Citations

A case involving a retired, elderly male war veteran with a symptomatic peroneus brevis muscle hernia causing superficial peroneal nerve compression with chosen surgical management is presented. Symptomatic muscle hernias of the extremities occur most commonly in the leg and are a rare cause of chronic leg pain. Historically, treating military surgeons pioneered the early documentation of leg hernias observed in active military recruits. A focal fascial defect can cause a muscle to herniate, forming a variable palpable subcutaneous mass, and causing pain and potentially neuropathic symptoms with nerve involvement. While the true incidence is not known, the etiology has been classified as secondary to a congenital (or constitutional) fascial weakness, or acquired fascial defect, usually secondary to direct or indirect trauma. The highest occurrence is believed to be in young, physically active males. Involvement of the tibialis anterior is most common, although other muscles have been reported. Dynamic ultrasonography or magnetic resonance imaging is often used to confirm diagnosis and guide treatment. Most symptomatic cases respond successfully to conservative treatment, with surgery reserved for refractory cases. A variety of surgical techniques have been described, ranging from fasciotomy to anatomical repair of the fascial defect, with no consensus on optimal treatment. Clinicians must remember to consider muscle hernias in their repertoire of differential diagnoses for chronic leg pain or neuropathy. A comprehensive review of muscle hernias of the leg is presented to highlight their history, occurrence, presentation, diagnosis and treatment.

AbstractHuman herpesvirus 6 (HHV‐6A and HHV‐6B) can cause primary infection or reactivate from latency in liver transplant recipients, which can result in a variety of clinical syndromes, including fever, hepatitis, encephalitis and higher rates of graft dysfunction as well as indirect effects including increased risks of mortality, CMV disease, hepatitis C progression and greater fibrosis scores. Although HHV‐6 infection is currently diagnosed by quantifying viral DNA in plasma or blood, biopsy to demonstrate histopathological effects of HHV‐6 remains the gold standard for diagnosis of end‐organ disease. HHV‐6 reactivation may be restricted to the infected organ with no evidence of active infection in the blood. HHV‐6 infections in liver transplant patients are mostly asymptomatic, but clinically significant tissue‐invasive infections have been treated successfully with ganciclovir, foscarnet or cidofovir. Inherited chromosomally integrated HHV‐6 (ciHHV‐6), in either the recipient or the donor organ, may create confusion about systemic HHV‐6 infection. Recipients with inherited ciHHV‐6 may have an increased risk of opportunistic infection and graft rejection. This article reviews the current scientific data on the clinical effects, risk factors, pathogenesis, diagnosis and treatment of HHV‐6 infections in liver transplant recipients.

Abstract Purpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human anti–insulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor–positive breast cancer. Experimental Design: Patients with hormone receptor–positive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored. Results: Ninety-three patients were randomized (arm A, n = 62; arm B, n = 31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)]. Conclusions: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1R–targeted therapies requires further validation. Clin Cancer Res; 22(2); 301–9. ©2015 AACR.

