Citations

Purpose To provide guidance to clinicians regarding the use of neoadjuvant chemotherapy and interval cytoreduction among women with stage IIIC or IV epithelial ovarian cancer. Methods The Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an Expert Panel and conducted a systematic review of the literature. Results Four phase III clinical trials form the primary evidence base for the recommendations. The published studies suggest that for selected women with stage IIIC or IV epithelial ovarian cancer, neoadjuvant chemotherapy and interval cytoreduction are noninferior to primary cytoreduction and adjuvant chemotherapy with respect to overall and progression-free survival and are associated with less perioperative morbidity and mortality. Recommendations All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy. The primary clinical evaluation should include a CT of the abdomen and pelvis, and chest imaging (CT preferred). Women with a high perioperative risk profile or a low likelihood of achieving cytoreduction to < 1 cm of residual disease (ideally to no visible disease) should receive neoadjuvant chemotherapy. Women who are fit for primary cytoreductive surgery, and with potentially resectable disease, may receive either neoadjuvant chemotherapy or primary cytoreductive surgery. However, primary cytoreductive surgery is preferred if there is a high likelihood of achieving cytoreduction to < 1 cm (ideally to no visible disease) with acceptable morbidity. Before neoadjuvant chemotherapy is delivered, all patients should have confirmation of an invasive ovarian, fallopian tube, or peritoneal cancer. Additional information is available at www.asco.org/NACT-ovarian-guideline and www.asco.org/guidelineswiki .

SummarySomatic mutation of the DNMT3A gene at the arginine R882 site is common in acute myeloid leukaemia (AML). The prognostic significance of DNMT3A R882 mutation clearance, using traditional diagnostic next generation sequencing (NGS) methods, during complete remission (CR) in AML patients is controversial. We examined the impact of clearing DNMT3A R882 mutations at diagnosis to the detectable threshold of ˂3% during CR on outcome in 56 adult AML patients. Mutational remission, defined as clearance of pre‐treatment DNMT3A R882 and all other AML‐associated mutations to a variant allele frequency ˂3%, occurred in 14 patients whereas persistent DNMT3A R882 mutations were observed in 42 patients. There were no significant differences in disease‐free or overall survival between patients with and without DNMT3A R882 mutation clearance. Patients with persistent DNMT3A R882 who cleared all other AML mutations and did not acquire new mutations (n = 30), trended towards longer disease‐free survival (1·6 vs. 0·6 years, P = 0·06) than patients with persistence of DNMT3A R882, in addition to other mutations or acquisition of new AML‐associated mutations, such as those in TET2, JAK2, ASXL1 and TP53 (n = 12). These data demonstrate that DNMT3A R882 mutations, as assessed by traditional NGS methods, persist in the majority of AML patients in CR.

Abstract Hepatocellular carcinoma is one of the most lethal cancers in the world. Most of the patients are diagnosed at advanced stage, and they receive sorafenib as their treatment modality. However, sorafenib can only extend patients’ survival to a median of 3-4 months. Hence, there is an urgent need to identify a new therapeutic target for treatment of this disease. Increasing evidence showed that tumor-initiating cells (T-ICs) are intrinsically resistant to conventional treatments. Identification of the signalling pathways that maintain the functions of T-ICs provides potential targets for treatment of HCC. For this purpose, we cultured serial passages of hepatospheres combined with chemotherapeutic regimens as a strategy to enrich liver T-IC population. Using cDNA microarray, we found upregulation of several key enzymes in lipogenesis in enriched T-IC population, among which Stearoyl CoA desaturase-1 (SCD1), the enzyme involved in the conversion of saturated into monounsaturated fatty acids, was the most significant. In HCC clinical samples, 62% (36/58) was found to be overexpressed (&gt; 2-fold) when compared with non-tumor counterparts and patients with SCD1 overexpression had shorter disease free survival. Using overexpression and knockdown approaches, SCD1 was found to regulate the traits of T-ICs, including tumorigenicity, self-renewal, drug resistance and expression of liver T-IC markers. SCD1 was found critical in survival of T-ICs, as enriched T-IC population are more sensitive to the inhibition of SCD1 compared to adherent lineages. Interestingly, SCD1 was found to be upregulated in sorafenib-resistant HCC cells. Pharmacological inhibition of SCD1 by A939572 not only suppressed self-renewal ability but also consistently enhanced the sensitivity towards sorafenib. Using a patient-derived xenograft model, we found that a new inhibitor against SCD1 demonstrated significant growth suppressive effect. By comparing the genetic profiles between SCD1 knockdown cells and control cells by RNA sequencing analysis, we found that upregulation of ER stress signature genes may be the potential downstream targets of SCD1 to maintain the properties of T-ICs. In conclusion, we demonstrated the crucial role of SCD1 in maintenance of liver T-ICs, and targeting SCD1 in combination with sorafenib might be a novel therapeutic regimen against HCC. Citation Format: Kin Fai Ma, Jessica Lo, Eunice Yuen-Ting Lau, John A. Copland, Irene Oi-Lin Ng, Terence Kin-Wah Lee. Targeting liver-tumor initiating cells via hampering the lipogenesis pathways through stearoyl - CoA desaturase. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1003.

