EUH Hunt Conference: What are the benefits of tamoxifen in treating encapsulating peritoneal sclerosis (EPS)?

The Bottom Line: Tamoxifen appears to exert its effect through inhibition and modulation of TGF-β. In vitro and animal models showed that Tamoxifen treatment blocked EMT induced by TGF-β, preserved the fibrinolytic activity and reduced the migration capacity of mesothelial cells leading to reduced fibrosis and reduced PD effluent levels of VEGF leading to reduced angiogenesis in the peritoneum. However, Tamoxifen has almost always been used in combination with corticosteroids, therefore the efficacy and safety of Tamoxifen alone in the treatment of EPS still remains to be evaluated.

Reference: Moinuddin Z, Summers A, Van Dellen D, Augustine T, et al. Encapsulating peritoneal sclerosis – a rare but devastating peritoneal disease. Frontiers in Physiology. 2014;5:470. Doi:10.3389/fphysi.2014.00470

Summary:  Encapsulating peritoneal sclerosis (EPS) is a devastating but rare complication of long-term peritoneal dialysis. The disease is associated with extensive thickening and fibrosis of the peritoneum resulting in the formation of a fibrous cocoon encapsulating the bowel leading to intestinal obstruction. The incidence of EPS ranges between 0.7 and 3.3% and increases with duration of peritoneal dialysis therapy.
Tamoxifen is a Selective Estrogen Receptor Modulator (SERM) with antifibrotic properties and has been used in the treatment of various fibrotic disorders like retroperitoenal fibrosis, fibrosing mediastinitis, fibrosing cerivicitis, and desmoid tumors

A large retrospective Dutch study demonstrated significantly reduced mortality in EPS patients that were treated with Tamoxifen (45.8%) when compared to those that were not treated with Tamoxifen (74.4%).The potential side-effects of Tamoxifen (deep vein thrombosis, endometrial cancer, and calciphylaxis) also need to be considered.

Advertisements

EUHM Report: Acute and subacute shortness of breath in patients with Pneumocystis Jirovecii Pneumonia

HIV-infected patients usually develop a subacute course of disease, while non-HIV infected immunocompromised patients are characterized by a rapid disease progression with higher risk of respiratory failure and higher mortality. The main symptoms usually include exertional dyspnea, dry cough, and subfebrile temperature or fever.

Salzer, Helmut J F, Guido Schäfer, Martin Hoenigl, Gunar Günther, Christian Hoffmann, Barbara Kalsdorf, Alexandre Alanio, and Christoph Lange. “Clinical, Diagnostic, and Treatment Disparities between HIV-Infected and Non-HIV-Infected Immunocompromised Patients with Pneumocystis Jirovecii Pneumonia.” Respiration. 96, no. 1 (2018): 52-65.

The diagnosis of PCP is mostly a presumptive diagnosis in resource-limited settings. Clinical signs and symptoms, particularly dyspnea, fever, dry cough, and hypoxia in absence of an alternative diagnosis in an immunocompromised patient with a CD4+ T lymphocyte count <200 cells/mL and concurrent radiological changes lead to the initiation of PCP treatment

Table 1. Disease characteristics of PCP in HIV-positive patients compared to patients with other reasons of immunosuppression (page 4)

 

 

VA Report: What is the relationship between uremia and altered mental status?

Measurement of the defects in mental function caused by uremia is also made difficult by the confounding effects of age, personal background, and other illnesses.  Not knowing which uremic solutes are toxic limits our ability to improve therapy. The contribution of retained solutes to the illness experienced by dialysis patients is difficult to dissect, but we believe it is large. We know that if dialysis is withheld, accumulation of waste solutes will cause confusion, coma, and then death.

Meyer TW, Hostetter TH. Approaches to Uremia. Journal of the American Society of Nephrology : JASN. 2014;25(10):2151-2158.

In studying the effects of uremia on mental function, we must also consider how much function will be improved by the reductions in solute levels we are able to achieve. It is worth considering what would be the effect on mental function of reducing levels of a known neuroactive compound, such as ethanol. Reducing very high ethanol levels by half could restore orientation in a stuporous person, analogous to the effect of initiating dialysis in a severely uremic patient.

Table 1.

