Gus J. Slotman

Concurrent cis-platinum and radiation with or without surgery for advanced head and neck cancer.

PURPOSEnThis study was undertaken to assess the efficacy of concurrent cis-platinum and radiation in patients with advanced head and neck cancer and to determine if patients responding to the preoperative regimens may be cured without radical surgery.nnnMETHODS AND MATERIALSnOne hundred and one patients with potentially operable Stage III and IV squamous cell carcinoma of the head and neck received 45 Gy at 1.8 Gy fractions and continuous infusion cis-platinum 20 mg/m2 over 24 h on days 1 through 4 and 22 through 25 of the radiation schedule. Three to 4 weeks later, radical surgery of the primary site and neck dissections for patients presenting with cervical adenopathy was undertaken or if a complete response had been achieved, continued with radiation to 72 Gy with another course of concurrent continuous infusion cis-platinum.nnnRESULTnComplete and partial responses were achieved in 92% of the primary sites and 95% of the nodes. Over 80% of the patients were rendered tumor free at surgery after only the initial course of chemotherapy and radiation. There were no grade 3 or 4 toxicities from chemotherapy and radiation. Ninety-five percent of the patients who initiated treatment completed it. With a median follow-up of 41 months for all patients, 49% of the patients have survived disease free up to 9 years, independent of whether or not their primary tumors were resected or were treated definitively by further chemotherapy sensitized radiation. The disease-specific survival is 78% after 3 years with no local failures thereafter.nnnCONCLUSIONnThese findings suggest that continuous infusion cis-platinum administered concurrently with radiotherapy can improve survival in advanced head and neck cancer. Patients responding to the preoperative regimen may be cured without radical surgery, which can be reserved for salvage.

Preoperative combined chemotherapy and radiation therapy plus radical surgery in advanced head and neck cancer five‐year results with impressive complete response rates and high survival

Radiation therapy combined with cisplatin as a chemoradiation sensitizer (CT/RT) has been reported to enhance tumor response in squamous cell carcinoma of the head and neck. In the present study, CT/RT was used preoperatively in advanced Stage III and IV head and neck cancer. Fifty‐three patients were entered prospectively into a Phase II study. Treatment consisted of 4500 cGy of radiation therapy in 5 weeks combined with cisplatin 20 mg/m2 for 4 days during weeks 1 and 4 of radiation therapy. This was followed 4 to 8 weeks later by curative surgery. Pretherapy dental care; long‐term nutritional support; individualized skin, mouth, and wound care; and continuous interdisciplinary communication were integral parts of this regimen. In four patients, CT/RT toxicity was seen (8%); three episodes of skin reaction or stomatitis and three episodes of leukopenia (less than 2500/μl) causing a delay in CT/RT treatment in one patient. Three patients died of other causes during the preoperative interval, without clinical evidence of toxicity. Fifty patients (94%) had a complete (CR) or partial response (PR) to CT/RT. Clinical CR was seen in 38 of 51 (75%) primary tumors and 21 of 27 (78%) cervical nodes. Forty‐one patients (77%) underwent curative surgery. In 27 of 32 (84%) resected CR primary tumors and 16 of 18 (89%) CR metastatic nodes, the surgical specimen was microscopically free of tumor. Postoperative morbidity was 32%. Five patients (12%) required additional surgery for their complications. Perioperative mortality was 5%. Five patients had tumor recurrence: three postoperatively after clinical PR to CT/RT and two in clinical CR patients who refused further treatment after CT/RT, then had a recurrence and were salvaged surgically. No patient with a CR in both the tumor and nodes who underwent surgery had a tumor recurrence. With a follow‐up of 8 years (median, 40 months), the median survival for all patients was 45 months. The 5‐year actuarial survival rate was 43% for all patients and 55% for patients who had CT/RT and surgery. This multimodality treatment of advanced head and neck cancer has low toxicity and impressive survival. It renders a significant number of patients tumor‐free before surgery. These patients may be candidates for additional study triaging additional CT/RT for complete CR only and surgery for PR and biopsy‐proved residual disease. Cancer 1992; 69:2736‐2743.

