Great Story -How CAR-T Came About

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While chimeric antigen receptor T-cell (CAR-T) therapy does not have much to do with pediatric gastroenterology, the development of this therapy, described recently (L Rosenbaum NEJM 2017; 377: 1313-5), holds lessons about perseverance and chance that are widely applicable.

CAR-T involves genetically engineering the patient’s own T cells to kill tumor cells. It recently received FDA approval to treat patients up to 25 years of age with relapsed or refractory acute lymphoblastic leukemia.

The story of the survival of Emily Whitehead, the index patient for this therapy, is suitable for Hollywood.  The groundwork for this very expensive treatment dates back to 1893 with William Coley’s recognition of the immune system’s potential for treating cancer –he injected streptococcus into an inoperable osteosarcoma and observed tumor shrinkage.

Key Steps in this Story:

  1. University of Pennsylvania’s immunologist Carl June spent his career working on CAR-T. His wife died of ovarian cancer in 2001 and he resolved to develop this emerging immunotherapy that he had wanted for her.
  2. Barbara and Edward Netter provided key funding for this project in 2008.  They too had lost a close family member to cancer.
  3. Emily Whitehead nearly died due to CAR-T therapy which triggered cytokine-release syndrome, which was not a recognized entity at the time.  In part due to chance, extremely high levels (>1000-fold) of interleukin-6 (IL-6) were detected quickly due to the ability of the institution and prodding by the researchers to their colleagues.  This allowed the experimental use of tocilizumab, a monoclonal antibody that targets IL-6.
  4. Her survival helped reenergize this line of research.

My take (borrowed from author): “Therapeutic advances are motivated by more than money –that it’s the hope, vision, and perseverance of both patients and investigators that made this …possible.”

Acute esophageal necrosis ina a 63 year-old that resolved with conservative treatment.  “The cause is unknown..[it] occurs most commonly in the distal third of the esophagus, which is hypovascular” often in the setting of chronic disease.

Do these antibiotics make me look fat?

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There has been a lot of interest and conflicting reports about whether antibiotics contribute to obesity.  Another interesting study on this theme:

  • ET Rogawski et al. JPGN 2017; 65: 350-6. 

The authors followed 1954 children twice weekly from birth to 2 years of age as part of the MAL-ED study.  There were 8 study sites, including in Bangladesh, India, Brazil, Pakistan, Nepal, South Africa, Peru, and Tanzania. Key finding:

  • Antibiotic use before 6 months of age was associated with increased weight from 6 months to 2 years of age.
  • Antibiotic use after 6 months did not affect growth.

The authors speculate: “If treatment of infections were the main mechanism, we would expect antibiotic exposure after 6 months to also have an impact.” Thus, they conclude that effects on the microbiome are likely a more important explanation.

My take (borrowed from te authors):  “Antibiotic use in low-resource settings” can improve growth, though the long-term consequences are not known.  In high-income settings, weight gain secondary to antibiotic exposure is more likely to be detrimental.

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Patient T-shirt

 

Diet and Stress in Pediatric Eosinophilic Esophagitis

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When it comes to eosinophilic esophagitis (EoE), I sometimes worry that some treatments are worse than the disease, depending on the severity of the EoE. A recent study (C Case et al. JPGN 2017; 65: 281-84) indicates that dietary therapy is often stressful for families.

This study examined children ages 2-18 during an annual American Partnership for Eosinophilic Diseases (APFED.org) patient education conference. What I found most interesting was Table 3. “Stress associated with eosinophilc esophagitis.”

Some of the data:

  • In response to ‘how stressful do you find the following since your child’s diagnosis of EoE?’ Family structure at mealtimes: Not stressful 13.5%, somewhat stressful 21.6%, moderate stressful 16.2%, significant stressful 32.4%, and severe stressful 16.2%
  • In response to ‘how stressful do you find the following since your child’s diagnosis of EoE? Buying and cooking separate foods/meals for your child: Not stressful 2.6%, somewhat stressful 21.1%, moderate stressful 21.1%, significant stressful 31.6%, and severe stressful 23.7%
  • In response to ‘how stressful do you find the following since your child’s diagnosis of EoE? Financial strain due to cost of food: Not stressful 10.5%, somewhat stressful 21.1%, moderate stressful 18.4%, significant stressful 23.7%, and severe stressful 36.3%
  • What is your current stress level in response to your child’s EoE? Not stressful 2.6%, somewhat stressful 15.8%, moderate stressful 36.8%, significant stressful 42.1%, and severe stressful 2.6%
  • 62% of respondents indicated that child’s EoE has affected marital relationship.