Abstract Background: Protein kinase Cβ (PKCβ) is critical for B-cell signaling and survival and overexpression of PKCβ in DLBCL is associated with inferior survival. ENZA, an oral serine/threonine kinase inhibitor, targets PKCβ. Here we report immunohistochemical (IHC) and fluorescence in-situ hybridization (FISH) correlative analyses. Methods: PRELUDE (NCT00332202) was a phase III, double-blind maintenance study of 758 pts with DLBCL who were randomized 2:1 to ENZA 500 mg daily (1125-mg loading dose) (n = 504) or PBO (n = 254), respectively, following CR to induction therapy with R-CHOP. The primary endpoint was disease-free survival (DFS). Overall survival (OS) and assessment of biomarkers specific to ENZA and DLBCL were secondary endpoints. Pre-treatment formalin-fixed, paraffin-embedded samples were assessed via IHC staining in a blinded manner (Eric Hsi) for cell of origin (COO) using Hans’ algorithm. In addition, IHC was performed for c-MYC, BCL2, BCL6, FOXP1, and MUM1 (10% increments/% tumor cells stained), markers relevant to ENZA, including PKCβ2. FISH was performed to identify translocations involving c-MYC, BCL2, and BCL6. Cox regression was used to determine statistical associations between efficacy outcomes and dichotomized markers, adjusting for treatment and additional baseline covariates. All tests of association were conducted at a 2-sided α = 0.05. Results: There was no difference in 4-year DFS (70% vs 71%) or OS (81% vs 82%) between ENZA and PBO arms, respectively. A total of 243 (32%) pts had ≥1 evaluable sample available for IHC and FISH. There was no difference in outcome for pts based on COO (GCB vs non-GCB). Independent of treatment, significant associations were observed for BCL2 (pre-specified cutpoint 20%) and MUM1 (cutpoint 30%) with OS, and FOXP1 (cutpoint 80%) by IHC with DFS (HR [95% CI]: 2.19 [1.01-4.73]), p = 0.031; 1.97 [1.04-3.71], p = 0.032; 1.74 [1.04-2.90], p = 0.032, respectively). Associations were not significant for other IHC markers, including c-MYC and BCL6. Low PKCβ2 (<50% expression) had numerically better (but not significant) DFS/OS vs high PKCβ2. Dual translocation lymphoma by FISH was identified in two pts (1.2%) each for c-MYC/BCL2 and c-MYC/BCL6, and one pt (0.6%) had a triple hit involving c-MYC/BCL2/BCL6. Conclusions: No difference in outcomes between treatment arms was observed for the trial. Independent of treatment, COO was not prognostic of outcomes. Pts with low PKCβ2 expression had numerically better DFS/OS compared with high PKCβ2 expression. Significant treatment-independent associations were observed for BCL2 and MUM1 with OS and for FOXP1 with DFS (low IHC expression corresponded to better outcomes). The small number of double hit and triple hit lymphomas seen in the study may reflect the enrollment of CR patients with more favorable biology. Citation Format: Eric D. Hsi, Kerry J. Savage, Sonali M. Smith, Fritz Offner, Scott P. Myrand, Thomas M. Habermann, Donald E. Thornton, Boris K. Lin, Tuan S. Nguyen, Oday Hamid, Michael Crump. Correlative results from PRELUDE, a phase III study of enzastaurin (ENZA) vs placebo (PBO) in patients (pts) with high-risk diffuse large B-cell lymphoma (DLBCL) following a response to R-CHOP therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5303. doi:10.1158/1538-7445.AM2015-5303

We describe a case of a 73-year-old man who presented with right-sided abdominal pain associated with palpable mass. Initial laboratory examination was normal except lactate dehydrogenase level. Subsequent CT image showed situs inversus and splenic mass with multiple lymph nodes enlargement. Biopsy taken from the splenic mass demonstrated mantle cell lymphoma. Staging CT examination was performed with intravenous contrast, and patient developed altered mental status, respiratory failure and acute kidney injury requiring intensive care unit care. Laboratory examination revealed hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia, which are consistent with spontaneous tumour lysis syndrome. The patient was successfully treated with rasburicase and haemodialysis, and completed the first course of chemotherapy without further complications.

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.

AbstractBackgroundRepair of complex incisional hernias poses a major challenge.AimThe aim of this study was to review the outcomes of the modified Rives‐Stoppa repair of complex incisional hernias using a synthetic prosthesis.MethodsWe reviewed patients undergoing a modified Rives‐Stoppa repair of complex incisional hernias from 1990 to 2003. Patients were followed through clinic visits and mailed questionnaires. Follow‐up data were complete in all patients (mean 70 months, range 24–177 months), and 87% of patients completed a mailed questionnaire. Primary outcome included mortality, morbidity, and hernia recurrence. Secondary outcome measures were duration of hospital stay, long‐term abdominal wall pain, and self‐reported patient satisfaction.ResultsAltogether, 254 patients underwent a modified Rives‐Stoppa repair. Among them, 60% had a significant co‐morbidity, and 30% had one or more previously failed hernia repairs. Mortality was zero, and overall morbidity was 13% (wound infection 4%, prosthetic infection 3%, seroma/hematoma 4%). The overall hernia recurrence rate was 5%, including explantation of mesh because of infection. Wound/prosthetic infection was predictive for hernia recurrence (31% vs. 4%, p = 0.003). Among the respondents, 89% reported overall satisfaction with their repair.ConclusionThe Rives‐Stoppa repair of complex incisional hernias using synthetic prosthetic materials is safe with a low recurrence rate (5%) and high patient satisfaction. Postoperative wound infection is a risk factor for hernia recurrence.