Ketoconazole: A thromboxane synthetase and 5-lipoxygenase inhibitor with antimetastatic activity in B16-F10 melanoma

Arachidonic acid metabolites have been implicated in the development of hematogenous tumor metastases. The purpose of this study was to determine the antimetastatic potential of ketoconazole, a thromboxane synthetase and 5-lipoxygenase inhibitor. One hundred seventy-four C57 black male mice were randomized to receive either placebo or 0.0057 mg/g of ketoconazole. Drug and placebo were delivered once daily by intraperitoneal injection beginning 24 hr prior to tumor injection and continuing until sacrifice. All animals were injected subcutaneously in the flank with 5 x 10(6) B16-F10 melanoma cells. Animals were sacrificed at 3 weeks (n = 60), 4 weeks (n = 84), and 5 weeks (n = 30). Metastases were assessed by circumferential inspection of the lungs of all animals at autopsy. Differences in survival and primary tumor mass between study groups were not statistically significant. Pulmonary metastases were present in 37/174 animals. Twenty-nine of the mice with metastases were in the placebo groups, and 8 were in the ketoconazole groups. The incidence of metastases was significantly reduced in the ketoconazole-treated mice compared to placebo both within each group and overall, P was less than 0.05 and 0.001, respectively. This effect was not mediated through changes in local tumor growth.

Prospectively validated prediction of physiologic variables and organ failure in septic patients: The Systemic Mediator Associated Response Test (SMART).

ObjectiveConventional outcomes research provides only percentage risk of such end points as mortality rate, utilization of resources, and/or broad groupings of multiple organ system dysfunction. These prognostications generally are not applicable to individual patients. The purpose of the present study was to determine whether the Systemic Mediator Associated Response Test (SMART) methodology could identify interactions among demographics, physiologic variables, standard hospital laboratory tests, and circulating cytokine concentrations that predicted continuous and dichotomous dependent clinical variables, in advance, in individual patients with severe sepsis and septic shock, and whether these independent variables could be integrated into prospectively validated predictive models. DesignData review and multivariate stepwise logistic regression. SettingUniversity research laboratory. PatientsThree hundred three patients with severe sepsis or septic shock who comprised the placebo arm of a multiple-institution clinical trial, who were randomly separated into a model building training cohort (n = 200) and a predictive cohort (n = 103). InterventionsNone. Measurements and Main ResultsFrom baseline data and baseline plus serial input, including patient demographics, hospital laboratory tests, and plasma concentrations of interleukin-6, interleukin-8, and granulocyte colony stimulating factor, multiple regression models were developed that predicted clinically important continuous dependent variables quantitatively, in individual patients. Multivariate stepwise logistic regression was used to develop models that prognosticated dichotomous dependent end points. Data from individual patients in the predictive cohort were inserted into each predictive model for each day, with prospective validation accomplished by simple linear regression of individual predicted vs. observed values for continuous dependent variables, and by establishing the receiver operator characteristics area under the curve for logistic regression models that predicted dichotomous end points. Of SMART models for continuous dependent variables, 100 of 143 (70%) were validated at r values >.7 through day 3, and 184 of 259 (71%) above r = .5 through day 5. SMART predictions of dichotomous end points achieved receiver operator characteristics areas under the curve >.7 for up to 84% of the equations in the first week. Many SMART models for both continuous and dichotomous dependent variables were validated at clinically useful levels of accuracy as far as 28 days after baseline. ConclusionsSMART integration of demographics, bedside physiology, hospital laboratory tests, and circulating cytokines predicts organ failure and physiologic function indicators in individual patients with severe sepsis and septic shock.

Prostacyclin is neither sufficient alone nor necessary to cause pulmonary dysfunction: results from infusions of prostacyclin and antiprostacyclin antibody in porcine septic shock.