Common features of uremia

Neural and Muscular                                         Endocrine and Metabolic
Loss of energy                                                            Amenorrhea and sexual dysfunction
Decreased mental acuity                                         Insulin resistancea
Anorexia and nausea                                                Reduced resting energy expenditure
Restless legs                                                               Increased protein/muscle catabolism
Defective taste and smell                                         Other
Peripheral neuropathy                                          Pruritus
Sleep disturbances                                                    Decreased red cell survivala
Reduced muscle membrane potential               Platelet dysfunctiona
Oxidant stressa

Grady Morning Report: What are the current guidelines concerning the management of acute pulmonary embolism (PE)?

The Bottom Line:

Only one of the phase 3 clinical trials investigating the use of new direct oral anticoagulants in patients with VTE reported efficacy results for the subgroup of patients with acute PE and RV dysfunction. Among patients with elevated NT‐proBNP levels, recurrent VTE occurred in 15 of 454 patients in the edoxaban cohort and in 30 of 484 patients in the warfarin group.

A new trial, the Pulmonary Embolism International Trial (PEITHO‐II) will focus on the safety, efficacy and cost‐effectiveness of dabigatran in the treatment of patients with acute intermediate‐risk PE. Patients will be treated with low molecular weight heparin for at least 72 hours followed by dabigatran treatment for 6 months.

References: Klock FA et al. Management of intermediaterisk pulmonary embolism: uncertainties and challenges. Eur J Haematol. 2015 Dec;95(6):489-97. doi: 10.1111/ejh.12612. Epub 2015 Jul 15.

Link to current trial (still recruiting patients): https://www.escardio.org/Working-groups/Working-Group-on-Pulmonary-Circulation-and-Right-Ventricular-Function/Education/peitho-2

Summary:

Reperfusion Treatment

A. The Pulmonary Embolism Thrombolysis Trial (PEITHO) compared, in a double‐blind manner, fibrinolysis with tenecteplase plus heparin vs. placebo plus heparin in 1005 patients with acute PE. Eligible patients had RV dysfunction, plus myocardial injury; that is, they were at intermediate‐high risk of an adverse early outcome. The primary outcome, a composite of all‐cause death or hemodynamic decompensation/collapse, was significantly reduced with tenecteplase. On the other hand, there was an increased incidence of hemorrhagic stroke after fibrinolytic treatment with tenecteplase; major non‐intracranial bleeding events were also increased in the tenecteplase group compared with placebo. This study strongly argues against the standard application of thrombolysis in hemodynamically stable PE patients.

B. Catheter‐directed techniques are considered an alternative to surgery. The safety and efficacy of pharmacomechanical fibrinolysis is supported by the results of a recent trial which enrolled 150 patients with submassive (intermediate‐risk) or massive (high‐risk) PE. Due to the lack of high‐quality studies in patients with PE in general as well as in patients with intermediate‐risk PE specifically, the safety and efficacy of these interventions remain unknown.

Anticoagulation Treatment

New non‐vitamin K‐dependent oral anticoagulants (NOACs), in particular direct factor IIa (thrombin) and factor Xa inhibitors, were developed and tested in large phase‐3 randomized clinical trials. A meta‐analysis of the phase III clinical trials on VTE showed that new oral anticoagulants were associated with a significantly lower risk of major as well as fatal hemorrhage compared to VKA treatment. The experience with NOACs in current trials on intermediate risk PE is limited.

 

 

EUH Morning Report: Should lasix (furosemide) be considered in the setting of hypercalcemia?

The Bottom Line: Avoid loop diuretics in the setting of acute hypercalcemia, except it may be considered for patients with concomitant volume overload.

DynaMed Plus provides the following information on loop diuretics:

  • inhibits calcium resorption in distal renal tubule
  • may worsen volume depletion and electrolyte derangements and should be used with caution
  • no evidence to support use in acute hypercalcemia
    • may be used to control volume overload
    • associated with hypokalemia and possibly contributes to dehydration

References: DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 – . Record No. 116018, Hypercalcemia; [updated 2016 Dec 27, cited 2018 Jul 19]; [about 10 screens]. Emory login required.

LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Annals of Internal Medicine. 2008;149(4):259-263.

