Perioperative Management of Gastric Cancer Patients Treated With (Sub)Total Gastrectomy, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Lessons Learned.

BACKGROUND: The PERISCOPE I study was designed to assess the safety and feasibility of (sub)total gastrectomy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin and docetaxel for gastric cancer patients who have limited peritoneal dissemination. The current analysis investigated changes in perioperative management together with their impact on postoperative outcomes. METHODS: Patients with resectable gastric cancer and limited peritoneal dissemination were administered (sub)total gastrectomy, CRS, and HIPEC with oxaliplatin (460 mg/m2) and docetaxel (escalating scheme: 0, 50, 75 mg/m2). Of the 25 patients who completed the study protocol, 14 were treated in the dose-escalation cohort and 11 were treated in the expansion cohort (to optimize perioperative management). RESULTS: A significant proportion of the patients in the dose-escalation cohort (n = 7, 50%) had ileus-related complications. In this cohort, enteral nutrition was started immediately after surgery at 20 ml/h, which was increased on day 1 to meet nutritional needs. In the expansion cohort, enteral nutrition was administered at 10 ml/h until day 3, then restricted to 20 ml/h until day 6, supplemented with total parenteral nutrition to meet nutritional needs. Ileus-related complications occurred for two patients (18%) of the expansion cohort. The intensive care unit (ICU) readmission rate decreased from 50 (n = 7) to 9% (n = 1; p = 0.04). CONCLUSION: The implementation of a strict nutritional protocol during the PERISCOPE I study was associated with a decrease in postoperative complications. Based on these results, a perioperative care path was described for the gastric cancer HIPEC patients in the PERISCOPE II study.

Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial.

BACKGROUND: This multicentre, randomised, double-blinded, placebo-controlled, phase II/III trial aimed to evaluate an oral THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract for prevention of refractory chemotherapy-induced nausea and vomiting (CINV). Here we report the phase II component results. PATIENTS AND METHODS: Eligible patients experienced CINV during moderate-to-high emetogenic intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Study treatment consisted of one cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) three times daily, from days -1 to 5, and 1 cycle of matching placebo in a crossover design, then blinded patient preference for a third cycle. The primary end point was the proportion of participants with complete response during 0-120 h from chemotherapy. A total of 80 participants provided 80% power to detect a 20% absolute improvement with a two-sided P value of 0.1. RESULTS: A total of 81 participants were randomised; 72 completing two cycles were included in the efficacy analyses and 78 not withdrawing consent were included in safety analyses. Median age was 55 years (range 29-80 years); 78% were female. Complete response was improved with THC:CBD from 14% to 25% (relative risk 1.77, 90% confidence interval 1.12-2.79, P = 0.041), with similar effects on absence of emesis, use of rescue medications, absence of significant nausea, and summary scores for the Functional Living Index-Emesis (FLIE). Thirty-one percent experienced moderate or severe cannabinoid-related adverse events such as sedation, dizziness, or disorientation, but 83% of participants preferred cannabis to placebo. No serious adverse events were attributed to THC:CBD. CONCLUSION: The addition of oral THC:CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC:CBD to placebo. Based on these promising results, we plan to recruit an additional 170 participants to complete accrual for the definitive, phase III, parallel group analysis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001036404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370473&isReview=true.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus palliative systemic chemotherapy in stomach cancer patients with peritoneal dissemination, the study protocol of a multicentre randomised controlled trial (PERISCOPE II).

BACKGROUND: At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. METHODS: In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3-4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. DISCUSSION: The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. TRIAL REGISTRATION: clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

Juvenile exposure to ketamine causes delayed emergence of EEG abnormalities during adulthood in mice.

