Primecuts – This Week in the Journals

October 9, 2017

PrimeCuts 7 min read

By Joanne Bruno, MD/PhD

Peer Reviewed 

There’s finally starting to be a bit more of a chill in the air, which can only mean one thing – pie season is finally here! While this time of year is rife with celebration and gluttony, it is also a time to give back to those in need. This is especially relevant this year given that Puerto Rico is still reeling from the devastation left by Hurricane Maria and Las Vegas just experienced one of the worst mass shootings in US history. Here are ways that we can help.[1 2] Now, let us turn to brighter news in the form of the recently published advancements in medicine in this week’s PrimeCuts.

Rituximab maintenance therapy prolongs disease-free and overall survival in patients with mantle cell lymphoma.

Mantle cell lymphoma has historically been categorized as an ultimately incurable cancer; although many patients temporarily achieve remission, they eventually relapse and become progressively less responsive to chemotherapy with each successive treatment regimen. While recent advances have been made in optimizing the chemotherapy cocktails used both prior and subsequent to patients undergoing autologous stem cell transplant, none of these ultimately resulted in prolongation of overall survival in these patients.[3] However, Le Gouill et al. hypothesized that treatment with rituximab, a monoclonal antibody against CD20, after transplantation may be useful in suppressing any tumor cells that remain and thereby inhibit disease progression.[4] In their randomized, prospective phase 3 trial published in NEJM this week, they show that patients randomized to receive rituximab maintenance therapy after autologous stem cell transplant experienced an increased rate of progression-free survival at 4 years (83% v. 64%, P<0.001) as well as an increased rate of overall survival (89% v. 80%, P=0.04) compared to those who only underwent observation post-transplantation. Thus, the number needed to treat to prevent one death during this time span is 11.1 patients. As is frequently the case with advancements in biomedical science, the findings from this study spurred even more questions. It will be interesting to see whether rituximab maintenance therapy has similar effects in those patients who receive alternative induction chemotherapy regimens, or whether its effect is specific to the regimen used in this study.  Additionally, in this study maintenance therapy was administered regardless of whether or not residual disease could be detected post-transplantation. It may be that there is a subset of patients whose response to the initial treatment is so robust that keeping them on maintenance therapy is superfluous. However, further work will need to be done to investigate this. 

Using lung recruitment and titrated PEEP strategies in patients with moderate to severe ARDS increases mortality compared to the conventional low PEEP strategy. 

Also in the vein of challenging medical dogma, a study published in JAMA this past week sought to oppose the low-PEEP strategy conventionally used for treatment of ARDS, comparing it with a lung recruitment maneuver that uses stepwise increases in PEEP to maximize respiratory system compliance[5]. This multicenter trial spanned 120 ICUs from 9 different countries, and randomized 1010 patients with moderate to severe ARDS requiring invasive mechanical ventilation to either the lung recruitment strategy (experimental) group or a low-PEEP strategy (control) group. Patients were excluded from the trial if they were on vasopressors, had contraindications to hypercapnia, or had a pneumothorax/pneumomediastinum. All patients received at least 3 hours of mechanical ventilation using a low-PEEP and low-tidal volume prior to randomization. The lung recruitment strategy was overwhelmingly inferior to the low-PEEP strategy, and was associated with increased mortality at 28 days (55.3% v. 49.3%, P=0.041), increased 6-month mortality (65.3% v. 59.9%, P=0.04), decreased ventilator-free days (5.3 v. 6.4, P= 0.03), increased risk of pneumothorax requiring chest tube placement (3.2% v. 1.2%, P=0.03), and risk of barotrauma (5.6% v. 1.6%, P=0.001). While these raw percentages may not seem strikingly different at face value, the number needed to harm for 6-month mortality with the lung recruitment strategy is only 18.5, which is significant given how relatively common ARDS is among critical care patients. 

Effective HCV treatment results in reduction of the risk of HCC except in those with established cirrhosis.                                                              

The advent of new direct-acting antiviral agents against hepatitis C has resulted in undetectable viral loads and what is essentially being called a cure for many patients. While it is intuitive that eradication of the hepatitis C virus stalls progression of disease to cirrhosis and liver failure, it has been unclear whether elevated risk of hepatocellular carcinoma (HCC) persists in these patients. A large cohort study published in Gastroenterology broaches this question by comparing the incidence of diagnosis of HCC in 22,500 HCV-positive patients in the Veterans Health Administration system with sustained viral response (SVR) after antiviral treatment to those who underwent treatment but did not achieve viral eradication[6]. The annual incidence of HCC diagnosis in those who achieved sustained viral response was 0.9 per 100 patient-years, compared to 3.45 per 100 patient-years in those with detectable viral load after treatment. Sustained viral response on the other hand was associated with a 76% decrease in the risk of HCC. The study also identified cirrhosis and alcohol use as factors that conferred a continued heightened risk of HCC despite viral clearance (1.82% v. 0.34% for cirrhotics and 1.01% v. 0.72% for alcohol users). While no causative associations can be made from this study, and there certainly could be confounding influences at play – for instance, perhaps those patients who were compliant with their treatment are likely also compliant with their other medications and in better health overall – these data clearly emphasize the importance of diagnosing our patients with hepatitis C early on in the course of their illness, and starting them on antiviral agents as quickly as possible.