Summary: The following is a review of LeGrand et al’s 2008 article (NEJM Journal Watch):

A literature review found little support for the use of the diuretic furosemide to treat hypercalcemia.

Many textbooks recommend saline and furosemide as first-line management for hypercalcemia. Investigators searched the literature since 1950 for studies of furosemide or bisphosphonate use for hypercalcemia in people.

They identified nine reports — the most recent from 1983 — involving 37 patients treated with furosemide for hypercalcemia; doses ranged from 240 mg to 2400 mg. Calcium normalized in 14 of 39 episodes, and within 12 hours in only two cases. Intensive monitoring was accompanied by replacement of fluid and electrolyte losses. Complications included hypernatremia, coma, metabolic acidosis, hypophosphatemia and hypomagnesemia, altered mental status, and tetany.

Investigators identified 56 clinical studies of bisphosphonates — 34 were randomized and included more than 1000 patients. In a systematic review of 26 studies of bisphosphonate use in hypercalcemia of cancer, calcium levels normalized in more than 70% of patients. The authors conclude that volume repletion and bisphosphonate therapy should be the standard management strategy for hypercalcemia, with furosemide used only for managing fluid overload.

COMMENT

Forced saline diuresis for hypercalcemia is a long-standing practice that persists, even in authoritative texts, despite the absence of evidence for its efficacy, the existence of known risks, and the availability of other proven treatments. Saline and bisphosphonates, with or without calcitonin, are the standard of care for hypercalcemia.

EUH Morning Report: What is the criteria for liver transplantion in patients with hepatocellular carcinoma?

The Bottom Line: Liver transplant is recommended for patients with potentially resectable or transplantable disease according to performance status or lack of severe comorbidity, or in patients with unresectable disease who meet Milan or United Network for Organ Sharing (UNOS) criteria. Controversy exists over liver transplantation in patients with tumors marginally outside Milan or UNOS criteria, but some institutions may still consider it (DynaMed Plus, 2017).

  • Milan criteria for liver transplantation for hepatocellular carcinoma includes either of:
    • single lesion ≤ 5 cm in diameter
    • 2-3 lesions all ≤ 3 cm in diameter
  • UNOS criteria for liver transplantation for hepatocellular carcinoma includes both of:
    • Milan criteria
    • no evidence of macrovascular involvement or extrahepatic disease

Reference: DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 – . Record No. 909499, Management of early hepatocellular carcinoma / Liver Transplant; [updated 2017 May 31, cited 2018 June 28]; [about 24 screens]. Emory login required.

Summary: 

(DynaMed Plus, 2017)

EUH Morning Report: Review of type 1 vs type 2 hepatorenal syndrome

The Bottom Line: Hepatorenal syndrome (HRS) is functional renal impairment in patients with advanced liver disease and without evidence of renal parenchymal disease, severe volume loss, or nephrotoxicity from medication.

    • type 1 hepatorenal syndrome
      • rapid decline in renal function
      • doubling of serum creatinine from baseline to > 2.5 mg/dL (221 mcmol/L) in < 2 weeks
      • usually triggered by precipitating event causing both a decline in liver function as well as a decline in other organ functions leading to hepatorenal syndrome
    • type 2 hepatorenal syndrome
      • steady, progressive decline in renal function (average serum creatinine 2 mg/dL [176.8 mcmol/L])
      • usually characterized by refractory ascites and sodium retention

Reference: DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 – . Record No. 116729, Hepatorenal syndrome; [updated 2018 May 30, cited 2018 June 28]; [about 15 screens]. Emory login required.

EUH Morning Report: What is Sister Mary Joseph’s nodule?

The Bottom Line: Sister Mary Joseph’s nodule is a metastatic cancer of the umbilicus that is typically associated with adult cancers of the gastrointestinal tract and ovary (Albano and Kanter, 2005). It is a rare but important physical finding and is a sign of advanced stage of malignancy (Tso et al, 2013).

References: Albano EA, Kanter J. Sister Mary Joseph’s Nodule. N Engl J Med. 5 May 2005;352(18):193.

Tso S, Brockley J, Recica H, Ilchyshyn A. Sister Mary Joseph’s Nodule: an unusual but important characteristic of widespread internal malignancy. Br J Gen Pract. 2013 Oct;63(615):551-552. Doi: 10.3399/bjgp13X673900.

