10/10 HUP Report – Small Bowel Mass

Today we discussed an interesting case of a patient with longstanding Crohn’s disease, well-managed off immunosuppression, who presented with an enterovesicular fistula. This is actually a really RARE complication of Crohn’s disease (approximately 3%), and almost always requires surgical intervention. Aside from being secondary to active inflammation from his IBD, this new clinical finding could be secondary to a small bowel neoplasm (small bowel cancer is also really rare, but the rate is increased in Crohn’s disease patients).

Here is our basic differential for a small bowel mass:

Malignant

  • Neuroendocrine tumor
  • Adenocarcinoma
  • Sarcoma
  • Lymphoma
  • Metastatic disease (hematogenous spread or direct spread from peritoneal carcinomatosis)

Benign

  • Lipoma
  • Fibroma
  • Leiomyoma
  • Adenoma
  • Desmoid tumor

Infectious

  • Tuberculosis
  • Abscess
  • Histoplasma

This patient’s biopsy was consistent with neuroendocrine tumor, and he had numerous metastases — this is a common finding at the time of diagnosis due to indolent and asymptomatic growth in many patients. First line treatment for neuroendocrine tumors is usually somatostatin receptor analogues. Symptomatic surgical debulking or curative surgical resection can be considered in appropriate candidates, but is less common. Prominent symptomatic liver mets can be managed with ablation techniques. Systemic chemotherapy can be attempted for refractory disease — everolimus, bevacizumab, and sunitinib have been used.

 

 

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10/4 Presby report: diagnosis of NSCLC, new targeted agents

Today we discussed the case of a middle aged man with newly diagnosed metastatic non-small cell lung cancer; this is a hot area because there have been a lot of exciting new developments in this area over the past few years– particularly the development of several new targeted agents and immune therapy.

Here’s a diagram showing the approach for a patient with newly diagnosed NSCLC:

Screen Shot 2017-10-05 at 4.39.55 PM.png

NEJM 2017

Takeaways

  • There are a growing list of targeted therapies based on driver mutations for NSCLC, noted in the table below
  • PD1 or PDL1 expression is important in determining the patient’s eligibility for immune therapy; 50% is the usual cut-off
    • Note that metastatic lesions may have different PD1 or PDL1 expression than the primary tumor; the reason for this is unclear, but basically means that they may still be a candidate for immune therapy even if the originally biopsied tumor had low PD expression
  • For EGFR positive patients that have disease progression on a 1st line agent like afatinib, you can get more tumor tissue and look for the T790M mutation which would make them a candidate for osimertinib (which per recent data is increasingly being used as a first line therapy for patients with EGFR exon 19 or 21 mutations)
  • It is exceedingly rare for more than one driver mutation to occur in one patient; if that happens, it may mean there are two primary cancers which would also be unusual
  • These targeted therapies don’t have the same adverse effects as standard chemo, so oncologists may have a lower threshold for giving them to patients with low performance status
Screen Shot 2017-10-04 at 9.59.31 AM

NEJM 2017

 

Lastly, remember that there is a trial showing the survival benefit of early palliative care in NSCLC. Obviously this finding can be extended to other types of malignancies, but at least here at Penn is mostly limited by the availability of access to palliative care.

References

  1. Precision Diagnosis and Treatment for Advanced Non–Small-Cell Lung Cancer. NEJM 2017.
  2. Temel J et al. Early Palliative Care for Patients with Metastatic Non-Small Cell Lung Cancer. NEJM 2010.

10/4 HUP Report: Systemic Mastocytosis

Today we discussed a case of a 37 year old male with history of recurrent and progressive episodes of hypotension and flushing, who was ultimately diagnosed with systemic mastocytosis. Here are some facts from our report!

 

Differential for Hypotension and Flushing (not comprehensive!)

