Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Hydration influences on the phase heterogeneity of segmented copolymers.

We elucidate the influences of hydration on the morphological heterogeneity of the class of hard-soft segmented copolymers by experimenting on three model members selected from this group. For influences on phase segmentation, we quantify the degree of phase separation, segment boundary diffusiveness and extent of interphase mixing. Qualitative variations induced by hydration in hydrogen bonding within the phases are also mapped. An inverse relationship between the degree of segmentation and inherent water miscibility of the polymer backbones is observed, that is, high miscibility reducing the degree of segmentation, whereas poor miscibility increasing it. We then quantify hydration induced variations in the size, volume fraction and interaction pair potentials of individual hard segments. The influences on hard segment assemblies are assessed by quantifying their size, volume fraction, interaction pair potential and intrasegment adhesion. This quantification reveals a complex interplay between the volume expansion of individual hard segments and simultaneous swelling and disassembly of their assemblies. Finally, we integrate the segmentation parameters with observed alterations in hydrogen bonding and the inherent polarizability of segments to present a mechanism that reasonably describes the hydrated state morphology. Besides revealing the influences of hydration on the morphological heterogeneity of this class of polymers, our insights give strategies for new synthesis methods for water contact applications and aids in predicting their hydration induced thermomechanical property alterations.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with early breast cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.

In view of the planned new edition of the most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of primary breast cancer published in 2015, it was decided at the ESMO Asia Meeting in November 2018, by both the ESMO and the Korean Society of Medical Oncology (KSMO), to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the latest ESMO 2019 guidelines to take into account the ethnic and geographical differences associated with the treatment of early breast cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with early breast cancer representing the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO) Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices, and the drug availability and reimbursement situations, in the individual participating Asian countries.

Outcomes of fulvestrant therapy among japanese women with advanced breast cancer: a retrospective multicenter cohort study (JBCRG-C06; Safari).

PURPOSE: This retrospective study evaluated the effect of clinical background and treatment line on time to treatment failure (TTF) in advanced/metastatic breast cancer (AMBC) patients receiving F500 in Japan (UMIN 000015168). METHODS: Patients who commenced F500 treatment were registered at 16 sites in Japan. Correlations between baseline clinicopathological factors, treatment line, and TTF were investigated by Kaplan-Meier analysis. TTF data were analyzed using univariate analysis and multivariate analysis with a Cox proportional hazards model. RESULTS: Data for 1072 patients were available; 1031 patients (96.2%) were evaluable for efficacy. F500 was administered as first-line treatment in 2.0%, second-line in 22.7%, third-line in 26.7%, and ≥fourth-line in 48.6% patients. Median TTF was 5.4 months. Multivariate analysis found that earlier F500 use (first and second vs. third vs. ≥fourth line; hazard ratio (HR) = 0.80, 95% confidence interval (CI) 0.74-0.86; P < 0.001), longer period from AMBC diagnosis to F500 use (≥3 vs. <3 years; HR 0.60, 95% CI 0.51-0.70; P < 0.001), and no prior palliative chemotherapy administered for unresectable or metastatic breast cancer (no vs. yes; HR 0.69, 95% CI 0.60-0.80; P < 0.001) were associated with significantly longer TTF. Among 691 patients, where information on histologic/nuclear grade was available, a low grade was also associated with a longer TTF, but this finding was not maintained among patients with recurrent breast cancer (N = 558). Among women with recurrent breast cancer, a longer DFI between a patient's initial breast cancer diagnosis and their recurrence was associated with a longer TTF on F500 therapy. CONCLUSIONS: Our study showed that treatment period of F500 was longer when used in earlier-line treatment. For patients on F500, TTF was also longer for patients who had not received prior palliative chemotherapy and for those who had a longer period from their AMBC diagnosis to F500 use.

Maternal and neonatal service usage and determinants in fragile and conflict-affected situations: a systematic review of Asia and the Middle-East.

