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.
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10/5 Presby report: possible PID

Thanks to Jake Martin and Malcolm Kearns for presenting a perplexing case of a young woman with several days of high fevers and abdominal pain, which later progressed to include transaminases in the 400s, a CK >1000, and RUQ pain–> all of which was ultimately thought to be due to pelvic inflammatory disease (although that’s not completely confirmed)!

What is pelvic inflammatory disease?

  • PID is an ascending infection that goes up from the cervix up to the uterus, fallopian tubes, ovaries and can even spread intraperitoneally, leading to liver capsule inflammation (Fitz-Hugh-Curtis syndrome)
    • PID can lead to high rates of infertility despite treatment: in one study, ~20% of women with treated PID reported infertility or ectopic pregnancy, suggesting that inflammation itself could lead to long-term damage despite adequate antimicrobial treatment

Clinical manifestations/microbiology

  • PID encompasses a broad spectrum of clinical manifestations (see table below)
    • Acute symptomatic PID: acute lower abdominal/pelvic pain, pelvic organ tenderness, possibly abnormal uterine bleeding or dyspareunia, RUQ pain if perihepatitis. Fever may not be present.
    • Subclinical PID: more indolent, with more atypical manifestations
    • Chronic PID: low grade fever, abdominal pain and weight loss over a long period, particularly associated with TB and Actinomyces (?association w/ IUDs)
Screen Shot 2017-10-05 at 2.53.41 PM.png

NEJM 2015

Diagnosis

PID is a clinical diagnosis, requiring:

  • Pelvic organ tenderness (CMT, uterine compression tenderness on bimanual exam, adnexal pain) PLUS
  • Lower GU tract inflammation (endocervical exudate or as yellow/green mucus on swab placed gently into the cervical os (positive “swab test”); cervical friability or increased WBCs on wet mount of vaginal secretions

The presence of fever or leukocytosis can help, but are not necessary. Imaging (TVUS, CT, MRI) can also be helpful: thickened, fluid-filled tubes/oviducts with or without free pelvic fluid could represent salpingitis, or tubo-ovarian abscess.

Unfortunately this clinical diagnosis only about 60-70% sensitive, which highlights the importance of empiric treatment given the high risk of withholding antibiotics.

All patients w/ suspected PID should undergo: vaginal exam w/ wet mount of secretions (to evaluate for increased WBCs), GC testing, HIV, RPR, pregnancy test, +/- ESR/CRP

We touched on the testing characteristics of GC testing. You can test for GC using NAAT (= gold standard), culture or gram stain.

  • For women, NAAT screening obtained by vaginal swab is best; endocervical swab is fine if you’re doing a pelvic exam anyway, but not necessary to do one just for NAAT
  • NAAT is >99% sensitive and specific for urogenital gonorrhea from cervical specimens (urine is about 10% less sensitive)

Lastly, treatment options

Screen Shot 2017-10-05 at 4.11.23 PM.png

Treatment duration is usually 14 days. Interestingly, removal of an indwelling IUD does not hasten resolution (and may even worsen it)

References

  1. Recommendations for the Laboratory-Based Detection of Chlamydia trachomatis and Neisseria gonorrhoeae — 2014

  2. Pelvic Inflammatory Disease. NEJM 2015.

10/5 HUP Report: Graves’ Disease

Today we talked about workup and management of hyperthyroidism. Here is a review of some of the high yield facts we discussed:

 

How to examine the thyroid

  • Ask patient to flex neck slightly
  • Place three middle fingers on neck below chin, near midline
  • Locate upper edge of thyroid cartilage (Adam’s apple)
  • Move inferiorly until you reach the cricoid cartilage
  • The first two rings of the trachea are located below the cricoid cartilage, and the thyroid isthmus is here
  • Palpate the isthmus, then palpate the lobes by moving out laterally
  • Size –> diffuse enlargement likely Grave’s, thyroiditis
  • Masses/consistency
  • Thrill/bruit –> likely Grave’s
  • Tenderness –> inflammation
  • Ask the patient to stick out tongue
    • Mass that elevates with tongue protrusion is thyroglossal duct cyst
  • Ask the patient to swallow to feel for symmetric elevation of thyroid
    • Asymmetric elevation can indicate unilateral mass

