Citations

SummaryThis single institution, open label Phase I‐II dose escalation trial evaluated the safety and efficacy of the combination of lenalidomide (Revlimid®), cyclophosphamide and prednisone (CPR) in patients with relapsed/refractory multiple myeloma. The maximal administered dose of CPR consisted of cyclophosphamide 300 mg/m2 on day 1, 8, and 15, lenalidomide 25 mg on d 1–21 and prednisone 100 mg every other day in a 28‐d cycle. Between November 2007 and June 2009, 32 patients were entered in cohorts of three at three dose levels. The median age was 64 years, 59% were male, with a median two prior regimens. Responding patients could stay on treatment until progression. The full‐dose CPR regimen produced no dose‐limiting toxicity and was delivered for a median of 16 months (3·5–65 months) with acceptable safety and tolerance. The overall response rate (≥ partial response) was 94% at a median follow up of 28 months. The median progression‐free survival was 16·1 months [95% confidence interval (CI); 10·9–22·5 months], while the median overall survival was 27·6 months (95% CI; 16·8–36·6 months). Only the beta‐2 microglobulin level at protocol entry correlated with a better survival (P = 0·047). These observations compare favourably with other 2‐ and 3‐ drug combinations for relapsed/refractory myeloma, and suggest that CPR should be evaluated further in the setting of relapsed/refractory disease, or in newly diagnosed patients.

Study Design Case report. Objective Multifocal epithelioid hemangioendothelioma (EHE) of the spine is a rare disorder. We describe a novel, multimodal treatment of a painful osteolytic lumbar lesion secondary to EHE. The minimally invasive treatment results in an excellent patient outcome with decreased morbidity compared to traditional techniques. Methods A previously healthy young adult presented with a painful osteolytic lesion at the L2 vertebrae. Imaging revealed multifocal spinal lesions consistent with a history of EHE. Core needle biopsy confirmed the diagnosis. Preoperative cryoablation of L2 was followed by a staged surgery, which included a partial L2 corpectomy, tumor resection, bone grafting, and vertebral reconstruction using a minimally invasive technique. This treatment was followed by prolonged therapy with interferon and bisphosphonate. Results At 3.5 years’ follow-up, the patient has maintained his vertebral body height, has not required a fusion, and has had no recurrence of disease. Conclusion Multimodal treatment consisting of tumor cryoablation, partial corpectomy, allograft reconstruction of the vertebrae, and adjuvant interferon and bisphosphonate can result in good outcomes for well-contained EHE tumors of the spine.

AbstractEndocrine regulation of uterine biology is critical for embryo receptivity and human reproduction. Uterine endometrium depends on extrinsic sex steroid input and hence likely has mechanisms that enable adaptation to hormonal variation. Emerging evidence suggests that sex steroid bioavailability in the endometrium is determined by adjusting their metabolic rate and fate via regulation of cytochrome (CYP) p450 enzymes. The CYP enzymes are targeted by ubiquitously expressed Sp/Krüppel-like (Sp/KLF) transcription factors. Specifically, KLF11 is highly expressed in reproductive tissues, regulates an array of endocrine/metabolic pathways via epigenetic histone-based mechanisms and, when aberrantly expressed, is associated with diabetes and reproductive tract diseases, such as leiomyoma and endometriosis. Using KLF11 as a model to investigate epigenetic regulation of endometrial first-pass metabolism, we evaluated the expression of a comprehensive array of metabolic enzymes in Ishikawa cells. KLF11 repressed most endometrial CYP enzymes. To characterize KLF11-recruited epigenetic regulatory mechanisms, we focused on the estrogen-metabolizing enzyme CYP3A4. KLF11 expression declined in secretory phase endometrial epithelium associated with increased CYP3A4 expression. Additionally, KLF11 bound to CYP3A4 promoter GC elements and thereby repressed promoter, message, protein as well as enzymatic function. This repression was epigenetically mediated, because KLF11 colocalized with and recruited the corepressor SIN3A/histone deacetylase resulting in selective deacetylation of the CYP3A4 promoter. Repression was reversed by a mutation in KLF11 that abrogated cofactor recruitment and binding. This repression was also pharmacologically reversible with an histone deacetylase inhibitor. Pharmacological alteration of endometrial metabolism could have long-term translational implications on human reproduction and uterine disease.