ObjectiveThis study evaluated whether prostacyclin is a necessary mediator of inflammation in graded bacteremia or is sufficient alone in pathophysiologic concentrations to cause the pulmonary derangement of bacteremic shock. DesignExperimental. SettingLaboratory. SubjectsTwenty-three anesthetized adult swine. IntervensionsSwine were studied in four groups for 4 hrs: a) an anesthesia control group (n = 6); b) a septic control group (n = 6), in which 1010/mL Aeromonas hydrophila was infused intravenously at 0.2 mL·kg−1·hr−1 and increased to 4.0 mL·kg−1·hr−1 over 3 hrs; c) a prostacyclin infusion group (n = 6), which received prostacyclin infusion to match septic control plasma concentrationsclm without bacteremia; and d) an antiprostacyclin antibody group (n = 5), which received continuous Aeromonas hydrophila infusion plus antiprostacyclin antibody infusion. Measurements and Main Results Pulmonary hemodynamics, arterial blood gases, and plasma concentrations of arachidonate metabolites were measured hourly over a 4-hr period. In the septic control group and antiprostacyclin antibody group, elevated pulmonary vascular resistance index and pulmonary artery pressure with decreased Pao2, as well as lower pH, were documented after 1 and 3 hrs of graded bacteremia compared with the anesthesia control group and prostacyclin infusion group (p < .05). Thromboxane B2 concentration increased significantly in all groups during septic shock. In the antiprostacyclin antibody group, leukotriene B4 increased immediately after starting antiprostacyclin antibody infusion and reached significance at 3 hrs compared with the septic control group (p < .05). The prostacyclin infusion group had consistently lower concentrations of leukotrienes C4, D4, and E4 than all other groups. ConclusionsProstacyclin does not mediate blood gas changes, alterations of pulmonary hemodynamics, or platelet abnormalities in porcine septic shock, because antiprostacyclin antibody infusion did not change the pulmonary hypertension and hypoxemia, and infusion of prostacyclin to pathophysiologic blood concentrations did not reproduce such changes. Antiprostacyclin blockade during bacteremia significantly increased concentrations of leukotrienes C4, D4, and E4 and leukotriene B4, whereas prostacyclin infusion suppressed concentrations of leukotrienes C4, D4, and E4, suggesting that endogenous prostacyclin may blunt leukotriene release.

Variation in Weight and Obesity Comorbidities After Open Roux-en-Y Gastric Bypass by Health Insurance: Medicaid vs Medicare vs Private vs Self-Pay in 4225 Bariatric Outcomes Longitudinal Database Patients

Author Affiliations: Section of Hematology/Oncology, Department of Medicine, North Florida/South Georgia Veterans Health System and the University of Florida, Gainesville (Duff); Department of Surgery, North Florida/ South Georgia Veterans Health System and the University of Florida, Gainesville (Peters, Zingarelli, Sarosi, Thomas); Department of Surgery, Mount Sinai Medical Center, Miami Beach, Florida (Ben-David).

The cardiovascular hemodynamics and leukotriene kinetics during prostacyclin and anti-prostacyclin antibody infusions in septic shock.

This study evaluated whether or not prostacyclin (PGI2) was necessary or sufficient by itself in a pathophysiologic concentration to mediate the cardiovascular dysfunction of septic shock. Anesthetized adult swine received anesthesia only (ANESTHESIA CONTROL, n = 6); graded Aeromonas hydrophila, 10(10)/mL, infusion at 0.2 mL/kg/h that increased to 4.0 mL/kg/h over 3 h (SEPTIC SHOCK CONTROL, n = 6); pathophysiologic prostacyclin infusion to match septic shock control plasma levels without bacteremia (PGI2 INFUSION, n = 6), or graded Aeromonas hydrophila plus anti-prostacyclin antibody infusion (ANTI-PGI2-Ab INFUSION, n = 5). This graded porcine bacteremia model was 100% lethal after 4 h. Cardiovascular hemodynamics, arterial blood gases, and plasma levels of arachidonate metabolites were measured at baseline and hourly over a 4-h period. The results showed that PGI2 was not a necessary mediator of impaired cardiovascular hemodynamics in graded bacteremia, as anti-PGI2 antibody infusion did not improve the cardiac index, systemic vascular resistance, or peripheral oxygen balance in septic animals. Also, PGI2 was not sufficient alone to cause the cardiovascular dysfunction of sepsis, as pathophysiologic infusion of PGI2 did not reproduce such changes in normal animals. PGI2 blockade during bacteremia significantly increased LTC4D4E4, and LTB4 whereas PGI2 infusion suppressed LTC4D4E4 concentration, suggesting that endogenous PGI2 may blunt leukotriene release during septic shock. These results indicate a complex dynamic equilibrium among prostacyclin and leukotrienes in septic shock.

Health insurance does matter: clinically significant variation in obesity-related diagnoses between insurance types in 83,059 morbidly obese patients

While obesity is not a classic pathogen such as influenza, it’s rampant and dramatic rise worldwide over a relatively short period of time has made it a significant threat to the health of mankind as a whole. Thus, obesity has been classified as an epidemic since the late 1990s.1 The most recent data from the World Health Organization shows 33.9% of Americans to be obese, and approximately 18.2% of people are obese worldwide.2 Obesity has nearly tripled over the last three decades and is projected to continue rising, hence it’s unfortunate but appropriate status as an epidemic.