Somatoform complaints in elderly of Germany

The aim of this paper is to report on the prevalence of somatoform disorders in older age. A total of 630 representatively selected persons older than 60 years were asked to complete the questionnaire SOMS 2 (Screening for somatoform disorders, Rief et al., 1997). The results show that somatoform pain is very common in old age. Of the people, 71.8% report at least one symptom, 50.5% on at least four symptoms and 23.4% suffer from at least eight symptoms. The frequency of somatoform symptoms is much higher in people over 60 years old than in persons who are younger than 60 years old. Pain is very often localized in several body regions. In contrast to findings from younger age groups, older women do not report more somatoform pain than older men. When looking at the differences between "young olds" and "old olds" somatoform pain increases with increasing age. The high frequency of somatoform pain in older people is in clear contrast to the low prevalences of somatoform disorders defined according to DSM-IV or ICD-10 (0%-0.3%). The results show that the real prevalence of somatoform disorders is extremely underestimated because of the restrictive criteria of the diagnosis systems.     

Trichinella spiralis-secreted products modulate DC functionality and expand regulatory T cells in vitro

Helminths and their products can suppress the host immune response which may benefit parasite survival. Trichinella spiralis can establish chronic infections in a wide range of mammalian hosts including humans and mice. Here, we aim at studying the effect of T. spiralis muscle larvae excretory/secretory products (TspES) on the functionality of DC and T cell activation. We found that TspES suppress in vitro DC maturation induced by both S- and R-form lipopolysaccharide(LPS) from enterobacteria. Using different toll-like receptor (TLR) agonists, we show that the suppressive effect of TspES on DC maturation is restricted to TLR4. These helminth products also interfere with the expression of several genes related to the TLR-mediated signal transduction pathways. To investigate the effect of TspES on T cell activation, we used splenocytes derived from OVA-TCR transgenic D011.10 that were incubated with OVA and TspES-pulsed DC. Results indicate that the presence of TspES resulted in the expansion of CD4(+) CD25(+) Foxp3+ T cells. These regulatory T (Treg) cells were shown to have suppressive activity and to produce TGF-β. Together these results suggest that T. spiralis secretion products can suppress DC maturation and induce the expansion of functional Treg cells in vitro.     

Subacute haematotoxicity after PRRT with <Superscript>177</Superscript>Lu-DOTA-octreotate: prognostic factors,incidence and course

Purpose

In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from ¹³¹I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with ¹⁷⁷Lu-DOTA⁰-Tyr³-octreotate (¹⁷⁷Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit.

Methods

The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined.

Results

Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0?×?10⁹/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67?±?7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq ¹⁷⁷Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients.

Conclusion

The incidence of subacute haematological toxicity after PRRT with ¹⁷⁷Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from ¹³¹I, seems not to be valid for PRRT with ¹⁷⁷Lu-DOTATATE.

     

Evaluation of biomarkers for treatment selection using individual participant data from multiple clinical trials

Biomarkers that predict treatment effects may be used to guide treatment decisions, thus improving patient outcomes. A meta‐analysis of individual participant data (IPD) is potentially more powerful than a single‐study data analysis in evaluating markers for treatment selection. Our study was motivated by the IPD that were collected from 2 randomized controlled trials of hypertension and preeclampsia among pregnant women to evaluate the effect of labor induction over expectant management of the pregnancy in preventing progression to severe maternal disease. The existing literature on statistical methods for biomarker evaluation in IPD meta‐analysis have evaluated a marker's performance in terms of its ability to predict risk of disease outcome, which do not directly apply to the treatment selection problem. In this study, we propose a statistical framework for evaluating a marker for treatment selection given IPD from a small number of individual clinical trials. We derive marker‐based treatment rules by minimizing the average expected outcome across studies. The application of the proposed methods to the IPD from 2 studies in women with hypertension in pregnancy is presented.     

Genitourinary Resection at the Time of Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis Is Not Associated with Increased Morbidity or Worsened Oncologic Outcomes: A Case-matched Study

Background

Cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC) has gained acceptance in the treatment of peritoneal carcinomatosis with reported morbidity and mortality rates of 27–56 and 0–11 %, respectively. The safety and oncologic outcome of genitourinary repair at the time of CRS and HIPEC remains unclear.

