Marc K. Wallack

Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: The final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial

BACKGROUND A phase III, randomized, double-blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia melanoma oncolysate (VMO) was performed in patients with stage III (American Joint Commission on Cancer) melanoma to determine the efficacy of VMO to increase the disease-free interval (DFI) or overall survival (OS) in these patients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using VMO, two subsets-men aged 44-57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease-showed an overall survival advantage with VMO therapy. A final analysis of data from this trial was performed in May 1996 and is reported here. The design of future melanoma vaccine trials is discussed based on information learned from this first randomized, multicenter trial of ASI therapy. STUDY DESIGN A polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus (V). Patients were accrued from 11 United States institutions and were randomized by the Statistical Center at the University of Alabama, Birmingham. Two hundred fifty patients were randomized to treatment with either VMO (1 U containing 2 mg of total protein derived from 5 x 10(6) melanoma cells and 10(5.6) 50% tissue culture infectious dose of vaccinia virus) or control V (1 U containing 10(5.4) 50% tissue culture infectious dose of vaccinia virus) once a week for 13 weeks and then once every 2 weeks for a total of 12 months, or until recurrence. Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis. RESULTS Two hundred seventeen patients were found to be eligible according to the inclusion criteria. Data from these patients were analyzed for DFI and OS after a median followup of 46.3 months (50.2 months for VMO and 41.3 months for V). This final analysis showed no statistically significant increase in either DFI (p = 0.61) or OS (p = 0.79) of patients treated with VMO (n = 104) compared with V (n = 113). At 2-, 3-, and 5-year intervals, 47.8%, 43.8%, and 41.7% of patients treated with VMO were disease-free, respectively, compared with 51.2%, 44.8%, and 40.4% of patients treated with V. At the same intervals, 70.0%, 60.0%, and 48.6% of patients treated with VMO survived, compared with 65.4%, 55.6%, and 48.2% of patients treated with V. In a retrospective subset analysis, male patients aged 44-57 years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3% improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treatment with VMO when compared with V (n = 18) (p = 0.046). CONCLUSIONS This study was a randomized, multicenter, placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO when compared with V showed no difference in either DFI or OS. In a retrospective subset analysis, however, a subset of men with one to five positive nodes, between the ages of 44 and 57 years, showed a survival advantage with VMO. This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma. An appropriate control arm also must be included in ASI trials.

Multilayer reconstruction of abdominal wall defects with acellular dermal allograft (AlloDerm) and component separation

Multiple techniques have been employed for the repair of abdominal incisional hernias with varying rates of success. Primary fascial apposition and prosthetic implantation have been associated with high rates of secondary recurrence, infection, and other complications, often due to insufficient alleviation of tension and implant intolerance. This study evaluates the repair of incisional and recurrent abdominal hernias with multilayered acellular dermal allograft (AlloDerm; LifeCell Corporation, Branchburg, NJ) and musculofascial separation. Patients with incisional or recurrent abdominal hernias were treated between January 2003 and March 2004. The surgical technique involved musculofascial release of the external oblique, followed by a double-layer implantation of dermal allograft. The primary allograft layer was placed as an “underlay” interposition, sutured under moderate tension beneath the fascial edges of the defect. When minimal tension remained, the native fascial margins of the defect were directly repaired. A second allograft layer was then placed and sutured to the superficial aspect of the ventral fascia to complete the repair. Data were reviewed retrospectively. Sixteen patients were treated. There were 10 males and 6 females, mean age 56 years (range 44–72 years). Fifteen patients (94%) had previous hernia repair procedures, and 6 patients (38%) had undergone 2 or more previous procedures. Nine patients (56%) were treated with hernia site infections or prosthetic exposure. Mean follow-up is 16 months (range 9 to 23 months). There were 2 seromas (13%). One patient (6%) developed a wound dehiscence with allograft exposure that healed by secondary intention. There were no recurrences. By minimizing tension and providing a durable biocompatible matrix for support, component separation with bilaminar acellular dermal allograft should be considered for the repair of complex and recurrent ventral hernias.

Modern management of omental torsion and omental infarction: a surgeon's perspective.

Omental infarction is a rare cause of acute abdomen that until recently was diagnosed only on exploratory surgery for presumed acute appendicitis or similar abdominal emergency. The increasing use of high-quality imaging, especially computerized tomography, in the diagnosis of appendicitis and the acute abdomen, has allowed preoperative diagnosis to be made much more often. Coupled with the increasing popularity of laparoscopic appendectomy, this finding has led to a spate of recent reports of omental infarction and omental torsion. It has also sparked a debate as to the best management of omental infarction, with strong support for both nonoperative management and definitive laparoscopic surgery. We present a case of omental torsion diagnosed preoperatively by the characteristic whirl sign and ultimately treated by laparoscopic surgery together with a brief review of the condition and our own recommendations.