Low TSH that is NOT Hyperthyroidism

  • Central HYPOthyroidism –> low TSH, low/normal thyroid hormones
  • Nonthyroidal illness, especially receiving glucocorticoids or dopamine –> low TSH, low/normal T4, low T3 (conversion inhibited)
  • Recovery from hyperthyroidism treatment (TSH lags behind normal thyroid hormones)
  • Biotin –> low TSH, high thyroid hormones (artifact from assay)
  • Pregnancy
  • Subclinical hyperthyroidism

Hyperthyroidism – Ddx

  • De-Novo thyroid hormone synthesis in thyroid
    • TSH-induced
    • Grave’s Disease
    • Toxic multinodular goiter and focal toxic adenoma
    • Amiodarone-induced –> can cause increased synthesis (usually underlying toxic nodule) OR can cause destructive thyroiditis (can also cause hypothyroidism)
    • Germ cell tumors secreting hCG (structural similarity with TSH)
  • Independent of increased thyroid hormone synthesis in thyroid
    • Exogenous thyroid hormone
    • Struma ovarii
    • Thyroiditis – with pain
      • DeQuervain’s (subacute granulomatous)
      • Radiation
      • Traumatic
    • Thyroiditis – without pain
      • Subacute lymphocytic thyroiditis (AKA silent or painless thyroiditis)
      • Postpartum thyroiditis
      • Fibrous (Riedel’s) thyroiditis — Usually HYPOthyroid or euthyroid
      • Chronic autoimmune thyroiditis (Hashimotos)

Grave’s Disease

  • Distinguished by presence of orbital manifestations and thyroid stimulating immunoglobulin
  • If patient has ophthalmopathy, thyroid exam diffusely enlarged without nodules, and labs consistent with hyperthyroidism, this is clinically diagnostic of Grave’s
  • If uncertain, then check thyroid receptor Ab –> can be negative early in disease
  • If Ab negative and high clinical suspicion, can check radioactive iodine uptake (should be diffusely increased) or ultrasound for vascularity

Management

Unless there is a contraindication, all patients presenting with symptomatic hyperthyroidism should be started on a beta-blocker to reduce adrenergic effects, and usually a cardioselective agent with daily dosing is preferred (atenolol). The hyperthyroidism can be treated with thionamides (PTU or methimazole; major side effects are agranulocytosis and hepatic toxicity), radioactive iodine ablation (may transiently worsen ophthalmopathy), or surgery.

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.

 

 

 

 

 

 

9/21 HUP Report: Evidence-Based Management of Severe Pancreatitis

Today we talked about management of severe pancreatitis and reviewed some of the evidence informing our practices.

First of all, how do we stratify severity of pancreatitis and why does it matter? It is really important to stratify severity because aggressive intervention for patients more likely to progress to severe pancreatitis can improve mortality.

Determining Severity

Revised Atlanta Criteria (for severity of acute pancreatitis):

  • Mild – no organ failure or systemic/local complications
  • Moderate – no or transient organ failure (<48 hrs) and/or local complications
  • Severe – organ failure >48 hrs, complications involving one or more organs

 

Lots of scoring systems have been devised, including Ranson’s Criteria, CT Severity Index, APACHE II, BISAP. They take into account variables like hemoconcentration (third-spacing in severe disease, studies with mixed findings based on cut-offs used), creatinine (possibly correlated with risk of necrosis), procalcitonin (most rapid acute phase reactant), CRP (most useful at 48 hours, >150 = severe), BUN (>20 at admission associated with increased risk of death). Some logistical considerations of the scoring systems:

  • BISAP is easy to clinically implement and comparable to APACHE II in predicting progression to severe disease
  • Ranson’s cannot be completed until 48 hours
  • APACHE II involves several clinical and lab data points that are not routinely obtained for all patients
  • CT Severity Index requires imaging, which is not always indicated

Overall, the American College of Gastroenterology recommends incorporating several clinical and laboratory parameters into an overall assessment of severity without relying on any particular scoring framework.