In addition, the study documented that “half of youth were affected by worry, anger, and sadness related to specialized diets.”  As this study relied on participants at an APFED meeting, this could skew the EoE population to be more severely affected.

My take: This study shows the emotional burden that dietary treatment of EoE places on families.

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Berry College

Top Anti-TNF for Ulcerative Colitis

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A recent retrospective cohort study (S Singh et al. Clin Gastroenterol Hepatol 2017; 15: 1218-25) compared infliximab and adalimumab in a nationwide Danish cohort of adults with ulcerative colitis (UC) from 2005-2014. The authors used propensity score and selected 171 patients who received infliximab (IFX) from a total of 1580 and 104 patients who received adalimumab (ADA) among a total of 139.

Key findings:

  • Patients who received ADA had higher hospitalization rates (HR 1.84) and a trend toward higher UC-related hospitalization (HR 1.71, CI 0.95-3.07) compared to IFX
  • Risk of abdominal surgery was not significantly higher in ADA patients (HR 1.35) compared to IFX
  • Serious infections were higher in ADA group, HR of 5.11 of needing hospitalization due to infections

There have been no randomized clinical trials  to determine if a specific anti-TNF agent is superior to another. In an associated editorial (MT Osterman, GR Lichtenstein, 1197-99), the authors note that while we don’t know which agent is superior, by comparing similar trials (ACT 1 & 2 for IFX and ULTRA 1 & 2 for ADA), “raw week 8 induction rates of clinical remission, clinical response, and mucosal healing are approximately 16%, 18%, and 19%, respectively, higher for infliximab”..”less dramatic differences favoring infliximab (approximately 9%, 13%, and 15%, respectively) are seen during maintenance at 1 year.”

My take: Due to the lack of randomized head-to-head studies, we do not know with certainty which anti-TNF is best for UC.  However, the data we have from retrospective cohort studies and from using raw data from prospective studies suggests that infliximab is effective in more patients.

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University of Virginia Rotunda Pctures

 

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Briefly: Notable Recent IBD Publications

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Vermeire S et al. Lancet 2017; 389: 266-75.  The “FITZROY ” study examined clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib, a orally administered selective JAK inhibitor.  This agent is 30 times more selective fo rJAK1 over JAK3. This study enrolled 174 patients in a phase II study. Key findings:

  • Among patients naive to anti-TNF agents, clinical remission (based on CDAI <150 at week 10) noted in 47% of filgotinib-treated compared with 23% of placebo group (P=.0077)
  • Among patients naive to anti-TNF agents, clinical response was noted in 67% of filgotinib-treated compared with 44% in the placebo group.

H Singh et al. Gastroenterol 2017; 153: 430-8.  Using the large Manitoba Epidemiology Database with 1.3 million population (2005-2014), the authors found that individuals with IBD had a 4.8 fold increase risk of Clostridium difficile infection.

T-D Kanneganti. NEJM 2017; 377: 694-6. This review examined the NLRP3 Inflammasome.  Neudecker et al (J Exp Med 2017; 214: 1737-52) identified microRNA miR-223 which functions “to suppress the Nlrp3 inflammasone during acute colitis.” Other useful points in this review of basic research:

  • “The majority of the immune cells in the body are located in the intestine, where they are spatially separated from more than 10 trillion microorganisms by a layer of mucus and a layer of epithelial cells.  Deterioration of this physical barrier …underlies inflammatory bowel disease.”
  • miR-223 is increased in the inflamed colon. “During inflammation, the expression of miR-223 is also upregulated..and the molecule binds to its complementary sequence in a regulatory part of Nlrp3 mRNA…lead[ing] to decreased Nlrp3 expression and the consequent dampening of interleukin-1β maturation and associated inflammation.”

Autoimmune Hepatitis and Hepatocellular Carcinoma

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Briefly noted:

A Tansel et al. Clin Gastroenterol Hepatol 2017; 15: 1207-17.  This systematic review and meta-analysis identified 25 studies and 6528 patients examining the relationship between autoimmune hepatitis (AIH) and hepatocellular carcinoma (HCC) .  In these studies the median followup was 8.0 years.  Key findings:

  • The pooled incidence of HCC was 3.06 per 1000 patient-years
  • 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their diagnosis

My take: This study demonstrates that AIH patients with cirrhosis are at increased risk for HCC.  In patients with AIH who do not have cirrhosis, there does not appear to be a significant risk of HCC.