Summary: The condition is named after Sister Mary Joseph (1856-1939), a surgical assistant for Dr. William Mayo, who noted the association between paraumbilical nodules observed during skin preparation for surgery and metastatic intraabdominal cancer confirmed at surgery (Albano and  Kanter, 2005).

EUH Morning Report: What is the rational clinical exam for ascites?

The Bottom Line: The examiner should ask about recent ankle edema, weight gain, or change in abdominal girth. Other potentially important items are a history of liver disease or congestive heart failure. The focused physical exam includes: (1) inspection for bulging flanks, (2) percussion for flank dullness, (3) a test for shifting dullness, and (4) a test for a fluid wave (Williams and Simel, 1992).

ascites

References: DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 – . Record No. 116330, Ascites; [updated 2017 Jul 31, cited 2018 Jun 22]; [about 20 screens]. Emory login required.

Williams JW Jr, Simel DL. The rational clinical examination. Does this patient have ascites? How to divine fluid in the abdomen. JAMA. 1992 May 20;267(19):2645-8.

Summary: Ascites is a symptom that may have important diagnostic, prognostic, and therapeutic implications. When clinically detectable, ascites may indicate underlying heart failure, liver disease, nephrotic syndrome, or malignancy (Williams & Simel, 1992).

Skin: assess for signs of liver disease

  • Jaundice
  • Spider veins
  • Palmar erythema
  • Caput medusa (abdominal wall collateral veins)

HEENT

  • Jugular venous distention may be present secondary to heart failure

Lungs

  • Look for associated pleural effusions (dependent rales)

Abdomen

  • Abdominal distention
  • Fluid wave
  • Shifting dullness
  • Umbilicus eversion
  • Low umbilicus position (Tanyol sign)
  • Flank dullness
    • About 1,500 mL of fluid must be present to be detected
    • If no flank dullness, patient has < 10% chance of ascites

Extremities

  • Look for associated peripheral edema
  • Leukonychia (white nails) may be seen in advanced liver disease

Genital

  • Penile or scrotal edema may be seen

(DyanMed Plus, 2018)

New Intern Orientation: Adjusted ASCVD Risk

The Bottom Line: Major guidelines recommend that decisions about aspirin, blood pressure, and statin treatments be informed by 10-year CVD risk estimates from the PCEs, which were derived in 2013 using data from 5 cohort studies. These PCEs are controversial because of reports that they substantially misestimate risk. Two basic strategies to revise the PCEs could improve their accuracy: updating the data from which they are derived and changing the statistical methods used to derive them (Yadlowsky et al, 2018).

In his review of the recent study by Yadlowsky et al (2018), Dr. Dan Dressler provides the following example: Assume the patient is a 68-year-old white man with the following favorable risk profile: Total cholesterol, 160 mg/dL; HDL cholesterol, 55 mg/dL; blood pressure, 120/70 mm Hg; and no history of diabetes, hypertension, or smoking. His 10-year CVD risk is 12% on the ACC/AHA calculator, but only 6% on this new model’s calculator. The latter risk is below the threshold at which most clinicians would recommend statin therapy (Dressler, 2018).

References: Dressler DD. 10-year cardiovascular risk might be lower than we thought. NEJM Journal Watch. 2018 Jun 21.

Yadlowsky S, Hayward RA, Sussman JB, McClelland RL, et al. Clinical implications of revised pooled cohort equations for estimating atherosclerotic cardiovascular disease risk. Ann Intern Med. 2018 Jun 5. doi:10.7326/M17-3011

Summary: The clinical implications of the results suggest that the revised PCEs will reduce overestimation of risk in general and may prevent adverse events, health care costs, and inflated expectations of absolute risk and corresponding absolute therapeutic benefit. Additionally, use of the updated equations will correct erroneous, implausible risk estimates for many African American adults (Yadlowsky et al, 2018).

The study by Yadlowskey et al (2018) validates what some clinicians have observed in practice: Some patients are classified inaccurately as “high risk.” Although guidelines that depend on risk calculation would not necessarily need to change if risk calculators are updated, the number of patients who would be affected by guideline recommendations could be lowered dramatically (Dressler 2018).