BACKGROUND: Increased susceptibility to cognitive impairment or psychosis in adulthood is associated with adolescent drug abuse. Studies in adults have identified impairments in attention and memory, and changes in EEG, as common consequences of ketamine abuse. In contrast, the effects of ketamine on the juvenile brain have not been extensively tested. This is a significant omission, since abuse of ketamine is often observed within this age group. OBJECTIVES: Juvenile mice (4-6 weeks of age) were administered ketamine (20mg/kg) for 14 days. EEG was assessed in response to auditory stimulation both at one week following ketamine exposure at 7 weeks of age (juvenile) and again at 12 weeks of age (adult). EEG was analyzed for baseline activity, event-related power and event-related potentials (ERPs). RESULTS: While no effects of ketamine exposure were observed during the juvenile period, significant reductions in amplitude of the P20 ERP component and event-related gamma power were seen following ketamine when re-tested as adults. In contrast, reductions in event-related theta were seen in ketamine-exposed mice at both time points. CONCLUSIONS: Age related deficits in electrophysiological components such as P20 or event-related gamma may be due to an interruption of normal neural maturation. Reduction of NMDAR signaling during adolescence leads to delayed-onset disruption of gamma oscillations and the P20 component of the ERP. Further, delayed onset of impairment following adolescent ketamine abuse suggests that methods could be developed to detect and treat the early effects of drug exposure prior to the onset of disability.

European outbreaks of atypical myopathy in grazing horses (2006-2009): determination of indicators for risk and prognostic factors.

REASONS FOR PERFORMING STUDY: Appropriate management of atypical myopathy (AM) requires the establishment of an accurate diagnosis and prognosis. Furthermore, preventive measures to avoid AM need to be refined. OBJECTIVES: The aims of the study were as follows: 1) to improve the diagnosis of AM; 2) to identify prognostic predictors; and 3) to refine recommended preventive measures based on indicators of risk factors. METHODS: An exploratory analysis of cases in Europe between 2006 and 2009 reported to the Atypical Myopathy Alert Group was conducted. Based on clinical data, reported cases were allocated into 2 groups: confirmed or highly probable AM (AM group; further divided into survivors and nonsurvivors); and cases with a low probability of having AM or with another final diagnosis (non-AM group). Using Welch's test and odds ratios corrected for multiple comparisons, the AM vs. non-AM groups were compared to identify indicators for diagnosis and risk factors, and survivors vs. nonsurvivors in the AM group were compared to identify prognostic factors. Sensitivity, specificity and positive and negative predictive values were calculated for specific clinical signs related to final diagnosis and outcome. RESULTS: From 600 reported cases, 354 AM cases (survival rate of 26%) and 69 non-AM cases were identified, while there were insufficient data to categorise the remainder. Variables valuable for diagnosing AM compared with similar diseases were as follows: presence of dead leaves and wood and/or trees on pastures; sloping pastures; full-time pasture access; no food supplementation; normal body condition; pigmenturia; normothermia; and congested mucous membranes. Nonsurvival was associated with recumbency, sweating, anorexia, dyspnoea, tachypnoea and/or tachycardia. Survival was associated with remaining standing most of the time, normothermia, normal mucous membranes, defaecation and vitamin and antioxidant therapy. CONCLUSIONS AND POTENTIAL RELEVANCE: This study refines the list of risk factors for AM. Clinical signs valuable for diagnosis and prognosis have been identified, enabling clinicians to improve management of AM cases.

Phase I/II trial of intravenous Doxil and whole abdomen hyperthermia in patients with refractory ovarian cancer.

OBJECTIVE: A phase I/II study of Doxil combined with whole abdomen hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase both liposomal delivery and drug extravasation into tumour xenografts resulting in enhanced cytotoxic effects. PATIENTS AND METHODS: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) Doxil at a dose of 40 mg m-2 as a 1-h infusion followed by whole abdomen hyperthermia. The phase I portion of the study was performed to determine the maximal tolerated dose (MTD) of hyperthermia. Quality of life (QoL) was performed at baseline, prior to each cycle and every 3 months. Plasma pharmacokinetic studies were performed with the first cycle. RESULTS: Ten patients participated in the phase I portion of the study which demonstrated that the MTD of hyperthermia was 60 min after either average vaginal and rectal temperatures of 40 degrees C had been achieved or after 30 min of power application, whichever was shorter. All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2-8) and six patients had been previously treated with Doxil. There were three partial responses for a response rate of 10% (95% CI: [2%, 27%]) and eight patients (27%; 95% CI: [12%, 46%]) had disease stabilization. The median time to progression or death was 3.4 months (95% CI: [2.6, 5.2]) and the median survival was 10.8 months (95% CI: [8.8, 17.4]). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only four (13%) experienced grade 3-4 PPE toxicity. Doxil systemic exposure was higher in those with grade 3-4 PPE compared to those with no PPE. None of the patients had grade 3-4 thermal toxicity due to hyperthermia. QoL was not decreased in patients responding to therapy. CONCLUSIONS: Therapy with intravenous Doxil and whole abdomen hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer is feasible and does not negatively impact quality of life.