 

Fluid Resuscitation

Best results have been seen with aggressive fluid resuscitation in the first 12-24 hours. Lactated Ringers has been shown to be associated with lower incidence of SIRS at 24 hours than normal saline, with a theorized mechanism involving the development of metabolic acidosis with NS which potentiates activation of trypsinogen to trypsin (one of the active pancreatic enzymes causing autodigestion and inflammation).

 

Nutrition

Several studies support early enteral nutrition in severe pancreatitis, as compared with bowel rest and/or total parenteral nutrition. One theory suggests that bowel rest causes mucosal atrophy, which then may increase bowel translocation and risk of infection.

 

Prophylactic Antibiotics

Meta-analyses now suggest that there is no benefit to prophylactic antibiotics in this patient population. Antibiotics are only indicated if there is clinical concern for superinfection (which may be difficult to clinically differentiate from severe pancreatitis!). Antibiotics with good pancreatic penetration include carbapenems, high dose cephalosporins, metronidazole, and fluorquinolones.

 

 

Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis–2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62:102.

Tenner S, Baillie J, DeWitt J, et al. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol 2013; 108:1400.

Wu BU, Johannes RS, Sun X, et al. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut 2008; 57:1698.

Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011; 9:710.

Li J-Y, Yu T, Chen G-C, et al. Enteral Nutrition within 48 Hours of Admission Improves Clinical Outcomes of Acute Pancreatitis by Reducing Complications: A Meta-Analysis. Rakonczay Z, ed. PLoS ONE. 2013;8(6):e64926. doi:10.1371/journal.pone.0064926.

9/20 PPMC report: extra-intestinal manifestations of celiac disease

We discussed a young woman who presented with psychotic episodes and multiple micronutrient deficiencies, and was ultimately diagnosed with celiac disease.

Celiac disease is a systemic immune-mediated disease triggered by exposure to gluten (found in wheat, rye, barley) in genetically susceptible patients, who can then have a broad range of systemic manifestations and variable damage to the small intestinal mucosa.

PEARLS

  • It affects many races and ethnic groups (not just Caucasians)
  • There can be a variety of very subtle clinical manifestations
    • Chronic diarrhea, weight loss, abdominal distention (40-50%), recurrent abdominal pain
    • Iron deficiency (w/ or w/o anemia)
    • High transaminase levels, recurrent oral ulcers
    • Chronic fatigue
  • Untreated celiac disease can lead to neurologic disorders, infertility or recurrent abortion, and rarely cancer (T-cell lymphoma and adenocarcinoma of the jejunum)

Remember that celiac disease has a number of extra-intestinal manifestations

Screen Shot 2017-09-20 at 6.51.47 AM.png

NEJM 2016

Diagnosis: the IgA anti-tissue transglutaminase (TTG) antibody, which has excellent test characteristics (94% Se, 97% Sp). This is the single best initial test.

  • IgA anti-endomysial antibodies are nearly 100% specific, but should only be used to confirm a borderline +TTG (if there’s concern that it’s a false positive)
  • A small bowel biopsy is required to confirm the diagnosis if TTG+
  • If the diagnosis is uncertain, consider sending HLA DQ2/DQ8 testing; being negative for those haplotypes essentially rules out celiac (ie it has a very high NPV)

Remember: sensitivity of testing is markedly decreased when patients are on a gluten free diet, so don’t be too eager to restrict their diet! Biopsy findings on endoscopy can also be falsely negative if the patient is on immune suppression (steroids, etc).