  • Anaphylaxis
  • Mastocytosis
  • Endocrine tumors
    • VIPoma
    • Pheochromocytoma
    • Carcinoid
    • Medullary thyroid cancer
  • Idiopathic capillary leak syndrome
  • Medication overdose (niacin, PDE5 inhibitor, calcium channel blocker, ACE inhibitor)
  • Toxin – scromboidosis

Mastocytosis

  • Distinguished between cutaneous and systemic forms — WHO classification belowmastocytosis

 

  • Clinical features of flushing and hypotension with involvement of the cardiovascular, gastrointestinal, and nervous systems in the absence of urticaria, angioedema, and upper-airway involvement suggest systemic mastocytosis
  • Symptoms result from mast cell mediators or direct organ infiltration
    • GI –> abdominal pain, emesis; acute abdomen and negative ex-lap
    • Recurrent anaphylaxis –> can be allergy/IgE mediated or nonspecific trigger
    • Neuropsychiatric –> depressive symptoms (wide range)
    • Musculoskeletal –> osteoporosis, pathologic fractures, lytic or sclerotic bone lesions
    • Cardiac –> epicardial coronary vasospasm from supraphysiologic histamine levels (called allergic angina, Kounis syndrome, hypersensitivity coronary syndrome)
  • Elevated total tryptase when patient is asymptomatic supports the diagnosis
    • Total tryptase is preformed in mast cell granules — surrogate for mast cell burden
    • B-tryptase is released during mast cell activation
    • Both will be elevated if measured during acute symptoms
    • Total tryptase will remain elevated and B-tryptase will normalize when asymptomatic in mastocytosis
  • Confirm dx with BMBx/aspirate
      • Associated with clonal hematologic neoplasm of non-mast cell lineage in 30-40% of cases
        • Determines prognosis
        • Often share KIT mutation and cytogenetic abnormalities with the mast-cell proliferation, indicating an origin from a common precursor cell
      • Need to exclude myeloid neoplasm with FIP1L1PDGFRA rearrangement
        • response to specific targeted therapies, such as imatinib mesylate, that are ineffective in systemic mastocytosis

Management

  • Aggressive systemic involvement or mast cell leukemia should be treated with cytoreductive therapy
    • First line is midostaurin (multikinase/TKI inhibitor)
    • Allogeneic stem cell transplant (if response to chemotherapy) can be curative, but high rates of post-transplant complications
  • If associated heme neoplasm, treat that process
  • Indolent mastocytosis should be treated with symptomatic management, trigger avoidance, and anaphylaxis preparedness
    • H1 and H2 blockade
    • Montelukast
    • Disodium cromoglycate (inhibits release of mediators from mast cells)
    • EpiPen x 2

 

Murali MR, Castells MC, Song JY, et al. Case records of the Massachusetts General Hospital. Case 9-2011. A 37-yearold man with flushing and hypotension. NEngl J Med 2011;364:1155-65.

 

 

 

 

 

 

9/18 HUP Report: IBS and Porphyria

Today we reviewed a case of a patient with chronic bouts of acute abdominal pain.  In doing so, we discussed the differential for chronic abdominal pain, reviewed the diagnostic criteria for the key diseases of chronic abdominal pain, and discussed porphyria.  Some of the key features of the case are noted below, and you can read more about this topic in the most recent NEJM.  Remember, this diagnosis is no rarer than pheochromocytoma, and we work that up all the time!

 

IBS Diagnostic Criteria – Symptoms 1 day per week for 3 months and 2-of-3 of the below symptoms:

  1. change in stool frequency
  2. change in stool form
  3. pain relieved by defecation

IBS can then be classified as predominanty diarrhea or constipation.  If a patient is in the diarrhea category, you must also think about IBD and Celiac disease.  The screen for IBD is ESR/CRP or Fecal Calprotectin, and the screen for Celiac is a CBC to look for anemia.

 

In this case, the key to the diagnosis was that the patient had a history of depression, her abdominal symptoms were associated with neurologic symptoms (brain fog), and her labs revealed a mild hyponatremia.  This is a classic presentation for Acute Intermittent Porphyria (AIP), although neurologic manifestations can be as severe as seizures.  We then reviewed a clinical approach to porphyria.