Colon cancer cell vaccine prepared with replication-deficient vaccinia viruses encoding B7.1 and interleukin-2 induce antitumor response in syngeneic mice

Abstract A replication-deficient recombinant vaccinia virus, NYVAC, was developed by deleting 18 open reading frames in the vaccinia virus genome. Recombinant NYVAC, encoding the murine T cell co-stimulatory gene B7.1 (CD 80) (NYVAC-B7.1) and the murine interleukin-2 gene (NYVAC-IL-2), were prepared and the expression of B7.1 and the secretion of IL-2 were respectively confirmed in vitro. The use of these viruses to prepare a potent tumor cell vaccine was studied in a syngeneic murine CC-36 colon adenocarcinoma model. Mice were immunized on days 1 and 8 with 106 irradiated CC-36 cells that were infected with 107 plaque-forming units of either NYVAC-B7.1, NYVAC-IL-2 or a control virus, NYVAC-HR, which encodes a vaccinia virus host-range gene. These mice were then challenged with 108 viable CC-36 tumor cells on day 15. All mice (10/10) in a group that had received no vaccination and all mice (20/20) in a group that had received a control vaccine of CC-36/NYVAC-HR developed tumor 4-weeks after tumor cell challenge. Interestingly, only 16/20 mice in a group that had received CC-36/NYVAC-B7.1 showed the development of tumor after the same interval. The protection against tumor development and the reduction in tumor burden (as mean tumor diameter, 4 weeks after tumor challenge) were significant in this group when compared to groups that were either unvaccinated or vaccinated with CC-36/NYVAC-HR (mean tumor diameter = 6.51±3.2 mm compared to 26.5±0.9 mm or 26.2±1.8 mm respectively) (P = < 0.05). The protection against tumor in a group of mice that received CC-36/NYVAC-IL-2 vaccination was similar to that in the unvaccinated group or the group receiving a CC-36/NYVAC-HR control vaccination. However, in a survival experiment, mice that received either CC36/NYVAC-B7.1 or CC-36/NYVAC-IL-2 vaccination on the day of tumor transplantation survived significantly longer than mice that had not been vaccinated (median survival 60+ days, 60+ days or 23.5 days respectively) (P = <0.05). Interestingly, when a therapeutic tumor vaccination was performed on day 4 after tumor transplantation, mice that had been vaccinated with either CC36/NYVAC-B7.1 or CC-36/NYVAC-IL-2 did not show an improved survival when compared to mice in the control that had not been vaccinated (median survival 28 days compared to 26 days or 25 days respectively). However, mice that had received a therapeutic vaccination with CC-36 cells infected with both NYVAC-B7.1 and NYVAC-IL-2, 4 days after tumor transplantation, survived significantly longer than control mice that had not received any vaccination (median survival 29.5 days compared to 25 days respectively) (P<0.05). These results suggest that a replication-deficient recombinant NYVAC encoding the B7.1 gene and NYVAC encoding the IL-2 gene can be used to produce an effective vaccinia-virus-augmented tumor cell vaccine.

Avoidance of anastomotic complications in low anterior resection of the rectum

PURPOSE: This retrospective study was designed to evaluate the efficacy of suction-irrigation drainage systems in reducing anastomotic complications. The current trend for lesions of the upper and middle rectum emphasizes maintaining an intact anal sphincter mechanism as long as limits of resection are not compromised. Removal of the rectosigmoid colon with an anastomosis below the peritoneal reflection accomplishes this goal but with appreciable morbidity and mortality, which is in great part related to subsequent anastomotic breakdown and resultant pelvic abscess and fecal fistula formation. The presence of collections of blood, serum, and cellular debris contribute significantly to anastomotic disruption by serving as a culture medium in which bacteria may thrive, leading to abscess formation with subsequent deleterious effects on the integrity of the adjacent low lying anastomosis. Many surgeons accepted this risk and routinely performed diverting colostomies to minimize the consequences of anastomotic disruption below the peritoneal reflection. The authors felt that if this risk could be sufficiently reduced, it would obviate the need for a protecting stoma. METHODS: From 1980 to 1988, 60 consecutive patients were subjected to anterior or low anterior resections in which a closed Shirley sump irrigation system was used to facilitate postoperative drainage of the pelvis and thus avoid hematoma formation. Since this original study group of 60 patients, another 100 consecutive patients have been entered into this study. This cohort group again consisted of patients with lesions of the upper, middle, and lower rectum who underwent anterior or low anterior resections of the rectum. RESULTS: Fifty-three of the original 60 patients did not have protecting stomas. Clinical leak rate for this series was 1.67 percent. Clinical leak rate for this updated series of 100 patients was 1 percent, with overall clinical leak rate of 1.25 percent in 160 consecutive patients. There were no deaths in the series, and overall morbidity was 7.5 percent. CONCLUSIONS: The authors felt that removing blood, serum, and cellular debris from the pelvis following resections of all or part of the rectum minimizes the risk of anastomotic disruption. With this routine, covering colostomies are no longer required for most patients undergoing anterior or low anterior resections of all or part of the mesorectum.