Prospective assessment of quality of life in ovarian cancer patients receiving whole abdomen hyperthermia and liposomal doxorubicin.

PURPOSE: Prospective assessment of quality of life (QoL) in patients with refractory, residual or recurrent ovarian cancer receiving whole abdomen hyperthermia and intravenous liposomal doxorubicin chemotherapy. METHODS: Treatment consisted of six cycles of intravenous liposomal doxorubicin at 40 mg m2 followed by whole abdomen hyperthermia with each cycle delivered every 4 weeks. QoL assessment was performed at baseline, prior to each cycle of chemotherapy and every 3 months during follow-up using self-administered questionnaires. Global QoL was rated on a seven-point scale and specific domains of QoL, disease related symptoms and treatment related toxicity were rated on a four-point scale. RESULTS: Thirty-two patients were enrolled on the study and 129 QoL questionnaires were completed. Average age was 57.9 (range 45-76); nine patients had persistent and 23 recurrent disease. Ten patients completed six cycles of therapy. Three patients returned follow-up surveys. Subjects rated their overall QoL and health at baseline as above average with mean scores 5.10 (95% CI=4.62-5.58) and 4.66 (95% CI=4.23-5.08), respectively. No significant change in overall QoL was found between baseline and cycles 4-6 of therapy. Mean ratings of overall health and subject reported differences in QoL between cycles were not significantly changed during therapy. Limited follow-up data were available, but scores suggest possible improvement in QoL for patients completing all therapy. Subjects rated the greatest negative impact on QoL in areas of role functioning and social functioning, where the mean (SD) over all cycles was 2.00 (0.67) and 1.98 (0.70), respectively. For physical symptoms, fatigue and sleep disturbance had the most negative impact on QoL with means (SD) of 2.26 (0.62) and 1.91 (0.70). The moderate treatment related toxicity seen in this study did not significantly impact patients reported QoL. CONCLUSIONS: Patients with unfavourable ovarian cancer responding to intravenous liposomal doxorubicin and whole abdomen hyperthermia maintained above average QoL during therapy. Limited data on patients completing protocol therapy demonstrated possible improvement in QoL.

Effects of nonsulfur and sulfur amino acids on the regulation of hepatic enzymes of cysteine metabolism.

To determine the role of nonsulfur vs. sulfur amino acids in regulation of cysteine metabolism, rats were fed a basal diet or diets supplemented with a mixture of nonsulfur amino acids (AA), sulfur amino acids (SAA), or both for 3 wk. Hepatic cysteine-sulfinate decarboxylase (CSDC), cysteine dioxygenase (CDO), and gamma-glutamylcysteine synthetase (GCS) activity, concentration, and mRNA abundance were measured. Supplementation with AA alone had no effect on any of these measures. Supplementation of the basal diet with SAA, with or without AA, resulted in a higher CDO concentration (32-45 times basal), a lower CSDC mRNA level (49-64% of basal), and a lower GCS-heavy subunit mRNA level (70-76%). The presence of excess SAA and AA together resulted in an additional type of regulation: a lower specific activity of all three enzymes was observed in rats fed diets with an excess of AA and SAA. Both SAA and AA played a role in regulation of these three enzymes of cysteine metabolism, but SAA had the dominant effects, and effects of AA were not observed in the absence of SAA.

Inositol 1,4,5-trisphosphate receptor expression in mammalian olfactory tissue.

Two cDNAs encoding inositol 1,4,5-trisphosphate (IP3) receptors were amplified from rat olfactory tissue, and both exhibited 100% sequence identity to the short (Segment II - ) variant of type I IP3 receptor. Type III IP3 receptor was also expressed in olfactory tissue. The distribution of IP3 receptors included the olfactory epithelium, lamina propria, and glandular tissue. These results demonstrate the co-expression of multiple IP3 receptor subtypes in olfactory cells, and suggest multiple functions for IP3 receptors in this tissue.

