Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016 was held in Montreal, Quebec, 5-7 February. Experts in radiation oncology, medical oncology, surgical oncology, and infectious diseases involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics: ■ Follow-up and survivorship of patients with resected colorectal cancer■ Indications for liver metastasectomy■ Treatment of oligometastases by stereotactic body radiation therapy■ Treatment of borderline resectable and unresectable pancreatic cancer■ Transarterial chemoembolization in hepatocellular carcinoma■ Infectious complications of antineoplastic agents.

Gbetagamma subunit combinations differentially modulate receptor and effector coupling in vivo.

In vitro, little specificity is seen for modulation of effectors by different combinations of Gbetagamma subunits from heterotrimeric G proteins. Here, we demonstrate that the coupling of specific combinations of Gbetagamma subunits to different receptors leads to a differential ability to modulate effectors in vivo. We have shown that the beta(1)AR and beta(2)AR can activate homomultimers of the human inwardly rectifying potassium channel Kir 3.2 when coexpressed in Xenopus oocytes, and that this requires a functional mammalian Gs heterotrimer. Modulation was independent of cAMP production, suggesting a membrane-delimited mechanism. To analyze further the importance of different Gbetagamma combinations, we have tested the facilitation of Kir 3.2 activation by betaAR mediated by different Gbetagamma subunits. The subunits tested were Gbeta(1,5) and Ggamma(1,2,7,11). These experiments demonstrated significant variation between the ability of the Gbetagamma combinations to activate the channels after receptor stimulation. This was in marked contrast to the situation in vitro where little specificity for binding of a Kir 3.1 C-terminal GST fusion protein by different Gbetagamma combinations was detected. More importantly, neither receptor, although homologous both structurally and functionally, shared the same preference for Gbetagamma subunits. In the presence of beta(1)AR, Gbeta(5)gamma(1) and Gbeta(5)gamma(11) activated Kir 3.2 to the greatest extent, while for the beta(2)AR, Gbeta(1)gamma(7), Gbeta(1)gamma(11,) and Gbeta(5)gamma(2) produced the greatest responses. Interestingly, no preference was seen in the ability of different Gbetagamma subunits to facilitate receptor-stimulated GTPase activity of the Gsalpha. These results suggest that it is not the receptor/G protein alpha subunit interaction or the Gbetagamma/effector interaction that is altered by Gbetagamma, but rather that the ability of the receptor to interact productively with the Gbetagamma subunit directly and/or the G protein/effector complex is dependent on the specific G protein heterotrimer associated with the receptor.

Validation of respiratory syncytial virus enzyme immunoassay and shell vial assay results.

The Pathfinder respiratory syncytial virus (RSV) enzyme immunoassay (EIA) (Kallestad), the shell vial (SV) technique, and conventional cell culture (CC) were compared for detection of RSV in nasopharyngeal aspirates. We found sensitivities, specificities, and positive and negative predictive values of 58.4, 100, 100, and 68.2%; 80.7, 97.2, 97.0, and 81.9%; and 77.6, 97.2, 96.9, and 79.5% for the CC, EIA, and SV methods, respectively. The SV and EIA techniques were both more sensitive than CC (P < 0.001). Finally, 29 respiratory viruses other than RSV were identified by CC.

Comparison of novel synthetic peptide-based DETECT-RUBELLA enzyme immunoassays with Enzygnost and IMx for detection of rubella-specific immunoglobulin G.

Enzyme immunoassays (EIAs) using synthetic peptides SP-E1 and SP-E1E2 (DETECT-RUBELLA [Bio-Chem]) were compared with two viral lysate-based EIAs (Enzygnost [Behring] and IMx [Abbott]) for the detection of rubella virus-specific immunoglobulin G antibodies. Sensitivities of 94.7, 100, 98.6, and 100% and specificities of 100, 97.4, 100, and 73.7% were found for the SP-E1, SP-E1E2, Enzygnost, and IMx EIAs, respectively.

Comparison of four enzyme immunoassays for the detection of cytomegalovirus IgG antibodies.