 

Visceral Porphyria – AIP is the most common form, although there are many other rarer types that you will probably never see.  If you suspect any visceral porphyria, check a urine porphobilinogen during a flare.  A positive test is diagnostic of AIP; if that test is negative, but you really think it’s porphyria, refer to online algorithms for next steps to evaluate the rarer forms of visceral porphyria.  Treatment is centered around giving Hematin therapy and avoiding offending medications.

 

Cutaneous Porphyria – These diseases do not cause abdominal pain, and were not implicated in this case, but we reviewed them for completeness.  The most common type is Porphyria Cutanea Tarda, and is often associated with other underlying causes (HIV, HCV, Hemochromatosis, Alcoholic Cirrhosis).   You should suspect this diagnosis when a patient burns too easily and has more severe sun reactions like blistering.  The diagnostic test is serum porphyrins.

9/11 PPMC report: PD-1 inhibitors, myocarditis

Thanks to Kari Torp for presenting a cool case of a middle aged woman with lung cancer who developed ventricular tachycardia after receiving pembrolizumab for NSCLC and was found to have pembrolizumab-mediated myocarditis.

Pearls

PD1 (programmed death-1) and CTLA4 inhibitors are relatively novel drugs used to treat a growing list of cancers (NSCLC, melanoma, Hodgkin’s lymphoma, head/neck cancers and others) under the umbrella of immune therapy.

These drugs basically unleash the immune system to fight cancers by blocking certain costimulatory molecules that would have kept T-cells quiet.

Screen Shot 2017-09-11 at 11.48.17 AM.png

Journal of Clinical Oncology

  • Most common side effects of immune therapy (PD1 or CTLA4)
    • fatigue
    • rash (30-40%), 3-4 weeks into treatment
    • colitis/diarrhea (~5-20%, esp CTLA4 agents), 6 weeks into treatment
    • pneumonitis (~5%), 3-4 months into treatment
    • Other: hepatitis, endocrinopathies, neurotoxicity (rare; transverse myelitis, MG), uveitis, and rarely myocarditis (<0.5%)
  • Myocarditis (and/or myositis) is more common with combined PD1 blockade (ex: nivolumab + ipilimumab)
  • Myocarditis should be treated with high dose steroids (1mg/kg), but may progress despite that even in the absence of underlying cardiac disease

We also touched briefly on the differential for elevated cardiac biomarkers in the absence of ACS and the differences between troponin I and T. See this old blog post for more info!

Finally- see reference #3 below for a review on myocarditis.

References

  1. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. NEJM 2016.

  2. Immune Checkpoint Blockade in Cancer Therapy. Journal of Clinical Oncology 2015.
  3. Myocarditis. Lancet 2011.

 

8/28 (HUP): Acquired Hemophilia A

With the help of heme-onc fellow Dr. Allyson Pishko, we went through the case of a patient with kappa light chain multiple myeloma who initially presented to his PCP with shoulder pain and was found to have a rotator cuff tear and large intramuscular hematoma.  His labs were notable for a 4g hemoglobin drop over 3 weeks and an isolated elevated aPTT to 90.  Ultimately, our patient was diagnosed with an acquired factor VIII inhibitor as the cause of his coagulopathy and bleed.

Coagulation Cascade

We reviewed that an isolated prolonged aPTT can be secondary to inherited causes (hemophilia A or B, factor XI or XII deficiency, deficiency of the contact factors including kininogen and prekallikrein, and von Willebrand disease) or acquired causes (heparin, inhibitors to factors VIII, IX, XI, XII, acquired von Willebrand disease, or lupus anticoagulant).

A history of bleeding is key in narrowing this differential:

  • Patients with inherited or acquired deficiencies in factor VIII or factor IX can present with significant and often life-threatening bleeding.
  • Patients with inherited or acquired von Willebrand disease may present with easy bruising or mucosal bleeding, or only with laboratory abnormalities.
  • Patients with acquired or inherited deficiencies of factor XI, factor XII, or the contact factors usually do not have significant bleeding and present more commonly with an isolated prolonged aPTT discovered incidentally on labs.
  • Patients with lupus anticoagulant present with thrombosis rather than bleeding.

