Investigating a clinically actionable BRAF mutation for monitoring low-grade serous ovarian cancer: A case report.

Low-grade serous ovarian cancer (LGSOC) poses a specific clinical challenge due to advanced presentation at diagnosis and the lack of effective systemic treatments. The aim of this study was to use a precision medicine approach to identify clinically actionable mutations in a patient with recurrent LGSOC. Primary, metastatic and recurrence tissue, and blood samples were collected from a stage IV LGSOC patient. Single-gene testing for clinically actionable mutations (BRAF V600, KRAS and NRAS) and subsequent whole-exome sequencing (WES) were performed. Droplet digital PCR was used to evaluate the presence of an identified BRAF D594G mutation in the matched plasma cell-free DNA (cfDNA). No clinically actionable mutations were identified using single-gene testing. WES identified a BRAF D594G mutation in six of seven tumor samples. The patient was commenced on a MEK inhibitor, trametinib, but with minimal clinical response. A newly designed ddPCR assay detected the BRAF alteration in the matched tissues and liquid biopsy cfDNA. The identification and sensitive plasma detection of a common "druggable" target emphasises the impact of precision medicine on the management of rare tumors and its potential contribution to novel monitoring regimens in this field.

Recent advances in immune-based approaches for the treatment of esophagogastric cancer.

INTRODUCTION: The year 2021 will be remembered as a transformational year in the management of both esophageal and gastric cancers. Decades of failed clinical trials had seen limited therapeutic advances beyond refinement of the traditional combined modality approach. Targeted strategies against specific molecular alterations did not - with the exception of Her2 - yield the desired breakthroughs, and it was unclear what immune-based approaches would bring to this group of cancers. The presence of tumor-infiltrating lymphocytes in esophagogastric cancer demonstrates that an endogenous immune response is already occurring and potentially amplifiable by immune checkpoint inhibition. Recent data have validated this with FDA approvals in both the locoregional (CheckMate 577) and metastatic disease (CheckMate 649, KeyNote 590 and KeyNote 811) setting which have altered the therapeutic landscape. AREAS COVERED: Here we discuss recent data and ongoing research efforts to better define the role of immune-based approaches and select the patient cohorts who might gain the most benefit from them. EXPERT OPINION: Immunotherapy, and specifically the incorporation of the immune checkpoint inhibitors (ICI) drug class, has altered the therapeutic paradigm of many cancers in recent years. Anti-PD-1 therapies are now the new standard of care for patients with local and advanced disease.

Allogeneic Mesenchymal Stromal Cells (MSCs) are of Comparable Efficacy to Syngeneic MSCs for Therapeutic Revascularization in C57BKSdb/db Mice Despite the Induction of Alloantibody.

Intramuscular administration of mesenchymal stromal cells (MSCs) represents a therapeutic option for diabetic critical limb ischemia. Autologous or allogeneic approaches may be used but disease-induced cell dysfunction may limit therapeutic efficacy in the former. Our aim was to compare the efficacy of allogeneic and autologous MSC transplantation in a model of hindlimb ischemia in diabetes mellitus and to determine whether allogeneic transplantation would result in the activation of an immune response. MSCs were isolated from C57BL/6 (B6) and diabetic obese C57BKSdb/db mice. Phosphate-buffered saline (control group), and MSCs (1 × 106) from B6 (allogeneic group) or C57BKSdb/db (syngeneic group) were administered intramuscularly into the ischemic thigh of C57BKSdb/db mice following the induction of hindlimb ischemia. MSCs derived from both mouse strains secrete several angiogenic factors, suggesting that the potential therapeutic effect is due to paracrine signaling. Administration of allogeneic MSCs significantly improved blood perfusion as compared with the control group on week 2 and 3, post-operatively. In comparison with the control group, syngeneic MSCs significantly improved blood perfusion at week 2 only. There was no statistical difference in blood perfusion between allogeneic and syngeneic MSC groups at any stages. There was no statistical difference in ambulatory and necrosis score among the three groups. Amputation of toes was only observed in the control group (one out of seven animals). Alloantibody was detected in three out of the eight mice that received allogeneic MSCs but was not observed in the other groups. In summary, we demonstrated comparable efficacy after transplantation of autologous and allogeneic MSCs in a diabetic animal model despite generation of an immune response.

Treating Hepatobiliary Cancer: The Immunologic Approach.