OBJECTIVE. The aim of this study was to review our institutional experience managing pheochromocytomas and paragangliomas in children.METHODS. A retrospective chart review of the Mayo Clinic database from 1975 to 2005 identified 30 patients <18 years of age with histologically confirmed pheochromocytoma or paraganglioma.RESULTS. There were 12 patients with pheochromocytomas and 18 with paragangliomas. The most common presenting symptoms were hypertension (64%), palpitation (53%), headache (47%), and mass-related effects (30%). Nine patients (30%) had a genetic mutation or documented family history of pheochromocytoma or paraganglioma. Fourteen patients (47%) had malignant disease, whereas 16 (53%) had benign disease. Logistic analysis showed that statistically significant risk factors for malignancy were (1) paraganglioma, (2) apparently sporadic, as opposed to familial, pheochromocytoma or paraganglioma, and (3) tumor size of >6 cm. Surgical resection was performed for 28 patients (93%), with perioperative mortality and major morbidity rates of 0% and 10%, respectively. Resection achieved symptomatic relief for 25 patients (83%). All patients with benign disease appeared cured after resection. For patients with malignant disease, the 5- and 10-year disease-specific survival rates were 78% and 31%, respectively, and the mean survival time was 157 ± 32 months.CONCLUSIONS. The incidence of malignant pheochromocytoma/paraganglioma was high in children (47%), particularly those with apparently sporadic disease, paraganglioma, and tumor diameters of >6 cm. Patients with a known genetic mutation or familial pheochromocytoma/paraganglioma were more likely to achieve resection with negative microscopic margins and had improved disease-specific mortality rates. Surgical resection remains the treatment of choice for pheochromocytoma and paraganglioma.

Abstract We report here the first association between vitamin D–resistant rickets, alopecia, and type 1 diabetes in a child with compound heterozygous mutations in the VDR gene. Transfection studies suggest dissociated effects of VDR gene mutations on the regulation of genes involved in vitamin D metabolism and dendritic cell maturation. Introduction: Whereas vitamin D may play a role in the immune tolerance process, no patient has been reported to associate hereditary vitamin D–resistant rickets (HVDRR) and an autoimmune disease, and no attempt has been made to delineate the outcome of mutations of the vitamin D receptor (VDR) on the transcription of genes controlling immune tolerance. Materials and Methods: The VDR gene was analyzed in a child with vitamin D–resistant rickets, total alopecia, and early childhood–onset type 1 diabetes. Patient's fibroblasts and COS-7 cells transfected with wildtype or mutant VDRs were studied for ligand-binding capacity, transactivation activity using two gene promoters [CYP-24, a classical 1,25(OH)2D3-responsive gene, and relB, a critical NF-κB component for regulation of dendritic cell differentiation], VDR-RXR heterodimers association to CYP 24 VDREs by gel mobility shift assays, and co-activator binding by Glutathione-S-transferase pull-down assays. Results: Two novel compound heterozygous mutations (L263R and R391S) were identified in the VDR ligand-binding domain in this child. Both mutations significantly impaired VDR ligand-binding capacity but had dissociated effects on CYP-24 and RelB promoter responses to vitamin D. CYP 24 response binding to SRC-1 and RXR-heterodimer binding to CYP24 VDREs were abolished in L263R mutants but normal or partially altered in R391S mutants. In the opposite, RelB responses to vitamin D were close to normal in L263R mutants but abolished in R391S mutants. Conclusions: We report the first clinical association between HVDRR, total alopecia, and early childhood–onset type 1 diabetes. Mutations in the VDR ligand-binding domain may hamper the 1,25(OH)2D3–mediated relB responses, an effect that depends on the site of the VDR mutation and cannot be anticipated from VDR ligand-binding ability or CYP-24 response. Based on these results, we propose to survey the immune function in patients with HVDRR, including those with moderate features of rickets.