BACKGROUND: Fragile and conflict-affected situations (FCS) in Asia and the Middle-East contribute significantly to global maternal and neonatal deaths. This systematic review explored maternal and neonatal health (MNH) services usage and determinants in FCS in Asia and the Middle-East to inform policy on health service provision in these challenging settings. METHODS: This systematic review was conducted using a standardised protocol. Pubmed, Embase, Web of Science, and selected development agency websites were searched for studies meeting inclusion criteria. Studies were assessed for methodological quality using an adapted evaluation tool. Qualitative and quantitative data were synthesized and pooled odds ratios generated for meta-analysis of service-usage determinants. RESULTS: Of 18 eligible peer-reviewed studies, eight were from Nepal, four from Afghanistan, and two each from Iraq, Yemen, and the Palestinian Territories. Fragile situations provide limited evidence on emergency obstetric care, postnatal care, and newborn services. Usage of MNH services was low in all FCS, irrespective of economic growth level. Demand-side determinants of service-usage were transportation, female education, autonomy, health awareness, and ability-to-pay. Supply-side determinants included service availability and quality, existence of community health-workers, costs, and informal payments in health facilities. Evidence is particularly sparse on MNH in acute crises, and remains limited in fragile situations generally. CONCLUSIONS: Findings emphasize that poor MNH status in FCS is a leading contributor to the burden of maternal and neonatal ill-health in Asia and the Middle-East. Essential services for skilled birth attendance and emergency obstetric, newborn, and postnatal care require improvement in FCS. FCS require additional resources and policy attention to address the barriers to appropriate MNH care. Authors discuss the 'targeted policy approach for vulnerable groups' as a means of addressing MNH service usage inequities.

Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

BACKGROUNDS: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. PATIENTS AND METHODS: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. RESULTS: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. CONCLUSION: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection.

Solvent transport through hard-soft segmented polymer nanocomposites.

We conducted transport studies of a common solvent (toluene) in its condensed state, through a model hard-soft segmented polyurethane-clay nanocomposite. The solvent diffusivity is observed to be non-monotonic in a functional relationship with a filler volume fraction. In stark contrast, both classical tortuous path theory based geometric calculations and free volume measurements suggest the normally expected monotonic decrease in diffusivity with increase in clay volume fraction. Large deviations between experimentally observed diffusivity coefficients and those theoretically estimated from geometric theory are also observed. However, the equilibrium swelling of a nanocomposite as indicated by the solubility coefficient did not change. To gain an insight into the solvent interaction behavior, we conducted a pre- and post swollen segmented phase analysis of pure polymers and nanocomposites. We find that in a nanocomposite, the solvent has to interact with a filler altered hard-soft segmented morphology. In the altered phase separated morphology, the spatial distribution of thermodynamically segmented hard blocks in the continuous soft matrix becomes a strong function of filler concentration. Upon solvent interaction, this spatial distribution gets reoriented due to sorption and de-clustering. The results indicate strong non-barrier influences of nanoscale fillers dispersed in phase segmented block co-polymers, affecting solvent diffusivity through them. Based on pre- and post swollen morphological observations, we postulate a possible mechanism for the non-monotonic behaviour of solvent transport for hard-soft segmented co-polymers, in which the thermodynamic phase separation is influenced by the filler.

Effect of pay for performance to improve quality of maternal and child care in low- and middle-income countries: a systematic review.

BACKGROUND: Pay for Performance (P4P) mechanisms to health facilities and providers are currently being tested in several low- and middle-income countries (LMIC) to improve maternal and child health (MCH). This paper reviews the existing evidence on the effect of P4P program on quality of MCH care in LMICs. METHODS: A systematic review of literature was conducted according to a registered protocol. MEDLINE, Web of Science, and Embase were searched using the key words maternal care, quality of care, ante natal care, emergency obstetric and neonatal care (EmONC) and child care. Of 4535 records retrieved, only eight papers met the inclusion criteria. Primary outcome of interest was quality of MCH disaggregated into structural quality, process quality and outcomes. Risk of bias across studies was assessed through a customized quality checklist. RESULTS AND DISCUSSION: There were four controlled before after intervention studies, three cluster randomized controlled trials and one case control with post-intervention comparison of P4P programs for MCH care in Burundi, Democratic Republic of Congo, Egypt, the Philippines, and Rwanda. There is some evidence of positive effect of P4P only on process quality of MCH. The effect of P4P on delivery, EmONC, post natal care and under-five child care were not evaluated in these studies. There is weak evidence for P4P's positive effect on maternal and neonatal health outcomes and out-of-pocket expenses. P4P program had a few negative effects on structural quality. CONCLUSION: P4P is effective to improve process quality of ante natal care. However, further research is needed to understand P4P's impact on MCH and their causal pathways in LMICs. TRIAL REGISTRATION: PROSPERO registration number CRD42014013077 .