Hepatobiliary cancer comprises a heterogeneous group of malignancies in which the standard treatments for advanced disease are minimally effective and evolve slowly over time. Like the majority of gastrointestinal cancers, with some notable exceptions, the impact of immune-based approaches is yet to be experienced. Notwithstanding this, the etiological background of hepatobiliary cancer - overlapping in almost every known causative or associated factor with inflammation - provides a strong clue that these approaches may have an impact on this group of diseases. This review seeks to put the management of hepatobiliary cancers in the context of its inflammation-based etiology, with the aim of pointing to the therapeutic opportunities in immune-based approaches currently entering the clinic or those that are about to do so.

Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750-an antisense oligonucleotide against eIF4E-in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer.

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose-limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.

A single-center evaluation of the risk for colonization or bacteremia with piperacillin-tazobactam- and cefepime-resistant bacteria in patients with acute leukemia receiving fluoroquinolone prophylaxis.

Fluoroquinolone prophylaxis is indicated to prevent neutropenic fever in patients with acute leukemia. However, fluoroquinolone use has been associated with development of multi-drug-resistant Pseudomonas aeruginosa and extended spectrum ß-lactamase producing gram-negative bacilli. Due to a presumed risk of multi-drug resistance associated with fluoroquinolone prophylaxis, patients admitted to our hospital with neutropenic fever receive empiric carbapenem therapy until cultures are negative for 72 h or identification of an organism. Our study seeks to identify the incidence of multi-drug-resistant organism colonization and bacteremia among patients who receive fluoroquinolone prophylaxis and to evaluate duration of empiric carbapenem therapy. A retrospective review of adult patients with acute leukemia receiving a fluoroquinolone as outpatient infection prophylaxis, admitted to our tertiary cancer center for treatment of neutropenic fever was completed. Surveillance and blood cultures were reviewed for antibiotic resistance. Duration of empiric carbapenem therapy was reviewed. One hundred patients and 177 admissions for neutropenic fever were included. Six patients harbored a piperacillin-tazobactam-resistant organism found during routine surveillance. Among these patients, two bacteremias were identified, one of which was a piperacillin-tazobactam-resistant organism. Five bacteremias were identified among 83 patients with negative surveillance cultures. Among the bloodstream infections, five organisms isolated were fluoroquinolone resistant. No cefepime-resistant organism was isolated on surveillance or bloodstream cultures. Adherence to the institution guideline of narrowing antibiotics after 72 h of negative cultures occurred in only 13% of neutropenic fever cases. The average duration of carbapenem therapy in 177 neutropenic fever episodes was 4.4 days. Our findings show that among our patient population, there is a low risk of bacteremia with a piperacillin-tazobactam-resistant or cefepime-resistant organism. However, prompt de-escalation of carbapenem therapy needs to be reiterated within hospital practice.

Targeting the microenvironment of pancreatic cancer: overcoming treatment barriers and improving local immune responses.

Historically, patients diagnosed with metastatic pancreatic cancer have faced a grim prognosis. The survival benefit seen with systemic chemotherapies and even combinations thereof have been disappointing. However, growing data suggest that the microenvironment of pancreatic cancer may be contributing to this poor prognosis. This microenvironment has a dense fibrotic stroma, and is hypoxic and highly immunosuppressive, all of which pose barriers to treatment. Newer strategies looking to disrupt the fibrotic stroma, target hypoxic areas, and improve local immune responses in the tumor microenvironment are currently undergoing clinical evaluation and seem to offer great promise. In addition to these therapies, preclinical work evaluating novel cytotoxic agents including nanoparticles has also been encouraging. While much research still needs to be done, these strategies offer new hope for patients with pancreatic cancer.

A phase II study of TRC105 in patients with hepatocellular carcinoma who have progressed on sorafenib.

BACKGROUND: Endoglin is an endothelial cell membrane receptor essential for angiogenesis and highly expressed on the vasculature of many tumor types, including hepatocellular carcinoma (HCC). TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis, and complements VEGF inhibitors. OBJECTIVE: The aim of this phase II study was to evaluate the efficacy of anti-endoglin therapy with TRC105 in patients with advanced HCC, post-sorafenib. METHODS: Patients with HCC and compensated liver function (Childs-Pugh A/B7), ECOG 0/1, were enrolled to a single-arm, phase II study of TRC105 15 mg/kg IV every two weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal two-stage design was employed with a 50% four-month PFS target for progression to the second stage. Correlative biomarkers evaluated included DCE-MRI as well as plasma levels of angiogenic biomarkers and soluble CD105. RESULTS: A total accrual of 27 patients was planned. However, because of lack of efficacy and in accordance with the Simon two-stage design, 11 patients were enrolled. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N = 3) and epistaxis (G1; N = 4). One patient had a confirmed partial response by standard RECIST criteria and biologic response on DCE-MRI but the four-month PFS was insufficient to proceed to the second stage of the study. CONCLUSIONS: TRC105 was well tolerated in this HCC population following sorafenib. Although there was evidence of clinical activity, this did not meet prespecified criteria to proceed to the second stage. TRC105 development in HCC continues as combination therapy with sorafenib.