We next reviewed the work-up of a prolonged aPTT in a bleeding patient:

  • Mixing Study: Differentiates a factor deficiency from a factor inhibitor.
    • Patient’s plasma and normal pooled plasma are mixed and aPTT is measured over 1 to 2 hours.
    • If the aPTT corrects, the patient has a deficiency of factor VII (which has been corrected by the addition of normal factors in the pooled plasma).
    • If the aPTT does not correct, the patient likely has an inhibitor (which also inhibits the normal factors in the pooled plasma). Some inhibitors will demonstrate “slow reaction kinetics”, in which the aPTT initially corrects, but over time becomes prolonged again as the inhibitor exerts its activity.
    • Our patient’s aPTT remained abnormally prolonged on the mixing study, suggesting the presence of an inhibitor.
  • Factor Assays:  Identify which factor has been affected by an inhibitor.
    • Our patient’s assay showed <1% factor VIII activity, confirming the diagnosis of an acquired factor VIII inhibitor.
  • Bethesda Assay: Confirms the presence of a factor VIII inhibitor AND quantifies the strength of the inhibitor.
    • Serial dilutions of the patient’s plasma are made with normal plasma.  The reciprocal of the dilution at which factor VIII activity is 50% is called the Bethesda Unit.  The stronger the inhibitor, the more dilutions required to attain 50% factor VIII activity, and the higher the Bethesda Units.
    • A low titer inhibitor is considered <5 Bethesda units and a high titer inhibitor is consider >5 Bethesda units.
    • Our patient had a Bethesda assay of 9 units.

A few notes on acquired factor VIII inhibitors (acquired hemophilia A):

  • Associated with pregnancy and the post-partum state in young patients and with rheumatic disease (RA and SLE), malignancies (solid>liquid), and drug reactions in older patients.  In up to one half of patients, an associated disorder is not identified.
  • Patients present with large hematomas and severe mucosal bleeding. Bleeding can be severe and life-threatening, including intracranial hemorrhage and retroperitoneal bleeds, so inpatient monitoring is essential while managing these patients.

We discussed that inhibitors can also be acquired in patients with inherited hemophilias, but in contrast to the presentation above, these inhibitors develop against the factor preparations that patients have been receiving for prophylaxis or treatment of bleeding due to their genetic condition.  These inhibitors are most common in patients with severe hemophilia and low factor VIII levels to begin with (immune system recognizes factor infusions as foreign) and can make management of bleeding in these patients challenging.  The Bethesda Assay is also used in these patients to quantify and trend inhibitor activity.  See this week’s NEJM for an RCT using a new monoclonal antibody agent as prophylaxis in patients with hemophilia A and factor VIII inhibitors.

Finally, we reviewed the goals for management of acquired factor VIII inhibitors: 1) control bleeding, 2) eradicate the inhibitor, and 3) treat the underlying disease.

Agents available to control bleeding come in two flavors.

  • Replacement agents: DDAVP, human factor VIII concentrate, and recombinant factor VIII concentrate.
    • Generally reserved for patients with no or only very mild bleeding and low Bethesda units as it is otherwise difficult to overcome the inhibitor with large quantities of factor VIII.
  • Bypassing agents: Activated prothrombin complex concentrate (aPCC; includes factors II, VII, IX, X; also called FEIBA or Factor Eight Inhibitor Bypassing Agent), recombinant activated human factor VIIa (Novo-7), and recombinant porcine factor VIII.
    • Used in most patients to bypass the need for factor VIII by utilizing the extrinsic coagulation pathway.  The major risk with these activated agents is thrombosis.

Eradicating the inhibitor is done with immunosuppression, usually prednisone +/- rituximab or cyclophosphamide.

Our patient received Novo-7 and FEIBA to control bleeding, then was started on prednisone and rituximab with normalization of his factor VIII activity and aPTT over the next several months.

REFERENCES:

1. Kruse-Jarres, et al. Acquired hemophilia A: Updated review of evidence and treatment guidance. American Journal of Hematology 2017.

