Eastern Cooperative Oncology Group phase II studies in advanced measurable colorectal cancer. I. Razoxane, Yoshi-864, piperazinedione, and lomustine

During a 6-month interval, Eastern Cooperative Oncology Group randomized 127 patients who had received prior chemotherapy, and who had advanced measurable, surgically incurable colorectal cancer, to receive piperazinedione (PZD), Yoshi-864, or razoxane (ICRF-159). The observed response (and median survival) rates were: PZD, one of 35 patients (17 weeks); Yoshi-864, one of 34 (19 weeks), and ICRF-159, none of 38 (23 weeks). Among 107 evaluable patients, there were five episodes of life-threatening toxicity with PZD (one death) and four with ICRF-159 (two deaths). In the same protocol, 42 evaluable patients who had not received prior chemotherapy were randomized to be treated with lomustine (CCNU) or one of the three drugs in the "previously treated" trial. One CR (41 weeks) was seen with ICRF-159 and two PRs were seen with CCNU. Life-threatening toxicity occurred in three patients, two who received CCNU (one death) and one who received PZD. No survival advantage was seen. We do not encourage further phase II trials in colorectal cancer with the agents studied.     

Bone material properties in premenopausal women with idiopathic osteoporosis

Idiopathic osteoporosis (IOP) in premenopausal women is characterized by fragility fractures at low or normal bone mineral density (BMD) in otherwise healthy women with normal gonadal function. Histomorphometric analysis of transiliac bone biopsy samples has revealed microarchitectural deterioration of cancellous bone and thinner cortices. To examine bone material quality, we measured the bone mineralization density distribution (BMDD) in biopsy samples by quantitative backscattered electron imaging (qBEI), and mineral/matrix ratio, mineral crystallinity/maturity, relative proteoglycan content, and collagen cross‐link ratio at actively bone forming trabecular surfaces by Raman microspectroscopy and Fourier transform infrared microspectroscopy (FTIRM) techniques. The study groups included: premenopausal women with idiopathic fractures (IOP, n = 45), or idiopathic low BMD (Z‐score ≤ ?2.0 at spine and/or hip) but no fractures (ILBMD, n = 19), and healthy controls (CONTROL, n = 38). BMDD of cancellous bone showed slightly lower mineral content in IOP (both the average degree of mineralization of cancellous bone [Cn.Ca_Mean] and mode calcium concentration [Cn.Ca_Peak] are 1.4% lower) and in ILBMD (both are 1.6% lower, p < 0.05) versus CONTROL, but no difference between IOP and ILBMD. Similar differences were found when affected groups were combined versus CONTROL. The differences remained significant after adjustment for cancellous mineralizing surface (MS/BS), suggesting that the reduced mineralization of bone matrix cannot be completely accounted for by differences in bone turnover. Raman microspectroscopy and FTIRM analysis at forming bone surfaces showed no differences between combined IOP/ILBMD groups versus CONTROL, with the exceptions of increased proteoglycan content per mineral content and increased collagen cross‐link ratio. When the two affected subgroups were considered individually, mineral/matrix ratio and collagen cross‐link ratio were higher in IOP than ILBMD. In conclusion, our findings suggest that bone material properties differ between premenopausal women with IOP/ILBMD and normal controls. In particular, the altered collagen properties at sites of active bone formation support the hypothesis that affected women have osteoblast dysfunction that may play a role in bone fragility. © 2012 American Society for Bone and Mineral Research.     