Methods

We identified 170 patients who underwent CRS-HIPEC at our institution between July 2007 and August 2011 with a minimum follow-up of 6 months. Thirty-four (20 %) underwent concomitant urologic reconstruction at the time of CRS-HIPEC and were matched by disease burden (intraoperative peritoneal cancer index [PCI]) and extent of surgery (ΔPCI) with a cohort of 38 (22.3 %) subjects without genitourinary involvement. The primary end points considered for this analysis included the development of major surgical (Clavien–Dindo Class III–V) complications and overall survival.

Results

Median follow-up was 9.4 months. The most commonly performed urologic interventions included partial cystectomy with primary repair in 23 (65.7 %) and segmental ureteral resection and repair in 11 (31.4 %). Patients with genitourinary reconstruction had more total organ involvement (6.5 vs. 4.3, p < 0.001) and more commonly underwent enteric anastomoses (82.4 vs. 57.9 %, p = 0.025). No significant differences were observed with regard to major morbidity, need for transfusion, operative time, intensive care unit admission, or length of stay. Among patients with appendiceal or colonic tumors (n = 46), overall survival was similar between genitourinary reconstruction and matched cohorts: 22.5 versus 15.1 months, respectively (p = 0.66).

Conclusions

Genitourinary reconstruction at the time of CRS-HIPEC occurs more commonly in patients with extensive disease burden undergoing radical debulking, yet does not adversely influence surgical morbidity or survival.     

Active elimination of the marine biotoxin okadaic acid by P-glycoprotein through an in vitro gastrointestinal barrier

The consumption of okadaic acid (OA) contaminated shellfish can induce acute toxic symptoms in humans such as diarrhea, nausea, vomiting and abdominal pain; carcinogenic and embryotoxic effects have also been described. Toxicokinetic studies with mice have shown that high cytotoxic doses of OA can pass the gastrointestinal barrier presumably by paracellular passage. However, in vitro studies using human intestinal Caco-2 cell monolayers to represent the intestinal barrier have shown that at low-dose exposure OA is transported against a concentration gradient suggesting an active efflux mechanism. Since P-glycoprotein (P-gp) transports a wide variety of substrates, we investigated its possible influence on the observed elimination of OA. We used two different cellular transwell models: (i) Caco-2 cell monolayer endogenously expressing human P-gp and simulating the intestinal barrier and (ii) MDCK-II cell monolayer stably over-expressing P-gp. Our study demonstrates clearly that OA at non-cytotoxic concentrations passes the monolayer barrier only to a low degree, and that it is actively eliminated by P-gp over the apical membrane. Therefore, our in vitro data indicate that humans appear to have efficient defense mechanisms to protect themselves against low-dose contaminated shellfish by exhibiting a low bioavailability as a result of active elimination of OA by P-gp.     

Secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation in multiple myeloma

In the course of multiple myeloma, patients may develop a M-protein band different from the original: secondary monoclonal gammopathy of undetermined significance. In this retrospective single center analysis, we describe the occurrence and clinical relevance of secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation (post-transplant monoclonal gammopathy of undetermined significance). A total of 138 patients who had undergone 139 allogeneic stem cell transplantations (39.6% in the upfront setting and 60.4% for relapsed multiple myeloma) were included in the study. Sixty-seven (48.2%) patients developed secondary monoclonal gammopathy of undetermined significance, after a median latency of 6.9 months. Secondary monoclonal gammopathy of undetermined significance occurred more often in patients who achieved at least very good partial response after allogeneic stem cell transplantation, compared to partial response or less (54.8% vs. 26.5%; P=0.005). The incidence was also higher in the upfront setting as compared to relapsed disease, or with a sibling donor compared to matched unrelated donor, but less often after T-cell depletion. Importantly, development of post-transplant monoclonal gammopathy of undetermined significance as a time-dependent variable independently predicted for superior progression-free and overall survival (median progression-free survival 37.5 vs. 6.3 months, P<0.001; median overall survival 115.3 vs. 31.0 months, P=0.004). Clinicians should be aware of the benign nature of this phenomenon, and secondary monoclonal gammopathy of undetermined significance should not be confused with relapse or progression of disease. (Trial registered with trialregister.nl; HOVON 108: NTR 2958.)