Herbal supplements are commonly used by patients for various problems. It is a well-known fact that most patients do not tell their physicians about the use of herbal supplements unless they are specifically asked. As a result, sometimes important information regarding drug side effects is missed in history taking. During our literature search, we found several retrospective studies and other meta-analyses that claim a lacking or weak link between black cohosh use and hepatotoxicity. We present a case of a 44-year-old female who developed subacute liver injury demonstrated on a CT scan and liver biopsy within a month of using the drug to resolve her hot flashes and discuss a possible temporal and causal association between black cohosh use and liver disease. Since the patient was not taking any other drugs, we concluded that the acute liver injury was caused by the use of black cohosh. We agree with the United States Pharmacopeia recommendations that a cautionary warning about hepatotoxicity should be labeled on the drug package.

BackgroundLong‐term follow‐up after stent dilation of native and acquired pulmonary artery stenosis is scarce in the pediatric population. Most cohorts include a myriad of anatomies and associated conditions.MethodIn order to establish objective performance criteria, we performed a retrospective review of all patients who underwent unilateral pulmonary artery stenting in biventricular physiology at three centers from June 2006 to June 2011.ResultsFifty‐eight patients received 60 stents with Palmaz Genesis stent used most commonly (78%). Average age at implantation was 10.4 ± 10.3 years and weight 31.6 ± 21.8 kg. The immediate success rate was 98%, with improvement in minimal diameter from 5.1 ± 2 cm to 10.6 ± 3 cm (P < 0.01). There were 10 complications (7 major and 3 minor) and no acute mortality. One‐year follow‐up studies were available in 48 patients (83%), including echocardiogram (60%), catheterization (28%), MRI (29%), and lung perfusion (31%). Follow‐up echocardiogram showed mild increase in stent gradient, from 5.7 ± 6.7 mm Hg post‐procedure to 17.1 ± 11.7 mm Hg. Follow‐up catheterization showed no significant change in minimal stent diameter (8.8 ± 2.6 to 7.8 ± 2.3 mm), gradient (7.7 ± 8.4 to 12.6 ± 12.2 mm Hg), or right ventricular pressures (43.7 ± 9 to 47.7 ± 10.5 mm Hg). Nine patients (16%) underwent scheduled stent redilation over a period of 12 days to 25 months.ConclusionIn conclusion, stent implantation shows excellent immediate and 1‐year follow‐up results with maintenance of improved caliber of the stented vessel and lowered right ventricular systolic pressures. © 2014 Wiley Periodicals, Inc.

Abstract Through their differential interactions with B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), the three BLyS family receptors play central roles in B cell survival and differentiation. Recent evidence indicates BLyS receptor levels shift following BCR ligation, suggesting that activation cues can alter overall BLyS receptor profiles and thus ligand sensitivity. In this study, we show that TLR stimuli also alter BLyS receptor expression, but in contrast to BCR ligation, TLR9 and TLR4 signals, preferentially increase transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI) expression. Although both of these TLRs act through MyD88-dependent mechanisms to increase TACI expression, they differ in terms of their downstream mediators and the B cell subset affected. Surprisingly, only TLR4 relies on c-Rel and p50 to augment TACI expression, whereas TLR9 does not. Furthermore, although all follicular and marginal zone B cells up-regulate TACI in response to TLR9 stimulation, only marginal zone B cells and a subset of follicular B cells respond to TLR4. Finally, we find that both BLyS and APRIL enhance viability among quiescent and BCR-stimulated B cells. However, although BLyS enhances viability among TLR stimulated B cells, APRIL does not, suggesting that TACI but not BLyS receptor 3 may share survival promoting pathways with TLRs.