Comparison of mortality following hospitalisation for ulcerative colitis in Scotland between 1998-2000 and 2007-2009.

BACKGROUND: Scottish nationwide linkage data from 1998 to 2000 demonstrated high 3-year mortality in patients hospitalised with ulcerative colitis (UC). AIM: To compare 3-year mortality, and factors related to mortality, in Scottish patients hospitalised with UC between 1998-2000 and 2007-2009. METHODS: The Scottish Morbidity Records and linked datasets were used to assess 3-year mortality, standardised mortality ratio (SMR) and multivariate analyses of factors associated with 3-year mortality. The 3-year mortality was determined after four admission types: surgery-elective or emergency; medical-elective or emergency. Age-standardised mortality rates (ASR) were used to compare mortality rates between periods. RESULTS: Ulcerative colitis admissions increased from 10.6 in Period 1 to 11.6 per 100 000 population per year in Period 2 (P = 0.046). Crude and adjusted 3-year mortality fell between time periods (crude 12.2% to 8.3%; adjusted OR 0.59, CI 0.42-0.81, P = 0.04). Adjusted 3-year mortality following emergency medical admission (OR 0.58, CI 0.39-0.87, P = 0.003) and in patients >65 years (38.8% to 28.7%, P = 0.02) was lower in Period 2. The SMR in period 1 was 3.04 and 2.96 in Period 2. Directly age-standardised mortality decreased from 373 (CI 309-437) to 264 (CI 212-316) per 10 000 person-years. On multivariate analysis, increasing age (50-64 years OR 7.11 (CI 2.77-18.27, P < 0.05); 65-74 years OR 14.70 (CI 5.65-38.25 P < 0.05); >75 years OR 46.42 (CI 18.29-117.78, P < 0.001) and co-morbidity (OR 3.02, CI 1.72-5.28, P < 0.001) were significantly associated with 3-year mortality in Period 2. CONCLUSIONS: Comparisons of crude and adjusted mortality rates suggest significant improvement in outcome over the last decade - however, mortality remains high, and older age and co-morbidity are important predictors of outcome.

Immunological off-target effects of standard treatments in gastrointestinal cancers.

The effects on immune cells and the inflammatory microenvironment of commonly applied cancer treatments (chemotherapeutic or biologic agents, interventional radiologic procedures) have become better appreciated. Likewise, the contribution of the immune system toward the effectiveness of these treatments is clearer. The relevance of immune evasion by developing tumors is endorsed by its inclusion as one of the (updated) hallmarks of cancer. A greater understanding of this dimension can potentially lead to novel applications of existing standard of care therapies, in addition to potentiating their effect. This review summarizes the immune aspects of currently employed therapies-cytotoxic chemotherapeutics, biologic agents and interventional radiologic procedures-in solid tumor malignancies with a particular focus on those agents used in gastrointestinal cancers.

Closing the gap: medialization of fascia with laparoscopic incisional hernia repair.

PURPOSE: Laparoscopic incisional hernioplasty (LIH) bridges the fascial gap between the rectus muscles with a posteriorly placed mesh, and is a low recurrence alternative to other reconstructions. It is unclear if this repair optimizes the function of the abdominal wall. We hypothesize that significant medialization of the fascial edges occurs in patients who undergo LIH. METHODS: Two hundred fifty-eight patients underwent LIH by a single surgeon between 2004 and 2012. 44 of these had pre- and postoperative CT scans that illustrated the gap between the rectus muscles. All 44 patients underwent LIH with polyester composite mesh, with suture and tack fixation. The distance between the fascial edges on the pre- and postoperative CT scans was compared. Percent medialization was calculated for each defect. RESULTS: Average fascial separation reduction was 0.8 cm (6.56-5.76 cm, 12.2 % medialization, p < 0.0001). 36 of 44 patients demonstrated a reduction in hernia defect width (81.8 %): these defects reduced 1.09 cm (6.47-5.38 cm, 16.9 % medialization, p < 0.0001). In defects wider than 5 cm, the width reduced by 0.94 cm (8.48-7.54 cm, n = 26, 10.6 % medialization, p = 0.004). The use of meshes ≥500 cm(2) reduced the defect by 0.95 cm (8.42-7.47 cm, 11.23 % medialization, n = 22, p = 0.005). CONCLUSIONS: Significant medialization of the rectus muscles is evident in most patients undergoing LIH. Although the rectus muscles are not ideally approximated, this may help improve the function of the anterior abdominal wall. Further technical refinements and material improvements may improve the reconstructive results of the LIH.

Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials.

BACKGROUND: There is currently no standard of care for the second-line treatment of advanced pancreatic cancer. The aim of this analysis was to compare the different therapeutic approaches in this setting. METHODS: We carried out a systematic analysis of second-line studies in advanced pancreatic cancer that have progressed on or following gemcitabine and published or presented from 2000 to 2012. RESULTS: Forty-four clinical trials (t) were identified; of which 34 met the inclusion criteria treating an aggregate total of 1503 patients (n). Patients who received treatments (t: 33; n: 1269) had a median overall survival (OS) of 6 months compared with 2.8 months for patients who received best supportive care only (t: 2; n: 234) (P = 0.013). The gemcitabine and platinum-based combination (t: 5; n: 154) provided a median progression-free survival and OS of 4 and 6 months compared with 1.6 and 5.3 for the rest of the regimens (t: 29; n: 1349) (P = 0.059 and 0.10, respectively) and 2.9 and 5.7 for the combination of 5-fluorouracil and platinum agents (t: 12; n: 450) (P = 0.60 and 0.22, respectively). CONCLUSION(S): Although not conclusive, these data showed that the advantage of second-line chemotherapy in pancreatic cancer is very limited and there is a need for more studies.

Functional role of vasoactive intestinal polypeptide in inhibitory motor innervation in the mouse internal anal sphincter.

There is evidence that vasoactive intestinal polypeptide (VIP) participates in inhibitory neuromuscular transmission (NMT) in the internal anal sphincter (IAS). However, specific details concerning VIP-ergic NMT are limited, largely because of difficulties in selectively blocking other inhibitory neural pathways. The present study used the selective P2Y1 receptor antagonist MRS2500 (1 µm) and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine (l-NNA; 100 µm) to block purinergic and nitrergic NMT to characterize non-purinergic, non-nitrergic (NNNP) inhibitory NMT and the role of VIP in this response. Nerves were stimulated with electrical field stimulation (0.1-20 Hz, 4-60 s) and the associated changes in contractile and electrical activity measured in non-adrenergic, non-cholinergic conditions in the IAS of wild-type and VIP(-/-) mice. Electrical field stimulation gave rise to frequency-dependent relaxation and hyperpolarization that was blocked by tetrodotoxin. Responses during brief trains of stimuli (4 s) were mediated by purinergic and nitrergic NMT. During longer stimulus trains, an NNNP relaxation and hyperpolarization developed slowly and persisted for several minutes beyond the end of the stimulus train. The NNNP NMT was abolished by VIP6-28 (30 µm), absent in the VIP(-/-) mouse and mimicked by exogenous VIP (1-100 nm). Immunoreactivity for VIP was co-localized with neuronal nitric oxide synthase in varicose intramuscular fibres but was not detected in the VIP(-/-) mouse IAS. In conclusion, this study identified an ultraslow component of inhibitory NMT in the IAS mediated by VIP. In vivo, this pathway may be activated with larger rectal distensions, leading to a more prolonged period of anal relaxation.

The incretin analogue D-Ala2GIP reduces plaque load, astrogliosis and oxidative stress in an APP/PS1 mouse model of Alzheimer's disease.

Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). Insulin is a neuroprotective growth factor, and an impairment of insulin signalling has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, normalises insulin signalling and also acts as a neuroprotective growth factor. GIP plays an important role in memory formation, synaptic plasticity and cell proliferation. We have shown previously that the long-lasting incretin hormone analogue D-Ala(2)GIP protects memory formation and synaptic plasticity, reduces plaques, normalises the proliferation of stem cells, reduces the activation of microglia, and prevents the loss of synapses in the cortex of the APPswe/PS1deltaE9 mouse model of Alzheimer's disease. D-Ala(2)GIP was injected for 35 days at 25 nmol/kg i.p. once daily in APP/PS1 male mice and wild-type (WT) littermates aged 6, 12 and 19 months. In a follow-up study, we analysed plaque load, the activation of astrocytes as a means of chronic inflammation in the brain, and oxidative stress in the brains of these mice (8-oxoguanine levels). D-Ala(2)GIP reduced the amyloid plaque load in 12- and 19-month-old mice, and the inflammation response as shown in the reduction of activated astrocytes in 12- and 19-month old APP/PS1 mice. Chronic oxidative stress in the brain was reduced in 12- and 19-month-old mice as shown in the reduction of 8-oxoguanine levels in the cortex of D-Ala(2)GIP-injected APP/PS1 mice. The results demonstrate that D-Ala(2)GIP has neuroprotective properties on key markers found in Alzheimer's disease. This finding shows that novel GIP analogues have the potential to be developed as novel therapeutics for Alzheimer's disease.