Four commercial enzyme immunoassays (EIA), namely the Behring Enzygnost EIA (BE-EIA), Abbott IMx, Whittaker CMV STAT Test Kit and Diamedix assay, were evaluated for the detection of CMV IgG. The methods were compared as to sensitivity, specificity, positive and negative predictive values, global agreement, ease of performance and, for a small number of specimens, reproducibility. Discordant results were resolved by using the Gull CMV indirect fluorescent antibody (IFA) method. Our data suggest that all four assays were valuable screening tools for the detection of CMV IgG based on their high sensitivity and high negative predictive value. However, differences were noted in the reproducibility level and in the incidence of false-positive, equivocal and nonspecific results regarding certain tests in particular. In our hands, the Abbott IMx and the BE-EIA ranked high in the performance characteristics for a good screening test, yet the Abbott IMx offers the added advantages of being the easiest to perform and having the most rapid turnaround time.

Comparison of a whole-virus enzyme immunoassay (EIA) with a peptide-based EIA for detecting rubella virus immunoglobulin G antibodies following rubella vaccination.

A total of 250 human serum samples were tested for rubella virus immunoglobulin G antibodies by two enzyme immunoassays (EIAs), one using whole rubella virus antigen and the other based on the use of synthetic peptide antigen. The samples were taken from 125 volunteers before and after their immunization with the RA 27/3 rubella vaccine. This study indicates that a synthetic peptide-based EIA can favorably replace current viral lysate-based EIAs to detect rubella virus antibodies following immunization. Because the synthetic peptide used in this newly developed EIA represents a putative neutralization epitope of the rubella virus, it could also be instrumental in determining rubella immune status and in assessing vaccine program efficiency.

Inhibition of ingestive behavior following fourth ventricle bombesin injection in chronic decerebrate rats.

To test the hypothesis that the effects of 4th ventricle bombesin (BN) injection on feeding require interaction with forebrain neural systems, intraoral sucrose (0.1 M) was measured in tube-fed control and tube-fed supracollicular decerebrate rats after 4th ventricle injections of 1, 5, 10, 20, and 50 ng BN. Fourth ventricle injections of all doses of BN reliably suppressed sucrose intake in both control and chronic decerebrate rats. These results indicate that caudal brain stem afferent signals produced by 4th ventricle BN injections are integrated by the local neural circuitry of the caudal brain stem, independent of the forebrain systems, to modulate ingestive behavior.

Phase II study of weekly intravenous menogaril in the treatment of recurrent astrocytomas in adults.

Twenty patients with astrocytomas recurrent after surgery +/- radiation were treated on a phase II protocol of the new anthracycline derivative menogaril 115 mg/m2 administered intravenously once per week. Sixteen patients were evaluable for treatment efficacy. No patient achieved a major therapeutic response. Three patients (19%) had stable disease for greater than 8 weeks, including one who showed minor evidence of tumor regression, but less than 50%. Thirteen patients failed. Treatment was well tolerated. One patient developed granulocytopenia, while none developed thrombocytopenia. Four patients required an interruption in their treatment for one to two weeks because of development of granulocytopenia (one patient) or other reasons. Other toxic effects included arm vein phlebitis and skin irritation, skin discoloration of the infused arm, mild to moderate nausea and vomiting, diarrhea, stomatitis, and a fatal central venous catheter infection. Despite the fact that menogaril appeared to have therapeutic activity against recurrent astrocytomas in our phase I studies, we could not document any activity in this phase II study.

Phase I study of oral menogaril administered daily for 14 consecutive days.

Twenty-eight patients were treated with oral menogaril daily x 14 every 4 weeks. Granulocytopenia was dose-limiting at 50-60 mg/m2 per day. Neutropenic fever occurred in one patient. Thrombocytopenia occurred in 3 of 6 patients treated with menogaril 60 mg/m2/day. Nausea and vomiting and other toxic effects were generally mild. No cardiac toxicity was seen. One partial remission and three minor responses were noted among 11 previously treated patients with carcinoma of the bladder. One minor response was noted among 3 patients with colorectal cancer. The dose recommended for phase II studies is 50 mg/m2 per day for 14 days. Phase II studies are recommended in carcinoma of the bladder. Gastrointestinal toxicity is substantially less on this schedule than with oral menogaril administered on a weekly or q4wk schedule, but thrombocytopenia may be more common.