2. Eby, CS. Bleeding and Thrombosis Risks in Plasma Cell Dyscrasias. American Society of Hematology Education Program 2007.

3. Oldenburg, et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. NEJM 2017.

8/24 (HUP): malignancy-induced TMA

Thanks to Amy Forrestel for presenting a crazy case today of a 48 year old man who presented with uremia and a presenting Cr of 25, and was ultimately diagnosed with a thrombotic microangiopathy (TMA) secondary to underlying multiple myeloma.

What is a TMA?

TMAs are defined by the presence of arteriolar and capillary vessel wall abnormalities that cause microvascular thrombosis. The hallmark triad of TMA is microangiopathic hemolytic anemia + thrombocytopenia + acute kidney injuryRemember, however that the presence of all three of those features is not specific for TMA, and can be representative of other conditions (see chart below) that manifest similarly. Also keep in mind that many of these disease entities share common pathophysiologic features, and as we were reminded by Dr. Hogan, the biology of TMAs is evolving and far from fully understood. 

Screen Shot 2017-08-24 at 9.44.55 AM.png

See this excellent NEJM review about primary TMA syndromes.

  1. When someone presents with the TMA triad (MAHA+thrombocytopenia+AKI), the first priority is to rule out TTP (caused by ADAMTS13 deficiency), as that requires emergent plasma exchange.
  2. Send off an ADAMTS13 level; less than ~10% activity suggests TTP (although some malignancies can decrease levels)– but don’t hesitate to empirically start plasma exchange (PEX/PLEX) and adjunctive steroids if you have a high suspicion for TTP and are waiting for ADAMTS13 to result.

In trying to differentiate clinically amongst the primary TMAs, a few pearls:

  • Have a high suspicion for Shiga-toxin mediated TMA in patients that present with diarrhea (although other TMAs can present with nonspecific GI sx as well)
  • Drug-induced TMA has been linked to quinine (found in tonic water, bitter lemon, antimalarials) most commonly, as well as quetiapine, gemcitabine, and in those that intravenously abuse oxymorphone. Classically, patients who become symptomatic from quinine-induced DITMA will remember the exact moment when they started to feel crummy (see this excellent NEJM case challenge on it which gives a great explanation). See picture below for suspected mechanism.

    Screen Shot 2017-08-25 at 10.55.09 AM.png

    NEJM 2017

  • TTP tends to have less severe AKI compared to the other TMAs, maybe because it’s a problem with ADAMTS13, and not an intrinsic immune-mediated problem with the renal vascular endothelium
    • The risk of post-TMA CKD varies between different causes of TMA (ex: high in quinine-induced TMA, low in Shiga-toxin TMA)
  • Complement-mediated TMA (aka atypical HUS) is very rare, and is sort of a diagnosis of exclusion (unless you’re able to send off testing for genetic complement mutations, which only a few places do); once you’ve excluded TTP (using a normal ADAMTS13 level) and the other TMAs by history, you can settle on complement mediated TMA (aka ‘atypical HUS’)
    • If complement-mediated TMA is suspected, eculizumab (a monoclonal antibody to C5 which blocks membrane attack complex formation) should be started ASAP.
    • Eculizumab caveats: very expensive (~$400K/year), and puts patients at high risk for invasive meningococcal infections (as well as Strep pneumo and H. flu B)
  • Random pearl: vasculitis causes glomerulonephritis most commonly; the absence of proteinuria does not rule out vasculitis, and in fact microscopic hematuria on UA is more sensitive for renal vasculitis than the presence of protein

Finally, see the algorithm below for an approach to TMAs

Screen Shot 2017-08-25 at 10.52.20 AM.png

UpToDate 2017

 

 

References

  1. Legendre et al. Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic-Uremic Syndrome. 2013 NEJM. 368 (23) 2169-81.
  2. Syndromes of TMA. NEJM.
  3. CDC MMWR. High Risk for Invasive Meningococcal Disease Among Patients Receiving Eculizumab (Soliris) Despite Receipt of Meningococcal Vaccine. 
  4. Approach to the patient with suspected TMA. UpToDate.