A role for MRP8 in in stent restenosis in diabetes.

OBJECTIVE: The most common cause of death in diabetes mellitus is cardiovascular disease. Patients frequently undergo vascular intervention such as stenting. The occurrence of in stent restenosis (ISR) has been reduced by the use of drug eluting stents in non-diabetic patients but the incidence of restenosis and stent thrombosis remains higher in diabetic patients. We investigated the pathogenesis of in stent restenosis in an animal model of type 2 diabetes mellitus. METHODS AND RESULTS: Stents were placed in Zucker Fatty rat (ZFR) and wild type rat carotid arteries, and tissues were harvested 14 days post surgery for morphometric analysis. Unstented carotid arteries from both groups were harvested for microarray analysis. In vitro apoptosis, proliferation and migration assays were performed on rat and human aortic endothelial cells (EC). ZFRs developed an exaggerated intimal response to stent placement compared to wild type controls 14 days post stent placement. MRP8 and MRP14 were up-regulated in unstented ZFR carotid arteries in comparison to controls. Expression of MRP8/14 was also elevated in EC exposed to high glucose conditions. EC function was impaired by high glucose concentrations, and this effect could be mimicked by MRP8 over-expression. MRP8 knockdown by shRNA significantly restored EC function after exposure to high glucose concentrations. MRP8 expression in glucose exposed cells was also inhibited using pharmacological blockade of glucose-induced pathways. CONCLUSIONS: EC dysfunction caused by elevated glucose levels could be mimicked by MRP8/14 over-expression and reversed/prevented by MRP8 knockdown. Thus, MRP8/14 likely plays a role in exaggerated ISR in diabetes mellitus, and MRP8 inhibition may be useful in improving outcome after stent placement in diabetes mellitus.

Pretreatment of endothelial progenitor cells with osteopontin enhances cell therapy for peripheral vascular disease.

Tissue necrosis resulting from critical limb ischemia (CLI) leads to amputation in a significant number of patients. Autologous cell therapy using angiogenic cells such as endothelial progenitor cells (EPCs) holds promise as a treatment for CLI but a limitation of this treatment is that the underlying disease etiology that resulted in CLI may also contribute to dysfunction of the therapeutic EPCs. This study aimed to elucidate the mechanism of EPC dysfunction using diabetes mellitus as a model and to determine whether correction of this defect in dysfunctional EPCs ex vivo would improve the outcome after cell transplantation in the murine hind limb ischemia model. EPC dysfunction was confirmed in a homogenous population of patients with type 1 diabetes mellitus and a microarray study was preformed to identify dysregulated genes. Notably, the secreted proangiogenic protein osteopontin (OPN) was significantly downregulated in diabetic EPCs. Furthermore, OPN-deficient mice showed impaired recovery following hind limb ischemia, suggesting a critical role for OPN in postnatal neovascularization. EPCs isolated from OPN KO mice showed decreased ability to adhere to endothelial cells as well as impaired angiogenic potential. However, this dysfunction was reversed upon exposure to recombinant OPN, suggesting that OPN may act in an autocrine manner on EPCs. Indeed, exposure of OPN knockout (KO) EPCs to OPN was sufficient to induce the secretion of angiogenic proteins (IL-6, TGF-α, and FGF-α). We also demonstrated that vascular regeneration following hind limb ischemia in OPN KO mice was significantly improved upon injection of EPCs preexposed to OPN. We concluded that OPN acts in an autocrine manner on EPCs to induce the secretion of angiogenic proteins, thereby playing a critical role in EPC-mediated neovascularization. Modification of cells by exposure to OPN may improve the efficacy of autologous EPC transplantation via the enhanced secretion of angiogenic proteins.

Changes in neuromuscular transmission in the W/W(v) mouse internal anal sphincter.