Prior studies in with irritable bowel syndrome with diarrhea (IBS-D) patients showed immune activation, secretion, and barrier dysfunction in jejunal or colorectal mucosa. We measured mRNA expression by RT-PCR of 91 genes reflecting tight junction proteins, chemokines, innate immunity, ion channels, transmitters, housekeeping genes, and controls for DNA contamination and PCR efficiency in small intestinal mucosa from 15 IBS-D and 7 controls (biopsies negative for celiac disease). Fold change was calculated using 2(−ΔΔCT) formula. Nominal P values ( P < 0.05) were interpreted with false detection rate (FDR) correction ( q value). Cluster analysis with Lens for Enrichment and Network Studies (LENS) explored connectivity of mechanisms. Upregulated genes (uncorrected P < 0.05) were related to ion transport (INADL, MAGI1, and SONS1), barrier (TJP1, 2, and 3 and CLDN) or immune functions (TLR3, IL15, and MAPKAPK5), or histamine metabolism (HNMT); downregulated genes were related to immune function (IL-1β, TGF-β1, and CCL20) or antigen detection (TLR1 and 8). The following genes were significantly upregulated ( q < 0.05) in IBS-D: INADL, MAGI1, PPP2R5C, MAPKAPK5, TLR3, and IL-15. Among the 14 nominally upregulated genes, there was clustering of barrier and PDZ domains (TJP1, TJP2, TJP3, CLDN4, INADL, and MAGI1) and clustering of downregulated genes (CCL20, TLR1, IL1B, and TLR8). Protein expression of PPP2R5C in nuclear lysates was greater in patients with IBS-D and controls. There was increase in INADL protein (median 9.4 ng/ml) in patients with IBS-D relative to controls (median 5.8 ng/ml, P > 0.05). In conclusion, altered transcriptome (and to lesser extent protein) expression of ion transport, barrier, immune, and mast cell mechanisms in small bowel may reflect different alterations in function and deserves further study in IBS-D.

Head and neck soft tissue sarcomas (HNSTSs) are rare and heterogeneous cancers in which radiation therapy (RT) has an important role in local tumor control (LC). The purpose of this study was to evaluate outcomes and patterns of treatment failure in patients with HNSTS treated with RT. A retrospective review was performed of adult patients with HNSTS treated with RT from January 1, 1998, to December 31, 2012. LC, locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and predictors thereof were assessed. Forty-eight patients with HNSTS were evaluated. Five-year Kaplan-Meier estimates of LC, LRC, DFS, and OS were 87, 73, 63, and 83%, respectively. Angiosarcomas were found to be associated with worse LC, LRC, DFS, and OS. Patients over the age of 60 had lower rates of DFS. HNSTSs comprise a diverse group of tumors that can be managed with various treatment regimens involving RT. Angiosarcomas have higher recurrence and mortality rates.

Abstract Background Therapeutic options for management of diabetic gastroparesis are limited. Failure to maintain upregulation of heme oxygenase ( HO 1) leads to loss of interstitial cells of Cajal and delayed gastric emptying ( GE ) in non‐obese diabetic mice. Our hypothesis was that hemin upregulation of HO 1 would restore normal GE in humans with gastroparesis. Aims To compare effects of hemin and placebo infusions on HO 1 activity and protein, GE , autonomic function, and gastrointestinal symptoms in diabetic gastroparesis. Methods In a single‐center, double‐blind, placebo‐controlled, randomized clinical trial, we compared intravenous hemin, prepared in albumin, or albumin alone (placebo) in 20 patients, aged 41 ± 5 ( SEM ) years with diabetic gastroparesis. After infusions on days 1, 3, and 7, weekly infusions were administered for 7 additional weeks. Assessments included blood tests for HO 1 protein and enzyme activity levels, GE with 13 C‐spirulina breath test, autonomic functions (baseline and end), and gastrointestinal symptoms every 2 weeks. Key Results Nine of 11 patients randomized to hemin completed all study procedures. Compared to placebo, hemin increased HO 1 protein on days 3 ( p = 0.0002) and 7 ( p = 0.008) and HO 1 activity on day 3 ( p = 0.0003) but not after. Gastric emptying, autonomic functions, and symptoms did not differ significantly in the hemin group relative to placebo. Conclusions & Inferences Hemin failed to sustain increased HO 1 levels beyond a week and did not improve GE or symptoms in diabetic gastroparesis. Further studies are necessary to ascertain whether more frequent hemin infusions or other drugs would have a more sustained effect on HO 1 and improve GE .

AbstractBackgroundDefecatory disorders (DD) are defined by clinical and objective features of impaired rectal evacuation. The epidemiology of DD in the population is unknown, partly because many constipated patients do not undergo anorectal tests. Our objectives were to estimate the incidence rate and clinical features of DD in the community.MethodsWe reviewed the medical records of all patients older than 16 years in Olmsted County, MN, who had constipation and underwent anorectal manometry from 1999 through 2008. Criteria for diagnosing DD were constipation for 6 months or longer and one of the following: (i) abnormal rectal balloon expulsion test; (ii) reduced or increased perineal descent; or (iii) two or more abnormal features with defecography or surface electromyography.Key ResultsOf 11 112 constipated patients, 516 had undergone anorectal tests; 245 of these (209 women, 36 men) had a DD. The mean (±SD) age at diagnosis was 44 years (±18) among women and 49 years (±19) among men. The overall age‐ and sex‐adjusted incidence rate per 100 000 person‐years was 19.3 (95% CI: 16.8–21.8). The age‐adjusted incidence per 100 000 person‐years was greater (p < 0.0001) in women (31.8, 95% CI: 27.4–36.1) than in men (6.6, 95% CI: 4.4–8.9). Prior to the diagnosis of DD, nearly 30% of patients had irritable bowel syndrome (IBS), 48% had a psychiatric diagnosis, 18% had a history of abuse, and 21% reported urinary and/or fecal incontinence.Conclusions & InferencesAmong constipated patients, DD are fourfold more common in women than men and often associated with IBS and psychiatric diagnoses.