach significance and there were no improvements in 90-day or 1 year mortality.

Autoantibodies Associated with Causes of Cirrhosis

 

Autoimmune hepatitis

IgG, ANA, antismooth muscle Ab, anti-liver-kidney microsome-1 Ab, anti-liver cytosol Ab-1

Primary biliary cirrhosis

ANA, anti-mitochondrial Ab

Primary sclerosing cholangitis

IgM (40-50%), p-ANCA (30-80%)

Wilson Disease (WD) & Hemolytic Anemia

  • Wilson’s disease (WD) is an inherent disease, caused by mutations in the ATP7B gene leading to decreased excretion of copper into the bile
  • Copper accumulation results in injury to the liver and the central nervous system (thank you Muazzum for you amazing neuro ROS)
  • WD presents in a fulminant form with hepatocellular dysfunction, hemolysis and various multiorgan failures (Wilson’s crises)
  • Wilson disease can cause a Coombs-negative hemolytic anemia WITHOUT schistocytes reported in the literature
  • The exact mechanism of the haemolytic process has yet to be defined. copper inhibits sodium potassium ATPase in the erythrocyte leading to haemolysis (and likely without schistocytes as in this case).
  • Medical treatment includes chelating agents and/or zinc, but these have not proved effective in fulminant liver failure, where only liver transplantation (LTx) is regarded as lifesaving.
  • Some limited data for plasmapheresis for rapid copper removal
  • Portends very poor prognosis, often leading to acute liver failure

 (see attached an article on a review of Wilson’s and Hemolytic anemia compliments of HH!!)

Blast from the past!!! Approach to Hemolytic Anemia (thank you Katie!!)

 

 

https://www.evernote.com/shard/s307/sh/16c1d172-fb95-4da7-93b0-d85e5c25854f/3768012329b5e8d8e358cacd312f033a

ZSFG Morning Report 6.12.2017 – High Flow Oxygen and PD-1 inhibitors

Thank you to the ICU team and Bennett Caughey for presenting the case of a middle-aged woman with advanced metastatic SCC of the lung, who presented with hypoxia and respiratory distress after esophageal stent placement.

Take Home Points

  • Escalating hi-flow oxygen needs should warrant ICU evaluation.
  • Differential for noninfectious causes of cavitary lung lesions includes neoplasm. SCC is the primary lung malignancy most likely to cavitate.
  • PD-1 inhibitor therapy can cause pneumonitis, but is a diagnosis of exclusion; infection and malignancy should be excluded. Median duration of treatment prior to development of pneumonitis is 2.8 months.

……………………………………………………………

High flow oxygen

  • What is it? Heated and humidified air that allows for comfortable delivery of higher flow oxygen
  • No specific threshold that absolutely warrants ICU level care (institution dependent) but an escalating requirement is worrisome and should prompt ICU evaluation
  • Liters per minute (LPM) and FiO2 are the two variables that can be manipulated, again this is institution dependent
  • High flow oxygen also provides a small amount of positive pressure. Also found to have decreased 90-day mortality in pts with nonhypercapnic acute hypoxemic respiratory failure.

What you need to know about PD-1 inhibitors:

  • PD1 stands for programmed cell death 1, and is involved in check point signaling pathway
  • PD1 inhibitors block normal inhibition response, and therefore boost immune response against cancer cells.
  • Nivolumab and pembrolizumab: currently being used in pts with advanced melanoma and non-small cell lung cancer.
  • The most common immune-related adverse events are typically transient, but can occasionally be severe or fatal. The most commonly implicated organ systems are dermatologic, diarrhea/colitis, hepatotoxicity, and endocrinopathies.
  • Overall incidence of PD-1 inhibitor related pneumonitis is ~5%
  • In general, mild symptoms can be observed and PD-1 therapy can be withheld. In more severe cases, checkpoint inhibitor therapy should be permanently discontinued, and consider use of steroids.

MOFFITT ENDOCRINE REPORT PEARLS 5/17/17: Hypercalcemia of Malignancy and PTHrP!

Hey Everyone! Thanks to Vaibhav for presenting the case of an older woman with newly diagnosed bladder cancer who presented with weight loss and failure to thrive, found to have severe hypercalcemia with workup pending. We suspected she might have PTHrP-mediated hypercalcemia, a known association with urothelial carcinomas. Pearls on PTHrP below!

*******************************************

Top Pearls:

  1. PTHrP is the most common cause of hypercalcemia in non-metastatic solid tumors
  2. PTHrP-related hypercalcemia is typically a finding in advanced disease with poor prognosis
  3. PTHrP acts primarily on bone and kidneys to cause hypercalcemia, not the GI tract

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For those who want more info:

Check out Myung’s pearls on hypercalcemia:

https://ucsfmed.wordpress.com/2017/02/15/hypercalcemia/

*Important general pearls on hypercalcemia of malignancy: 1) It occurs in 10-30% of patients with advanced tumors. 2) It is the most common cause of hypercalcemia in the inpatient setting. 3) Prognosis is poor (up to 50% 30-day mortality).

Now some more specific info on PTHrP!

What is PTHrP?

  • Normal gene product expressed in several tissues
  • Also called humoral hypercalcemia of malignancy (HHM)
  • The most common cause of hypercalcemia in patients with non-metastatic solid tumors
  • Most often in patients with advanced disease and poor prognosis (not usually an early finding)
  • Solid tumor associations: SCC, renal/bladder, breast, ovarian
  • Liquid tumor associations: NHL, CML (blast phase), T-cell leukemia/lymphoma

How is PTHrP related to PTH?

  • First 13 N-terminal amino acids are homologous to PTH (PTH = 84 AAs, PTHrP =139-173 AAs)
  • Binds to same PTH-1 receptor as PTH: bone resorption, renal Ca reabsorption/phos wasting
  • Structural divergence after first 13 amino acids: less likely to stimulate 1,25 vit D production, does not increase intestinal Ca absorption
  • Thus, PTHrP hyperCa is from bone/renal only, while PTH hyperCa is also from GI
  • Lab findings in PTHrP hyperCa: 1) elevated PTHrP, 2) low PTH, 3) normal/low 1,25-vit D

How is measurement of PTHrP useful (aside from diagnosis)?

  • Tumor marker: helps to assess treatment response
  • Prognostic marker: worse survival if PTHrP level > 12 pmol/L, which predicts less robust response of hyperCa to bisphosphonate therapy

HyperCa Malignancy

Evernote: https://www.evernote.com/shard/s272/sh/f935a1b0-b47f-45e7-8ef0-611a9c5c1e55/ba948d973b82ab3470b7c86533c6a7d7

 

Have a great day everyone!

SamMy