Low-dose cyclosporine mediates donor hyporesponsiveness in a fully mismatched rat kidney transplant model

Tolerance induction protocols have been successfully tested in animal models, yet their compatibility with immunosuppressive drugs remains to be fully elucidated. Our own previous data have indicated that cyclosporine A (CsA) affects the balance of effector and regulatory mechanisms with low-dose CsA doses promoting hyporesponsiveness. Here, we present a fully mismatched rat kidney model in which low-dose CsA treatment induces donor hyporesponsiveness to secondary renal allografts. Lewis recipients of DA kidney grafts received low, medium or high doses of CsA × 10 days. By 30 days, the primary transplant was removed and a second transplant of donor origin was engrafted. Following low-dose CsA, but not high-dose CsA treatment of the primary recipient, secondary transplants were accepted long-term in the absence of immunosuppression. Regulatory T-cell function was unimpaired and independent of the CyA dosage. Of note, low-dose CsA significantly reduced alloantibody titers in primary recipients. Adoptive transfer of graft infiltrating cells or splenocytes from hyporesponsive recipients supported long-term acceptance of donor kidney allografts. These results demonstrate a dose-dependent and transferable "pro-tolerogenic" effect of low-dose CsA treatment. This model is of clinical relevance to test the interference of CsA with tolerance induction in the absence of additional immunosuppression.     

Fibroblast subpopulations in intra-oral wound healing

The objective of this study was to characterize fibroblasts at sequential time points during intra-oral wound healing in the rat. Experimental wounds were made at several time points in the mucoperiosteum of the palate of 35-day-old Wistar rats. Fibroblasts were cultured from the biopsies under standard conditions for the same number of passages. The expression of the integrin subunits alpha 1, alpha 6, and beta 1; and the intermediate filaments alpha-smooth muscle actin and vimentin were analyzed by flow cytometry. Western blot analysis was performed at 0, 8, and 60 days postwounding to confirm the expression of both intermediate filaments. The phenotypic profiles of fibroblasts cultured from subsequent stages in the wound healing process differed considerably. We conclude that distinct fibroblast phenotypes can be isolated from different stages in wound healing. These phenotypes remained stable during in vitro culturing. In addition, cryosections of the wound areas were made at identical time points and were immunohistochemically stained for the same antigens. The immunohistochemical staining correlated well to the flow-cytometric data. These results suggest the occurrence of multiple subpopulations of fibroblasts with a specialized function during wound healing. We hypothesize that undesirable consequences of wound healing might be prevented through the modulation of specific fibroblast subpopulations.     

Impaired skeletal health and neuromuscular function among amphetamine users in clinical treatment

Summary

This study examined musculoskeletal health in amphetamine users, compared with healthy age-matched controls. We show that amphetamine users have reduced bone mass at several skeletal sites and attenuated maximal muscle strength and force development capacity in the lower extremities.

Introduction

Amphetamine use may cause poor bone quality and elevated risk of osteoporosis. The purpose of this study was to investigate whether amphetamine users exhibit reduced regional and whole body bone mineral density (BMD), altered bone metabolism, and how muscle function may relate to the patient groups’ skeletal health.

Methods

We assessed hip, lumbar spine and whole body BMD, and trabecular bone score (TBS) by dual x-ray absorptiometry (DXA), and bone metabolism markers in serum and maximal strength and force development capacity in 36 amphetamine users (25 men, 30?±?7 years; 11 women 35?±?10 years) and in 37 healthy controls (23 men, 31?±?9 years; 14 women, 35?±?7 years).

Results

Whole body BMD was lower in amphetamine users (8 % in males and 7 % females, p?<?0.01), as were BMD at the total hip and sub-regions of the hip (9–11 % in men and 10–11 % in women, p?<?0.05). Male users had 4 % lower TBS (p?<?0.05) and higher serum level of type 1 collagen amino-terminal propeptide (p?<?0.01). This coincided with reduced lower extremity maximal strength of 30 % (males, p?<?0.001) and 25 % (females, p?<?0.05) and 27 % slower muscular force development in males compared to controls (p?<?0.01).

Conclusions

These findings demonstrate that amphetamine users suffer from a generalized reduction in bone mass, which was associated with attenuated maximal muscle strength and force development capacity in the lower extremities.

