Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma.

BACKGROUND: Neoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC. EXPERIMENTAL DESIGN: Treatment consisted of cetuximab load at 400 mg/m(2) followed by cetuximab 250 mg/m(2) weekly and gemcitabine 50 mg/m(2) twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection. RESULTS: Thirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three (92%) of these had negative surgical margins. Pathology revealed that 24% of resected tumors had grade III/IV tumor kill, including two pathological complete responses (8%). Median survival was 24.3 months in resected patients. Outcome did not vary by epidermal growth factor receptor status. CONCLUSIONS: Neoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC. Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival. Pathological complete responses can occur. This combination warrants further investigation.

Combined actions of 5-fluorouracil and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea on human colonic carcinoma cells in vitro.

Two lines of human colonic carcinoma cells have different sensitivities to 5-fluorouracil and 1-(2-chlorethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU). The growth of the BE line is 50% inhibited by 330 microM 5-fluorouracil and 15 microM methyl-CCNU, and the HT-29 line is 50% inhibited by 85 and 140 microM, respectively. On cloning, 50% of BE cells are killed by 500 microM 5-fluorouracil and 6 microM methyl-CCNU, and the HT-29 cells are killed by 250 and 120 microM respectively. When the drugs were combined, there were additive effects which occurred in cell growth of both lines and killing of BE cells. Synergism occurred in killing HT-29 cells when a low concentration of 5-fluorouracil was combined with methyl-CCNU. The synergism did not increase with increasing concentrations of 5-fluorouracil. Both drugs caused growth delay of spheroids (HT-29 cells), an effect that was additive when the drugs were combined. Growth inhibition of both lines in monolayer culture by 5-fluorouracil was more sensitive than was cell killing or inhibition of spheroid growth but, with methyl-CCNU, killing of BE cells was more sensitive than was growth inhibition. HT-29 cells showed similar sensitivity to methyl-CCNU in all three systems. The type and sensitivity of drug effect seen in vitro depends on the particular drug used, the cell line tested, and the parameter measured.

Intraoperative interstitial microwave-induced hyperthermia and brachytherapy.

Intra-operative placement of 11-gauge nylon catheters into deep-seated unresectable tumors for interstitial brachytherapy permits localized heating of tumors (hyperthermia) using microwave (915 MHz) antennas which are inserted into these catheters. Four preliminary cases are described where epithelial tumors at various sites were implanted with an antenna array and heated for 1 hour, both before and after the iridium-192 brachytherapy. Temperatures were monitored in catheters required for the appropriate radiation dosimetry but not required for the interstitial microwave antenna array hyperthermia (IMAAH) system. Additional thermometry was obtained using nonperturbed fiberoptic thermometry probes inserted into the catheters' housing antennas. No significant complications, such as bleeding or infection, were observed. This approach to cancer therapy is shown to be feasible and it produces controlled, localized hyperthermia, with temperatures of 50 degrees C or more in tumors. This technique may offer a therapeutic option for pelvic, intra-abdominal and head and neck tumors.

Short-term outcome after mesh or shouldice herniorrhaphy: a randomized, prospective study.

BACKGROUND: Retrospective analyses have shown that long-term recurrence rates after Lichtenstein mesh and Shouldice herniorrhaphies are low. Therefore differences in short-term outcome may be important determinants of one's choice of repair. Although proponents of the mesh repair claim that their methods is less morbid, to our knowledge no prospective comparative studies of short-term morbidity have been reported. METHODS: One hundred five adult patients were randomized to undergo either a mesh or Shouldice inguinal hernia repair. Postoperative pain, narcotic use, and time to resumption of usual activities and employment were recorded. Patients were blinded to the type of repair received until all data were collected. RESULTS: There was no difference between the herniorrhaphy methods with respect to postoperative pain, duration of narcotic use, and time to resumption of usual activity and employment. Recovery was rapid for both groups of patients. By 3 days after operation, 50% of patients rated their pain as very mild or less and no longer required narcotic analgesics. Patients in both groups returned to usual activity and work by a median of 9 days after operation. CONCLUSION: Both of these well-established methods can be used to repair inguinal hernias with local anesthetics in an outpatient setting with minimal morbidity. Despite the "tension-free" design of the mesh repair, short-term outcomes of mesh and Shouldice repairs of inguinal hernias do not differ.