A note on screening: no clear consensus exists on this, but consider screening 1st degree relatives of patients with celiac, and other high risk groups (unexplained IDA, Down syndrome, other autoimmune diseases w/ suggestive sx, etc)

In this case, the patient presented with psychosis at the age of 45, which is unusual: psychosis usually presents in the early 20s, and there’s also a small peak around menopause. While psychosis as a manifestation of celiac is rare, it’s important to remember the more (and more common) subtle neuropsychiatric signs of celiac.

Screen Shot 2017-09-20 at 11.27.38 AM.png

NEJM 2016

It’s very hard to avoid gluten- it’s present in tons of food (especially processed food) in subtle ways, and even in certain medications as a binder/filler; this makes adherence with a gluten free diet very difficult.

References

  1. Jackson J et al. Neurologic and psychiatric manifestations of celiac disease and gluten sensitivity. Psychiatr Q. 2012.
  2. Kabbani et al. Celiac Disease or Non-Celiac Gluten Sensitivity? An Approach to Clinical Differential Diagnosis. Am J Gastroenterology 2014.
  3. Celiac disease. NEJM.

9/20 HUP Report: Cystic Lung Disease, Pneumothorax ex-vacuo

Today at report we were joined by radiology to review some cases with interesting imaging. Here are some clinical pearls we discussed related to a couple of the cases:

 

Cystic Lung Disease

True cystic lung disease is rare! Other pathologic processes that may resemble cystic lung disease on imaging include:

  • emphysema, particularly bullous disease
  • cavitary lesions
  • honeycombing
  • bronchiectasis
  • pneumatocele

Below are some key identifying characteristics of four relatively more common cystic lung diseases:

  • Lymphangioleiomyomatosis (LAM)
    • seen almost exclusively in females; there have been case reports in males with tuberous sclerosis complex (TSC)
    • symptom onset usually age 20s-30s
    • can be associated with TSC; signs/symptoms include cutaneous angiofibromas, intellectual disability, seizures, ash-leaf spots, and shagreen patches
    • angioleiomyomas are also commonly found in kidneys
    • may be associated with chylous effusions (pleural effusion with most cystic lung diseases is rare)
    • radiology findings include diffuse homogenous cysts
  • Pulmonary Langerhan’s Cell Histiocytosis (LCH)
    • slight female predominance, symptom onset usually age 20s-40s
    • seen almost exclusively in current or former smokers
    • extrapulmonary manifestations are present in approximately 20% and include DI and cystic bone lesions
    • radiology findings progress from nodules to uneven and bizarrely shaped cysts with sparing of the costophrenic angles
  • Birt-Hogg-Dube Syndrome
    • autosomal dominant inheritance, symptom onset usually age 30s-40s
    • cutaneous fibrofolliculomas, common in midface
    • associated with renal neoplasms
    • radiology findings include lentiform/elliptical cysts especially basilar and abutting the mediastinum and pleura
  • Lymphoid Interstitial Pneumonia (LIP)
    • associated with auto-immune diseases or immunodeficiency; most strongly associated with Sjogren’s disease (present in 25-50%)
    • radiology findings include few thin-walled cysts in areas of ground glass opacity, may have internal septae or nodules

 

Pneumothorax Ex-Vacuo

A pneumo ex-vacuo is a air between the parietal and visceral pleura that is present when a lung cannot expand to fill this space following thoracentesis. This may happen for one of two reasons:

  • Lung entrapment: the lung cannot expand due to active disease that restricts the intrinsic elastic recoil of the lung or visceral pleura. This can occur due to malignancy, infection, or inflammatory processes.
  • Trapped lung: the visceral pleura can develop collagenous or fibrous rind (scar) from a remote or chronic inflammatory process that “traps” the lung and prevents it from expanding. This can occur due to history of inflammatory insult to the pleural such as infection, hemothorax, thoracic surgery or can result from chronic pleural effusion.

References:

https://www.uptodate.com/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?source=search_result&search=cystic%20lung%20disease&selectedTitle=1~150

https://www.uptodate.com/contents/diagnosis-and-management-of-pleural-causes-of-unexpandable-lung?source=search_result&search=trapped%20lung&selectedTitle=1~46