Results from the Phase 1 trail for an Anti-Zika Virus Vaccine show that the DNA vaccine is capable of eliciting anti-Zika virus immune responses. 

Although Zika virus was first discovered in 1947, it has only begun to plague human populations in recent years. Zika infection can be transmitted by mosquitoes or via exchange of bodily fluids between individuals. In most humans, infection with Zika appears to be relatively benign with the majority of those infected experiencing vague symptoms similar to that of the common cold. However, infection with Zika during pregnancy can have severe consequences for fetal brain development resulting in microcephaly [7]. Preclinical studies have confirmed the immunogenicity of a DNA vaccine against the ZIKA premembrane and envelope proteins, as well as its effectiveness in protecting against Zika infection in mice and primates [8]. However, further studies have been necessary to confirm its safety and efficacy in humans. To this end, a phase 1, open-label clinical trial recently published in the New England Journal of Medicine is suggestive of vaccine safety with 0 of the 40 participants experiencing any serious adverse events. The participants received three doses of the vaccine with detectable antibody development against Zika virus in all participants at two weeks after administration of the third dose. Additionally, application of the serum from Zika-vaccinated individuals was protective against Zika infection in both tissue culture and murine models. While it still remains to be seen whether the vaccine will be efficacious in conferring immunity against Zika virus in humans, these initial studies are certainly promising and a step in the right direction.

Other interesting reads this week in Minicuts….

In a randomized trial of patients undergoing orthopedic surgery, using genotype to guide warfarin dosing rather than conventional clinical guidance reduced the rate of major bleed, VTE, supratherapeutic INR, and death.[9]

Whole genome sequencing on patients with idiopathic pulmonary hypertension identifies a cohort of patients with biallelic mutations in the EIF2AK4 gene who have a younger age of diagnosis with negative CT findings. Patients who fit these criteria would likely benefit from genetic testing, which could allow for less time to diagnosis and earlier referral to lung transplant.[10]

Rapid antigen tests that more accurately distinguish Zika virus from dengue viruses may be on the horizon.[11]

Finally, there is now proof that increased physical activity diminishes genetic susceptibility to weight gain.[12]

Dr. Joanne Bruno is a 1st year internal medicine resident at NYU Langone Health 

Peer reviewed by Amar Parikh, MD, associate editor of Clinical Correlations and chief resident of internal medicine at NYU Langone Health

References: 

  1. J H. How you can help hurricane victims in Puerto Rico. Secondary How you can help hurricane victims in Puerto Rico 2017. http://www.pbs.org/newshour/rundown/can-help-hurricane-victims-puerto-rico/.
  2. John T. How you can help the victims of the mass shooting in Las Vegas. Secondary How you can help the victims of the mass shooting in Las Vegas. 2017. http://time.com/money/4964866/las-vegas-shooting-how-to-help-victims/.
  3. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet 2016;388(10044):565-75 doi: 10.1016/S0140-6736(16)00739-X[published Online First: Epub Date]|.
  4. Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma. N Engl J Med 2017;377(13):1250-60 doi: 10.1056/NEJMoa1701769[published Online First: Epub Date]|.
  5. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial I. Effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: A randomized clinical trial. JAMA 2017 doi: 10.1001/jama.2017.14171[published Online First: Epub Date]|.
  6. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology 2017;153(4):996-1005 e1 doi: 10.1053/j.gastro.2017.06.012[published Online First: Epub Date]|.
  7. Mlakar J, Korva M, Tul N, et al. Zika Virus Associated with Microcephaly. N Engl J Med 2016;374(10):951-8 doi: 10.1056/NEJMoa1600651[published Online First: Epub Date]|.
  8. Larocca RA, Abbink P, Peron JP, et al. Vaccine protection against Zika virus from Brazil. Nature 2016;536(7617):474-8 doi: 10.1038/nature18952[published Online First: Epub Date]|.
  9. Gage BF, Bass AR, Lin H, et al. Effect of genotype-guided warfarin dosing on clinical events and anticoagulation control among patients undergoing hip or knee arthroplasty: The gift randomized clinical trial. JAMA 2017;318(12):1115-24 doi: 10.1001/jama.2017.11469[published Online First: Epub Date]|.
  10. Hadinnapola C, Bleda M, Haimel M, et al. Phenotypic Characterisation of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically with Pulmonary Arterial Hypertension. Circulation 2017 doi: 10.1161/circulationaha.117.028351[published Online First: Epub Date]|.
  11. Bosch I, de Puig H, Hiley M, et al. Rapid antigen tests for dengue virus serotypes and Zika virus in patient serum. Sci Transl Med 2017;9(409) doi: 10.1126/scitranslmed.aan1589[published Online First: Epub Date]|.
  12. Wang T, Huang T, Heianza Y, et al. Genetic Susceptibility, Change in Physical Activity, and Long-term Weight Gain. Diabetes 2017;66(10):2704-12 doi: 10.2337/db17-0071[published Online First: Epub Date]|.