Moose-motor vehicle collisions. An increasing hazard in northern New England.

OBJECTIVE: To analyze the epidemiology and epizootiology of moose-motor vehicle collisions (MMVC) and outcomes in severely injured patients to identify variables that might be modified to reduce the impact of this mutually deleterious interspecies interaction. DESIGN: Wildlife and Traffic Safety databases permitted retrospective, population-based assessment of MMVC epidemiology. A case series compiled from hospital trauma registries characterized morbidity and mortality from MMVC. SETTING: New Hampshire and Maine area. PATIENTS: All victims of MMVC (1980 through 1991) were included in population-based analyses. Twenty-three patients hospitalized at three rural trauma centers (January 1990 through June 1994) were included in the case series. MAIN OUTCOME MEASURES: Location, time of day and seasonal occurrence of MMVC were determined. Injury patterns and Injury Severity Scores were analyzed in 23 representative patients. Maine's 1991 traffic and medical data were linked, and factors predictive of injury from MMVC were identified using multivariate logistics. RESULTS: Most MMVC occur from April through October after dark. Of 23 subjects, 70% sustained head and/or face injuries and 26%, cervical spine injuries. Mortality was 9%. Mean Injury Severity Score was 15.7 (SD=9.0). Safety belt use, rear seat location, and light truck occupancy were associated with reduced injury (p<.05). CONCLUSIONS: Moose-motor vehicle collisions are increasing in rural regions. Prevention programs should emphasize defensive driving and seat belt use, especially during high-risk periods. Injury patterns in MMVC suggest a need for automobile design modifications that better protect the passenger compartment form direct impact.

Nonoperative management of adult splenic injury due to blunt trauma: a warning.

An analysis of 11 patients with splenic injury initially receiving nonoperative treatment revealed that 73 percent subsequently required surgery for delayed hemorrhage. The influence of age and the anatomic differences between the adult's spleen and child's spleen may account for the increased incidence of delayed bleeding seen in this series. Which patients might avoid surgical intervention cannot be predicted with certainty from the mechanism of injury or the lack of early physical signs and symptoms. The corresponding medical problems that often exist with the older patient may make nonoperative management, with the inherent risk of hypotension and large transfusion requirements, inappropriate. Although not advocating immediate splenectomy, we encourage early operative intervention with splenorrhaphy. Although improved diagnostic techniques will uncover a greater incidence of splenic injury, the inability to identify the nonoperative patient remains a clinical dilemma. The true role of nonoperative management of splenic injuries in the adult and the criteria for selection need to be further defined with larger prospective series. Although this approach may be useful for some patients, its application cannot be universal, and one must be willing to accept the consequences of delayed hemorrhage.

Do pigeons show incidental timing? Some experiments and a suggested hierarchical framework for the study of attention in animal cognition.

Three experiments are reported that examine pigeons' ability to process incidental time cues when time cues are placed in compound with either a visual pattern cue or a spatial position cue. In experiments 1 and 2, it was found that incidental timing suffered relative to timing on control tests in which time-only cues were presented. However, these experiments did not involve explicit training to match duration when the carrier stimulus consisted of a visual pattern or spatial position. When such explicit training was given prior to testing in experiments 3A and 3B, it was found that pigeons matched time sample stimuli equally accurately when duration trials only were given throughout a session or were randomly intermixed with visual pattern or spatial position matching trials. It was concluded that pigeons can process time accurately while simultaneously processing a stimulus from another dimension.

CGRP function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood pressure in the rat.