Bioavailability and pharmacology of oral idarubicin.

A total of 9 patients entered in a phase I trial who received oral idarubicin daily for 3 days took part in pharmacokinetic studies, and bioavailability studies were performed on 13 additional patients receiving single doses of oral idarubicin alternating with i.v. treatment. The data were best fit by a two-compartment model (distribution and elimination compartments for i.v. drug and absorption and single-phase elimination for oral drug). For different idarubicin doses in the phase I and bioavailability studies, the median values for the terminal half-life of idarubicin varied from 5.6 to 11.6 h. High concentrations of the active metabolite idarubicinol were formed. Idarubicinol was eliminated more slowly than was the parent compound, with median half-lives for different dose levels varying from 8 to 32.7 h. Although most pharmacokinetic parameters were similar in plasma and whole blood, peak concentrations and AUCs in whole blood were about 3-4 times those calculated in plasma for idarubicin and about 1.5-2 times those determined in plasma for idarubicinol, indicating fairly extensive uptake into erythrocytes. Oral bioavailability was determined by comparing oral idarubicin to i.v. drug with respect to the combined idarubicin and idarubicinol plasma AUCs, and it varied from 12%-49% (median, 29%). Bioavailability was essentially the same (30%) when whole-blood values were used. Urinary excretion of the drug was less than 5% of the delivered dose by 96 h. Granulocytopenia correlated with plasma idarubicinol "estimated" clearance and steady-state volume of distribution, with whole-blood idarubicinol AUC, area under the moment curve (AuMC), and "estimated" clearance and volume of distribution, and with whole-blood combined idarubicin and idarubicinol AUCs. This suggests that drug contained in erythrocytes plays a major role in toxicity and that idarubicinol may play a larger role in toxicity than does the parent compound.

Phase I study of idarubicin administered orally on a daily x 3 schedule.

Twenty-one adult patients with refractory solid tumors were treated on a phase I study of idarubicin (4-demethoxydaunorubicin) administered daily for 3 days every 3 weeks. Nineteen of the patients had received previous chemotherapy (including 13 with prior anthracyclines), and 12 had received prior radiotherapy. Idarubicin dose levels of 10, 15, 17.5, 20, and 25 mg/m2 were explored. Hematological toxicity was dose-related. Other toxicity was acceptable. Only one patient (treated with an idarubicin dose of 17.5 mg/m2/day) developed neutropenic fever, from which he recovered. Further dose escalations beyond 25 mg/m2 were not carried out because of the increasing length of time required for recovery from granulocytopenia at higher doses. No patient experienced a major response, but minor responses were seen in 3 patients with carcinomas of the colon, breast, and kidney respectively. Further phase II studies of oral idarubicin at a starting dose of 20-25 mg/m2 daily times 3 days in patients with good bone marrow reserves are recommended. Because of the degree of neutropenia expected, patients would have to be observed carefully.

Phase I study of oral menogaril administered on a once weekly schedule.

Forty-seven patients with solid tumors were treated on a phase I study of menogaril administered by mouth once per week. Nausea and vomiting were excessive at weekly doses of 350 and 450 mg/m2/week but were tolerable and controlled reasonably well by antiemetics at lower doses. There appeared to be a relatively shallow dose-vs-granulocytopenia curve above a menogaril dose of 180 mg/m2/week. No patient receiving chronic dexamethasone for cerebral edema developed granulocytopenia, even at menogaril doses of 350-450 mg/m2/week. Two patients developed neutropenic infection. No patient developed thrombocytopenia. Mild arrhythmias were seen in 3 patients. Two patients suffered possible myocardial infarcts that may not have been related to treatment. Asymptomatic blood pressure fluctuations were common and were probably not related to treatment. Diarrhea was dose-related but was generally not severe. Alopecia and stomatitis occurred occasionally. Minor responses were seen in two patients with gliomas, and three of five evaluable prostate cancer patients experienced marked pain relief. The dose recommended for phase II studies is 250-300 mg/m2/week with antiemetic pretreatment. This schedule appears to allow an oral menogaril dose-intensity that is approximately double that attainable with other oral schedules that have been studied.