Also: Link for Online Resource for Hepatopulmonary Syndrome (Canadian Sponsored site). This site has content for patients and for practitioners, including a useful video.

 

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Probiotics Lower Risk of Sepsis in Newborns

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Summary of recent study from NPR: Probiotic Bacteria Can Protect Newborns from Deadly Infections

Previous studies have shown that probiotics lower the risk of necrotizing enterocolitis in premature infants.  Now, a study (full text link below) from India examines whether probiotics could lower other infections.

An excerpt:

Feeding babies the microbes dramatically reduces the risk newborns will develop sepsis, scientists report Wednesday in the journal Nature.

Sepsis is a top killer of newborns worldwide. Each year more than 600,000 babies die of the blood infections, which can strike very quickly…

Babies who ate the microbes [Lactobacillus plantarum] for a week — along with some sugars to feed the microbes — had a dramatic reduction in their risk of death and sepsis. They dropped by 40 percent, from 9 percent to 5.4 percent.

But that’s not all. The probiotic also warded off several other types of infections, including those in the lungs. Respiratory infections dropped by about 30 percent…

The only significant side effect seen in the study was abdominal distension, which occurred in six babies. But there were more cases reported in the placebo group than in the group that got the probiotic.

Full text link (thanks to Kipp Ellsworth’s twitter feed for this link): A randomized synbiotic trial to prevent sepsis in newborns in rural India. P Panigrahi et al.

My take: Whether probiotics would be useful broadly in full-term infants in developed countries is uncertain –more studies are needed.

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We Are Last in Health Care Among High-Income Countries

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In a recent commentary (EC Schneider, D Squires. NEJM 2017; 377: 901—4) explains why the U.S. Health Care System is last among high-income countries.

Overall, the U.S. “begins with a challenge: its population is sicker and has higher mortality than those of other high-income countries.”  The U.S. has a rate of death from “conditions that can be managed and treated effectively (referred to as ‘mortality amenable to health care’) is far higher than in other high-income countries.

Four areas that have to be addressed to help U.S. move from last to first:

  • U.S. must confront lack of access to health care. The top-ranked countries offer universal insurance coverage with minimal out-of-pocket costs for preventive and primary care.
  • Underinvestment in primary care. In other countries, a higher percentage of “the professional workforce is dedicated to primary care than to specialty care.”
  • Administrative inefficiency. “Both patients and professionals In the United States are baffled by the complexity of obtaining care and paying for it.”
  • Disparities in the delivery of care. This may be mediated in part by a less robust social safety net than other high-income countries.  “Social spending [for] stable housing, educational opportunities, nutrition, and transportation may reduce the demand for” many health care services.

My take: It makes me mad that our health care system performs so poorly compared to other countries.

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Statin Use for Patients with Cirrhosis

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There have been a number of studies suggesting a beneficial effect of statins for individuals chronic liver disease due to HBV infection, HCV infection, and nonalcoholic steatohepatitis. The potential reasons include lower portal hypertension due to increased nitric oxide availability, anti-inflammatory effects through reduction in some cytokines, and antifibrotic effects. In addition, statins may inhibit tumor initiation/hepatocellular carcinoma (HCC).

The background on these prior studies is detailed in a new population-based study (F-M Chang et al Hepatology 2017; 66: 896-907, editorial 697-9) of statins in patients with cirrhosis. In this nested case-control study from Taiwan, the authors examined patients (n=1350) with cirrhosis from 2000 to 2013.  The index cases of cirrhosis were identified among a representative, well-validated general population database of 1,000,000 people.

Key findings:

  • “Statin use decreased the risk of decompensation, mortality, and HCC in a dose-dependent manner.”
  • Risk of decompensation among chronic HBV statin users, HR 0.39
  • Risk of decompensation among chronic HCV statin users, HR 0.51
  • Risk of decompensation among alcohol-related cirrhosis patients taking statins, HR 0.69

My take: In adults with cirrhosis, particularly HBV-related and HCV-related, taking a statin was associated with a 50-60% lower likelihood of decompensation. A prospective study could confirm these findings.

Prague -Charles Bridge

WIC Formula Selection in Infants and Children

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Over the past year, I have been working with the Georgia Chapter of the American Academy of Pediatrics alongside Stan Cohen, MD and Kylia Crane RDN, LD to develop an algorithm to improve formula selection for young children who use the WIC program.  This project was modeled after a similar project for infants.  Here are two of the slides and then the entire slideset is included below:

Link to slideset: AAPformulaAlgorithmsWIC