BACKGROUND AND PURPOSE: Calcitonin gene-related peptide (CGRP) receptor antagonists effectively abort migraine headache and inhibit neurogenic vasodilatation in humans as well as rat models. Monoclonal antibodies typically have long half-lives, and we investigated whether or not function-blocking CGRP antibodies would inhibit neurogenic vasodilatation with a long duration of action and therefore be a possible approach to preventive therapy of migraine. During chronic treatment with anti-CGRP antibodies, we measured cardiovascular function, which might be a safety concern of CGRP inhibition. EXPERIMENTAL APPROACH: We used two rat blood flow models that measure electrically stimulated vasodilatation in the skin or in the middle meningeal artery (MMA). These vasomotor responses are largely dependent on the neurogenic release of CGRP from sensory afferents. To assess cardiovascular function during chronic systemic anti-CGRP antibody treatment, we measured heart rate and blood pressure in conscious rats. KEY RESULTS: Treatment with anti-CGRP antibodies inhibited skin vasodilatation or the increase in MMA diameter to a similar magnitude as treatment with CGRP receptor antagonists. Although CGRP antibody treatment had a slower onset of action than the CGRP receptor antagonists, the inhibition was still evident 1 week after dosing. Chronic treatment with anti-CGRP antibodies had no detectable effects on heart rate or blood pressure. CONCLUSIONS AND IMPLICATIONS: We showed for the first time that anti-CGRP antibodies exert a long lasting inhibition of neurogenic vasodilatation in two different rat models of arterial blood flow. We have provided strong preclinical evidence that anti-CGRP antibody may be a suitable drug candidate for the preventive treatment of migraine.

Airway pressure gradient during high-frequency ventilation.

Six mongrel dogs, each serving as its own control, underwent ventilatory trials on high-frequency positive-pressure ventilation (HFPPV) and high-frequency oscillation (HFO), before and after oleic acid-induced lung injury. Central and distal airway pressures were compared to simultaneous measurements of oxygen transport and shunt fraction. Airway pressure differences were more pronounced with HFO. Mean proximal pressure with HFO was 4.91 +/- 1.9 mm Hg, rising to 11.6 +/- 3.6 mm Hg distally. HFPPV produced somewhat higher proximal and distal pressures of 9.5 +/- 5.2 and 14.2 +/- 6.9 mm Hg, respectively. After induction of lung injury with a subsequent decrease in compliance, central (proximal) airway pressures remained relatively unchanged, while distal pressures showed a further rise, thus increasing the pressure gradient to 9.2 +/- 3.8 mm Hg for HFO and 6.6 +/- 4.6 mm Hg for HFPPV. Shunt fraction increased with decreased oxygen transport after lung injury in both models; however, the increase was less pronounced with HFO, which maintained a greater pressure gradient. The distal increase in airway pressures may be important in maintaining critical closing volumes in the diseased lung. By creating a pressure gradient, high-frequency ventilation by either jet or oscillator may improve functional residual capacity and oxygenation.

PH-dependent drug release from certain commercial tablets.

A dissolution-dialysis profile for each of several brands of nitrofurantoin, hydrochlorothiazide and sulfisoxazole tablets was developed at three pH levels. The study used a two-compartment diffusion cell with a semipermeable cellophane membrane. Nitrofuratoin tablets were tested at pH values of 7.2, 4.7 and 1.2; sulfisoxazole tablets at 7.2, 5.5 and less than 1. Studies with hydrochlorothiazide tablets were terminated because the pH of the dissolution medium had no effect of practical significance on dissolution or dialysis rates. The dissolution rates of the nitrofurantoin and sulfisoxazole tablets were highly brand-individualized and complex. The effects of pH upon a particular formulation were unpredictable. The results suggest that dissolution testing at one fixed pH, as commonly practiced, may be insufficient for some products. This pH-dependent release characteristic may not correspond to a change in bioavailability in all cases, but it represents a potential problem which should be considered by the formulator.

Body percept change in obese females after weight reduction therapy.

Video-image representations of body size were measured on a television monitor that was modified to give a display continuum that ranged from 50% under- to 50% over-estimation of objective size. Sixty-eight females who were undergoing weight reduction counseling were measured before and after treatment. All Ss judged themselves to be significantly more obese than they actually were, with a tendency for errors to be greatest among the more obese Ss. After therapy, more realistic estimates of their physiques ensued. A drop-out rate of 23% was recorded; the drop-outs saw themselves as significantly more obese than those who graduated from the program.

Peripheral argon laser iridectomy in narrow-angle glaucoma.

Gas argon laser peripheral iridectomy was attempted as an alternative to surgical peripheral iridectomy in the treatment of acute angle-closure glaucoma and the prophylactic treatment of fellow eyes. Success was achieved in eyes with a blue iris if sufficient energy was given to achieve a permanent red reflex. Reasons for failure in eyes with a heavily pigmented iris are discussed. The procedure must be greatly improved before surgical peripheral iridectomy is superseded as the treatment of choice.