Citations

Abstract Erdheim‐Chester disease ( ECD ) is a non‐Langerhans cell histiocytosis that affects multiple body organs, notably the skeletal system. We examined a 58‐year‐old man who presented with ataxia and T2 hyperintensity of the middle cerebellar peduncles and dentate nuclei without contrast enhancement on MRI brain. Workup for malignancy revealed “hairy kidneys” on CT scan of the abdomen, and excisional biopsy of the retroperitoneal mass for concerns of lymphoma revealed foamy histiocytes that tested positive for CD 68 and negative for CD 1a, confirming the diagnosis of ECD . Further genetic testing on excised tissue revealed BRAF (V600E) gene mutation that is present in 50% of ECD patients. Treatment was initiated with targeted therapy using the BRAF inhibitor Dabrafenib. X‐ray of the lower extremities did not reveal sclerosis of the long bones, and bone scan with technetium 99 was negative except for a nonspecific tracer uptake in left calvarial bone with no corresponding CT changes or T1/T2 signal changes on MRI . His MRI brain revealed classic cerebellar involvement in ECD without other central nervous system ( CNS ) involvement. It has been postulated that bone involvement is almost universal in ECD ; however, our patient with ECD had ataxia and cerebellar involvement without significant bone involvement, as evidenced by bone scan. This is a rare presentation of ECD affecting the CNS and sparing the skeletal system. It confirms the wide spectrum of presentation this multisystem disease can have.

AbstractBackgroundWhile high resolution esophageal manometry combined with impedancometry has demonstrated that gastric pressurizations lead to rumination, the contribution of upper esophageal sphincter (UES) and esophagogastric junction (EGJ) function to rumination is unclear. Behavioral therapy with diaphragmatic breathing (DB) can reduce rumination. We aimed to evaluate the pressures in the stomach, EGJ and UES during rumination and the effects of DB augmented with biofeedback therapy.MethodsSixteen patients with rumination were studied with manometry and impedancometry before and after a meal. The postprandial assessment comprised three periods: before, during, and after DB augmented with biofeedback therapy.Key ResultsAll patients had postprandial rumination, which was associated (p < 0.001) with increased gastric pressure and reversal of the postprandial gastroesophageal pressure gradient from −4 (−43 to 18) before to 20 (7–79) mmHg during rumination. The EGJ pressure was lower (p < 0.001) during gastric pressurizations that were associated with rumination vs those that were not. The UES also relaxed, almost completely, during rumination. Patients had a median (range) of 5 (2–10) rumination episodes before, 1 (0–2) (p < 0.001) during, and 3 (1–5) after (p < 0.001 vs during) diaphragmatic breathing. During manometry and impedancometry, DB was well‐tolerated and learned within 5 min. Diaphragmatic breathing increased EGJ pressure (p < 0.001) and restored a negative gastroesophageal pressure gradient (−20 mmHg [−80 to 7]).Conclusions & InferencesDiaphragmatic breathing aided with high resolution esophageal manometry is well‐tolerated, effective and averts the gastroesophageal pressure disturbance that leads to rumination.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients requiring initial therapy are often older and frailer and unsuitable candidates for standard chemoimmunotherapy regimens. Shorter duration combination monoclonal antibody (mAb) therapy using alemtuzumab and rituximab has been shown to be effective and tolerable treatment for CLL. Standard dose anti‐CD20 mAb therapy causes loss of CD20 expression by surviving CLL cells, which can be minimized by decreasing the mAb dose. We report a randomized phase II clinical trial enrolling older (≥ 65 years) patients (median age 76 years, n = 31) with treatment naïve progressive CLL. Patients received 8‐12 weeks of standard subcutaneous alemtuzumab with either intravenous standard (375 mg/m2 weekly)(n = 16) or low dose (20 mg/m2 3x week)(n = 15) rituximab. This study was closed before full accrual because the manufacturer withdrew alemtuzumab for treatment of CLL. The overall response rate was 90% with an 45% complete response rate, median progression‐free survival of 17.9 months and no significant differences in outcome between the low and standard dose rituximab arms. The major toxicities were cytopenia and infection with one treatment fatality caused by progressive multifocal leukoencephalopathy but no other opportunistic infections. Combination mAb therapy was effective and tolerable treatment for older and frailer patients with progressive CLL, achieving a high rate of complete remissions. These data support the role of mAb in therapy for less fit CLL patients and the further study of low dose higher frequency anti‐CD20 mAb therapy as a potentially more effective use of anti‐CD20 mAb in the treatment of CLL. Am. J. Hematol. 91:308–312, 2016. © 2015 Wiley Periodicals, Inc.

© 2016 Heart Rhythm Society, the American College of Cardiology Foundation, and the Society for Cardiovascular Angiography and Interventions

Background Idiopathic dilated cardiomyopathy ( DCM ) is typically diagnosed in adulthood, yet familial cases exhibit variable age‐dependent penetrance and a subset of patients develop sporadic DCM in childhood. We sought to discover the molecular basis of sporadic DCM in an 11‐year‐old female with severe heart failure necessitating cardiac transplantation. Methods and Results Parental echocardiograms excluded asymptomatic DCM . Whole exome sequencing was performed on the family trio and filtered for rare, deleterious, recessive, and de novo variants. Of the 8 candidate genes identified, only 2 had a role in cardiac physiology. A de novo missense mutation in TNNT 2 was identified, previously reported and functionally validated in familial DCM with markedly variable penetrance. Additionally, recessive compound heterozygous truncating mutations were identified in XIRP 2 , a member of the ancient Xin gene family, which governs intercalated disc ( ICD ) maturation. Histomorphological analysis of explanted heart tissue revealed misregistration, mislocalization, and shortening of ICD s, findings similar to Xirp2 −/− mice. Conclusions The synergistic effects of TNNT 2 and XIRP 2 mutations, resulting in perturbed sarcomeric force generation and transmission, respectively, would account for an early‐onset heart failure phenotype. Whereas the importance of Xin proteins in cardiac development has been well established in animal models, this study implicates XIRP 2 as a novel modifier gene in the pathogenesis of DCM .

Abstract Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types. Significance: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer. Cancer Discov; 6(2); 166–75. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109