Citations

ABSTRACT In four groups of subjects free of thyroid disease, the following determinations were made: serum concentrations of thyroxine (T 4 ), triiodothyronine (T 3 ), reverse T 3 (rT 3 ) and diiodothyronine (T 2 ), and calculated indices of free thyroxine (FT 4 ) and free triiodothyronine (FT 3 ). Group A comprised healthy subjects aged 16–64; Group B, 24 healthy elderly subjects aged 68–95; Group C, 23 elderly patients with mild well‐controlled chronic illnesses, aged 70–85; Group D, 40 nursing home residents aged 66–100. Serum T 4 and T 2 concentrations and the FT 4 index were not affected by age; the rT 3 concentration was slightly but significantly elevated only in Group D patients. Serum T 3 concentration was significantly lower in all groups of elderly subjects and decreased FT 3 index measurements were detected after age 75. It was concluded that old age, without complicating illness, is accompanied only by a decrease in the serum level of T 3 and the FT 3 index; values for other iodothyronines are unchanged. Clinicians should consider the age‐related changes in T 3 and FT 3 values when interpreting thyroid function tests.

Background— Long-QT syndrome (LQTS) may result in syncope, seizures, or sudden cardiac arrest. Although 16 LQTS-susceptibility genes have been discovered, 20% to 25% of LQTS remains genetically elusive. Methods and Results— We performed whole-exome sequencing child–parent trio analysis followed by recessive and sporadic inheritance modeling and disease-network candidate analysis gene ranking to identify a novel underlying genetic mechanism for LQTS. Subsequent mutational analysis of the candidate gene was performed with polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing on a cohort of 33 additional unrelated patients with genetically elusive LQTS. After whole-exome sequencing and variant filtration, a homozygous p.D18fs*13 TRDN -encoded triadin frameshift mutation was discovered in a 10-year-old female patient with LQTS with a QTc of 500 milliseconds who experienced recurrent exertion-induced syncope/cardiac arrest beginning at 1 year of age. Subsequent mutational analysis of TRDN revealed either homozygous or compound heterozygous frameshift mutations in 4 of 33 unrelated cases of LQTS (12%). All 5 TRDN-null patients displayed extensive T-wave inversions in precordial leads V 1 through V 4 , with either persistent or transient QT prolongation and severe disease expression of exercise-induced cardiac arrest in early childhood (≤3 years of age) and required aggressive therapy. The overall yield of TRDN mutations was significantly greater in patients ≤10 years of age (5 of 10, 50%) compared with older patients (0 of 24, 0%; P =0.0009). Conclusions— We identified TRDN as a novel underlying genetic basis for recessively inherited LQTS. All TRDN-null patients had strikingly similar phenotypes. Given the recurrent nature of potential lethal arrhythmias, patients fitting this phenotypic profile should undergo cardiac TRDN genetic testing.

SummaryPatients with mantle cell lymphoma (MCL) generally respond to first‐line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL‐001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long‐term efficacy follow‐up of the prospective phase II MCL‐001 study (N = 134), including new exploratory analyses with baseline Ki‐67 (MIB1), a biological marker of tumour proliferation. With longer follow‐up, lenalidomide showed a 28% overall response rate [ORR; 8% complete response (CR)/CR unconfirmed (CRu)]. Median duration of response (DOR), progression‐free survival and overall survival were 16·6, 4·0 and 20·9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki‐67. Ki‐67 data in 81/134 MCL‐001 patients showed similar ORRs in both low (<30% or <50%) versus high (≥30% or ≥50%) Ki‐67–expressing groups, yet lower Ki‐67 levels demonstrated superior CR/CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post‐bortezomib.

Principles and Practice of Nursing Home Care . Edited by Paul R. Katz, MD and Evan Calkins, MD. New York, Springer Publishing Company, Inc., 1989. 443 pages. $43.95.

Key Points The mTOR pathway is constitutively activated in the TCL cells and is responsible for TCL proliferation. This is first trial to demonstrate that mTORC1 inhibitors (everolimus) have substantial antitumor activity (44% overall response rate) in patients with relapsed TCL.

Background and objectives New-onset diabetes and concomitant weight loss occurring several months before the clinical presentation of pancreatic cancer (PC) appear to be paraneoplastic phenomena caused by tumour-secreted products. Our recent findings have shown exosomal adrenomedullin (AM) is important in development of diabetes in PC. Adipose tissue lipolysis might explain early onset weight loss in PC. We hypothesise that lipolysis-inducing cargo is carried in exosomes shed by PC and is responsible for the paraneoplastic effects. Therefore, in this study we investigate if exosomes secreted by PC induce lipolysis in adipocytes and explore the role of AM in PC-exosomes as the mediator of this lipolysis. Design Exosomes from patient-derived cell lines and from plasma of patients with PC and non-PC controls were isolated and characterised. Differentiated murine (3T3-L1) and human adipocytes were exposed to these exosomes to study lipolysis. Glycerol assay and western blotting were used to study lipolysis. Duolink Assay was used to study AM and adrenomedullin receptor (ADMR) interaction in adipocytes treated with exosomes. Results In murine and human adipocytes, we found that both AM and PC-exosomes promoted lipolysis, which was abrogated by ADMR blockade. AM interacted with its receptor on the adipocytes, activated p38 and extracellular signal-regulated (ERK1/2) mitogen-activated protein kinases and promoted lipolysis by phosphorylating hormone-sensitive lipase. PKH67-labelled PC-exosomes were readily internalised into adipocytes and involved both caveolin and macropinocytosis as possible mechanisms for endocytosis. Conclusions PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect.

BACKGROUNDBiomarkers are routinely used to predict responses to systemic therapies, but their utility for predicting responses to local therapy for breast cancer is not known. This study determined whether biomarkers could predict responses to breast‐conserving therapy (BCT) and mastectomy.METHODSA review of the Surveillance, Epidemiology, and End Results database identified women diagnosed with early‐stage invasive ductal breast cancer and treated with BCT or mastectomy from 1998 to 2008. The estrogen receptor (ER) status and the histologic grade were used to construct 3 biomarker profiles: low risk (ER‐positive, low/intermediate grade), intermediate risk (ER‐positive, high grade), and high risk (ER‐negative, any grade). The primary measured outcome was disease‐specific survival (DSS).RESULTSBCT and mastectomy were performed in 114,486 patients (59.2%) and 79,035 patients (40.8%), respectively. There were 122,420 low‐risk patients (63.3%), 34,341 intermediate‐risk patients (17.7%), and 36,760 high‐risk patients (19.0%). Multivariate analyses were performed separately for patients with low‐, intermediate‐, and high‐risk tumors. The adjusted hazard ratios for DSS for patients who underwent mastectomy versus BCT for low‐, intermediate‐, and high‐risk tumors were 1.66 (95% confidence interval [CI], 1.54‐1.79; P < .001), 1.40 (95% CI, 1.29‐1.53; P < .001), and 1.27 (95% CI, 1.19‐1.35; P < .001), respectively.CONCLUSIONSPatients with ER‐positive, low‐grade breast cancers who underwent mastectomy had a 66% increase in disease‐specific mortality versus those who underwent BCT. Biomarker profiles defined by the ER status and grade may improve the selection of local therapy for breast cancer. Cancer 2015;121:2705‐2712. © 2015 American Cancer Society