Giant cell pneumonia due to respiratory syncytial virus. Occurrence in severe combined immunodeficiency syndrome.

A 6-month-old male infant with a severe combined immunodeficiency syndrome was hospitalized for progressive respiratory distress. Examination during hospitalization disclosed widespread pulmonary infiltrates that did not respond to intensive therapy. The patient died eight days after admission. Autopsy disclosed Pneumocystis carinii pneumonia and widespread giant cell pneumonia. Respiratory syncytial virus (RSV) was grown from a lung specimen obtained at autopsy. Specific immunofluorescent staining of the cytoplasm of alveolar lining cells with RSV antiserum was demonstrated. The electron microscopic appearance of giant cells was compatible with RSV infection. The RSV should be added to the list of viruses causing giant cell pneumonia.

Cardiac function monitored by impedance cardiography during changing seatback angles and anti-G suit inflation.

Impedance cardiography (IC) appears to be a promising noninvasive technique for monitoring small changes in pilot cardiovascular status during conditions simulating flight. Heart rate (HR), stroke volume (SV), cardiac output (CO), ventricular ejection time (VET), and thoracic impedance (Zo) were monitored in ten volunteers for 5 min at each of four seatback angles from vertical: 12 degrees, 30 degrees, 45 degrees, and 60 degrees. Data were also obtained at three seatback angles (12 degrees, 30 degrees, 60 degrees) for 6 min each before, during, and after inflation of the standard USAF anti-G suit to 1.5 psi. Significant differences (p less than 0.05) in HR, SV, CO, VET and Zo were observed among the four positions. Inflation of the standard anti-G suit to 1.5 psi at 1.0 +Gz did not significantly alter HR, SV, or CO; whereas, 1 min of deflation of the anti-G suit significantly altered HR, SV, CO compared to inflation values. The results suggest IC can detect small differences in HR, SV, CO, VET, and Zo within subjects as a function of minor changes in body position.

Interrelationship between glomerular filtration rate and renal transport of sodium and chloride during fetal life.

The maturation of the glomerular filtration rate (GFR) and the interrelationship between the GFR and the renal transport of sodium and chloride have been evaluated during the last trimester of gestation with the use of long-term experiments in fetal lambs. An increase in GFR (milliliters per minute) parallel to the increase in fetal body weight was demonstrated; however, no significant change was shown when the GFR (milliliters per minute per kilogram of fetal body weight) (1.141 +/- 0.079) was related to fetal body weight or gestational age. There was a constant increase in sodium and chloride reabsorption (microequivalents per minute) during the last third of gestation. This increase in sodium and chloride reabsorption was less than the increase in GFR (milliliters per minute) before 129 days but became higher than the rise of GFR (milliliters per minute) after 129 days of gestation.

Nasopharyngeal carcinoma and Burkitt's lymphoma in a Canadian family. I. HLA typing, EBV antibodies and serum immunoglobulins.

Two nasopharyngeal carcinomas of the lymphoepithelioma type and two Burkitt's lymphomas with the characteristic histopathologic features developed in three siblings and one first-degree cousin in a large French-Canadian family. Epstein-Barr virus antibody titres in the two lymphoepithelioma cases but not in the Burkitt's lymphoma cases were, as expected, greatly elevated. HLA typing of the family members failed to disclose HLA antigens A2 and B Sin-2, which have been associated with lymphoepithelioma in Asia. The occurrence, however, of a plasmacytoma in one other first-degree cousin and low serum IgA values in several siblings and cousins suggests the possibility of a genetically determined predisposing B-cell dysfunction in the development of these tumours.