     

Evidence for a curvilinear relationship between posttraumatic growth and posttrauma depression and PTSD in assault survivors

Two studies of assault survivors (Ns = 180, 70) examined associations between posttraumatic growth (PTG) and posttrauma psychopathology. Both studies found significant curvilinear associations between PTG and posttraumatic stress disorder, whereas only Study 1 found a curvilinear association between PTG and depression symptom severity. Survivors with no or high growth levels reported fewer symptoms than those who reported moderate growth. Study 1 also investigated potential PTG predictors. Non‐Caucasian ethnicity, religiousness, peritraumatic fear, shame, and ruminative thinking style, assessed at 2 weeks, predicted growth at 6 months. Posttraumatic growth may thus be most relevant in trauma survivors who attach enduring significance to the trauma for their lives and show initial distress. Moderate levels of PTG do not seem to ameliorate posttrauma psychopathology.     

Leukocyte Depletion in Allogeneic Blood Transfusion Does Not Change the Negative Influence on Survival Following Transthoracic Resection for Esophageal Cancer

Background  Perioperative transfusion of allogeneic blood has been hypothesized to have an immunomodulatory effect and influence survival in several cancer types. This study evaluates the association between receipt of leucocyte-depleted and non-depleted allogeneic blood and survival following esophagectomy for cancer. Methods  A retrospective analysis was performed including 291 patients with esophageal cancers who underwent transthoracic en bloc esophagectomy and extended mediastinal lymphadenectomy. Neoadjuvant chemoradiation was administered in 152 (52.2%) patients. Perioperative blood transfusions were quantified and the potential prognostic cutoff for transfused units was calculated according to LeBlanc. Results  The median number of perioperative blood transfusions was 2 (0–24), and 106 patients (36.4%) received no transfusions. Patients with one or less blood transfusion showed a significantly improved survival compared to patients receiving more than one unit (p < 0.009). In multivariate analysis, blood transfusion categories showed significance (p < 0.015) next to pT, pN, pM category, and residual tumor categories (R-categories). Separate analysis of 183 patients treated after the mandatory introduction of leukocyte-depleted blood transfusions detected a strong tendency, but no significant difference in survival for patients getting one or less or more than one transfusion (p = 0.056). Receipt of leukocyte-depleted versus non-depleted units, however, had no influence on survival (p = 0.766). Conclusions  The need for perioperative allogeneic blood transfusions is significantly associated with poorer survival following resection for esophageal cancer by univariate and multivariate analysis. Our data suggest that the reduction of leukocytes in allogeneic transfusions is not sufficient to overcome the negative influence on survival. This paper was presented at DDW 2008 in the San Diego Convention Center, San Diego, CA, May 17–22, 2008.     

Prevalence of lymph nodes in the apex of level V: a plea against the necessity to dissect the apex of level V in mucosal head and neck cancer

BACKGROUND: We assessed the prevalence of histologically proven normal or invaded lymph nodes in the apex of level V. METHODS: Seventy neck dissections were performed in 41 patients with mucosal head and neck squamous cell carcinoma (SCC). Fifty-one neck dissections were performed in 30 previously untreated patients (group 1); 19 neck dissections were carried out in 11 patients previously irradiated (group 2). RESULTS: Pathologic analysis was unable to identify any lymph node in 70% of the apex specimens. In group 1, no lymph nodes were detected in 63%, whereas one or more noninvaded lymph nodes were present in 37%; in group 2, no lymph nodes were identified in 89%, whereas one or more normal lymph nodes were found in 11% (p = .03). Metastatic lymph nodes were never identified. CONCLUSIONS: The prevalence of lymph nodes in the apex was 30%. No invaded lymph nodes were identified. In addition to anatomic evidence, these results suggest that dissection of the apex is not necessary in mucosal head and neck SCC.     

The PCBP1 gene encoding poly(rc) binding protein i is recurrently mutated in Burkitt lymphoma

The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG‐MYC juxtaposition. However, these translocations alone are insufficient to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole‐genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron‐less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K‐Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre‐mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20–40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis. © 2015 Wiley Periodicals, Inc.