BACKGROUND: Intramuscular interstitial cells of Cajal (ICC-IM) have been shown to participate in nitrergic neuromuscular transmission (NMT) in various regions of the gastrointestinal (GI) tract, but their role in the internal anal sphincter (IAS) is still uncertain. Contractile studies of the IAS in the W/W(v) mouse (a model in which ICC-IM numbers are markedly reduced) have reported that nitrergic NMT persists and that ICC-IM are not required. However, neither the changes in electrical events underlying NMT nor the contributions of other non-nitrergic neural pathways have been examined in this model. METHODS: The role of ICC-IM in NMT was examined by recording the contractile and electrical events associated with electrical field stimulation (EFS) of motor neurons in the IAS of wildtype and W/W(v) mice. Nitrergic, purinergic, and cholinergic components were identified using inhibitors of these pathways. KEY RESULTS: Under NANC conditions, purinergic and nitrergic pathways both contribute to EFS-induced inhibitory junction potentials (IJPs) and relaxation. Purinergic IJPs and relaxation were intact in the W/W(v) mouse IAS, whereas nitrergic IJPs were reduced by 50-60% while relaxation persisted. In the presence of L-NNA (NOS inhibitor) and MRS2500 (P2Y1 receptor antagonist), EFS gave rise to cholinergic depolarization and contractions that were abolished by atropine. Cholinergic depolarization was absent in the W/W(v) mouse IAS while contraction persisted. CONCLUSIONS & INFERENCES: ICC-IM significantly contributes to the electrical events underlying nitrergic and cholinergic NMT, whereas contractile events persist in the absence of ICC-IM. The purinergic inhibitory neural pathway appears to be independent of ICC-IM.

Pancreatic adenocarcinoma in a young patient population--12-year experience at Memorial Sloan Kettering Cancer Center.

BACKGROUND: There is a dearth of data in a younger population of patients with pancreatic ductal adenocarcinoma (PAC) regarding epidemiology, genetics, prognosis, and outcome. This report examines a large cohort of patients with PAC

Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC).

BACKGROUND: The incidence of gallbladder cancer (GBC) in the US is 1.2/100,000. This report examines the patterns of presentation, adjuvant treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10-year period. METHODS: A retrospective analysis of patients referred to MSKCC with a diagnosis of GBC between January 1995 and December 2005 was performed. Patients were identified from the MSKCC cancer registry. Information extracted included, demographics, clinical and pathological stage, surgical management, pathology, adjuvant and palliative therapy, date of relapse, death or last follow-up. Date of diagnosis was defined as date of surgery or biopsy. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Four hundred thirty-five GBC cases were identified: 285 (65.5%) females,150 (34.5%) males. Median age 67 years (range 28-100). Pathology: 88% adenocarcinoma, 4% squamous, 3% neuroendocrine, 2% sarcoma. 36.6% presented as AJCC Stage IV. 47% were discovered incidentally at laparoscopic cholecystectomy. One hundred thirty-six of these were re-explored, of whom 100 (73.5%) had residual disease. Of those who underwent curative resections (N = 123), 8 (6.5%) received adjuvant chemotherapy, 8 (6.5%) chemoradiation alone and 8 (6.5%) both chemoradiation and systemic chemotherapy. Median overall survival for the cohort was 10.3 months (95% CI 8.8-11.8) with a median follow up of 26.6 months. The median survival for those presenting with stage Ia-III disease was 12.9 months (95% CI 11.7-15.8 months) and 5.8 months (95% CI 4.5-6.7) for those presenting with stage IV disease. Median survival was 15.7 months (95% CI 12.4-18.4) for those discovered incidentally at laparoscopic cholecystectomy. For those who underwent re-exploration, median survival was 14.6 months (95% CI 12.6-18.3) if residual disease was present, and 72 months (95% CI 34 to infinity) if no evidence of disease. The median survival for those who received adjuvant therapy was 23.4 months (95% CI 15.7-47). CONCLUSIONS: GBC is commonly diagnosed incidentally (47%). Re-exploration reveals a high incidence of residual disease (74%). Median survival is better for patients who have no evidence of disease on re-exploration (72 months) compared to those with residual disease detected (P < 0.0001). Overall prognosis is poor. Although we did not observe a survival benefit for those who received adjuvant therapy, the study did not have sufficient power to address this question. In addition, the number of patients who received adjuvant therapy was small with marked heterogeneity in clinical and therapeutic details, precluding any definitive conclusions being drawn. Prospective randomized trials of adjuvant therapy are needed in this disease.