The effect of UVA irradiation on the epidermal melanocyte after 8-MOP and TMP administration.

Morphological and numerical changes in the epidermal melanocytes of black C57BL mice after phototoxic drug administration followed by ultraviolet A irradiation were studied to compare the effects of photochemotherapy on the epidermal melanocytes using 8-methoxypsoralen and trimethylpsoralen. One hour after intraperitoneal injection of the phototoxic drugs, 1.5 mg/kg in the small dose group and 6.0 mg/kg in the large dose group, the mice were exposed to UVA irradiation. This procedure was performed twice a week for 8 weeks at the small dose group and for 5 weeks in the large dose group. Skin biopsies were taken before irradiation in both groups, and follow up biopsies were done at each week. The number and size of the melanocytes were observed in a split-DOPA preparation. In the drug treated groups, there was an increase in the size of the perikaryon, and the number, length, width, and arborization of dendrites. Such changes were more clearly seen in the group treated with trimethylpsoralen compared with the 8-methoxypsoralen treated group. Therefore, trimethylpsoralen is more effective than 8-methoxypsoralen in the increase of the perikaryon size, and the number, length, width, and arborization of dendrites of melanocytes in the intraperitoneal injection.

Glucose-insulin interactions during cardiopulmonary bypass. Hypothermia versus normothermia.

Since hypothermia is commonly used to lower local and general metabolism during cardiopulmonary bypass, we attempted to identify its specific effects on glucose-insulin interactions. A group of nondiabetic patients undergoing hypothermic (28 degrees C) cardiopulmonary bypass with ischemic (cold) cardiac arrest was compared to a similar group operated on under normothermic conditions with potassium cardioplegia. In the absence of exogenous dextrose administration, hypothermia blocked insulin secretion for the duration of the operation. It also inhibited insulin secretion in response to an exogenous dextrose load (e.g., the priming fluid of the cardiopulmonary bypass circuit) or a glucagon injection, but this inhibition was lifted by rewarming. Blood glucose levels, which during normothermia were mildly elevated even in the absence of dextrose administration, remained normal during the hypothermic phase of cardiopulmonary bypass. By the end of the rewarming period, however, blood glucose levels had reached the same level as observed under normothermic bypass, a fact suggesting that the cold inhibition of hepatic glucose production had been only temporary. Cold inhibition of hepatic glucose production also explains why glucose clearance after a sudden dextrose load was initially faster at low body temperature than at normal temperature. Glucose-clamp studies indicated that insulin resistance was initiated by anesthesia and surgical trauma, and further accentuated by cardiopulmonary bypass, in association with elevated levels of hormones indicative of surgical stress. Regardless of body temperature changes, the assimilation of glucose by nondiabetic subjects during and immediately after bypass called for the infusion of large doses of insulin. A comparison with diabetic subjects showed that insulin-dependent patients (type I diabetes) required no more insulin during cardiopulmonary bypass than normal subjects, whereas patients with type II diabetes exhibited a marked insulin resistance during the operation and in the immediate postoperative period.

Absorption of trace metals in the zinc-deficient rat.

The effects of zinc deficiency on the whole-body absorption and intestinal content of Zn, Cd, Cu, Co, Fe, Mn, and Cr were determined in the rat 1 h after oral administration of the isotopes. Both the absorption and intestinal content of Zn and Cr were increased in zinc-deficient rats, and the intestinal content of Feand Co was also increased in the zinc-deficient animals. Zinc administered orally with Cr decreased both absorption and intestinal content of the isotope in zinc-deficient rats. Chromium administered orally with Zn decreased intestinal content and absorption of Zn in zinc-deficient rats. Fractionation of mucosal supernatants by gel filtration showed that both zinc and chromium eluted in the same low molecular weight fraction. The elution patterns of zinc and cadmium from that of zinc-supplemented animals. These experiments provide some insight into the specificity of the zinc absorption pathway and present some explanations for the interaction or lack of interaction among trace elements.