Active specific immunotherapy with vaccinia colon oncolysate enhances the immunomodulatory and antitumor effects of interleukin-2 and interferon α in a murine hepatic metastasis model

SummaryThe role of cytokines as primary or adjuvant antineoplastic agents has been well established. Interleukin-2 (IL-2) and the interferons have, particularly, proven to be effective antitumor agents when given alone, and seem to act synergistically on the eradication of metastases from immunogenic tumors. Active specific immunotherapy, in the form of viral oncolysates, has also shown effectiveness in cancer therapy. Bearing this in mind, we decided to combine these agents in an adjuvant triple regimen and compare their effectiveness to other treatments in terms of tumor burden and survival in a murine colon cancer hepatic metastases model. BALB/c mice were injected with CC-36, a weakly immunogenic murine colon adenocarcinoma, intrasplenically, to produce artificial liver metastases. The animals were divided into one control group and seven treatment groups receiving either vaccinia colon oncolysate (VCO), IL-2, interferon-α (IFNα) alone, or combinations of these agents. Half the animals were followed for survival and the other half were sacrificed at the end of the experiment for quantification of tumor burden. The blood of the sacrificed animals was utilized in a series of immunological tests in order to demonstrate the cytolytic potential of the peripheral blood lymphocytes (PBL) in each treatment group, as well as to characterize phenotypically the cells acting as effectors. The tripleadjuvant regimen group was by far the most effective treatment group, demonstrating 100% survival and a significant reduction in tumor burden when compared to other groups. Furthermore, the PBL from the animals in this group showed 69.4% lysis of the CC-36 target cells in vitro. These effector lymphocytes were characterized as ASMG1-/Lyt2.2+ cytolytic lymphocytes. We conclude that these lymphocytes were stimulated by the administration of VCO and further augmented by the immunomodulation of the cytokines given in the triple regimen, and that such a regimen might prove beneficial in the treatment of established hepatic metastases from weakly immunogenic tumors.

Carcinoma of the breast during pregnancy: a review and update on treatment options

Gestational breast cancer is occurring with increasing incidence because more women are delaying childbirth into their thirties and forties. Although breast cancer during pregnancy or within the first year postpartum is occurring more often, there is still some confusion regarding its treatment. Although breast conservation therapy has evolved as the major treatment in breast cancer, it has been thought that pregnancy was a contraindication for this type of breast cancer therapy due to risks imposed on the fetus by chemotherapy and radiation. However, recent studies have shown that the use of chemotherapeutics during the second and third trimesters is possible. Also, if chemotherapy is initiated after a lumpectomy, radiation can be withheld until after the birth of the baby when the cancer is detected in the second or third trimester.

Pyogenic liver abscess secondary to asymptomatic sigmoid diverticulitis.

A patient with multiple pyogenic abscesses in both lobes of the liver secondary to asymptomatic sigmoid diverticulitis is presented. The rarity of this illness is noted. It is suggested that barium enema be performed in patients who present with pyogenic liver abscess of unknown etiology because of the association with asymptomatic sigmoid diverticulitis.

Coronary artery bypass grafting in patients with human immunodeficiency virus

Abstract The role of surgery in the natural history of HIV disease is in evolution. A review was conducted of 2980 CABG operations taking place between January 1992 and January 1996 at St. Vincents Hospital; four of these patients were known to be HIV‐positive prior to the operation. Preoperative work‐up, operative course, and postoperative events were largely unremarkable. Only 1 of the 4 patients required rehospitalization within 30 days. Follow‐up averaged 28 months (range 7–49 months). Three of four patients were in NYHA Class II or better at follow‐up. Other reviews of CABG performed on HIV + patients also indicate that, although CPB can be linked with immune supression, there is no conclusive evidence of the acceleration of HIV into AIDS associated with CPB. In conclusion, due to the lack of controlled trials and large patient reviews, no firm recommendations about the effect of CPB on immunocompromized patients can be generated.

Overview analysis of adjuvant therapies for melanoma—a special reference to results from vaccinia melanoma oncolysate adjuvant therapy trials

A phase III, randomized, double-blind, multi-institutional vaccinia melanoma oncolysate (VMO) trial was performed for patients with stage III (AJCC) melanoma. When compared with the control vaccinia virus (V) therapy, VMO therapy did not show clinical efficacy in the final analysis of data from this trial. However, the data did allude to significant therapeutic efficacy with VMO therapy if it had been compared with an observation arm. Therefore, a comparative overview statistical analysis was performed to identify the therapeutic efficacy of VMO. This review compares VMO results with data from the treatment and observation arms of other prominent randomized anti-melanoma biologic trials (i.e., ECOG EST 1684; SWOG, IFN-gamma (J. Natl. Cancer Inst. 87 (1995) 1710); WHO IFN-alfa-2a (ASCO 14 (1995) 410); Mayo IFN-alfa-2a (J. Clin. Oncol. 13 (1995) 2776); French IFN-alfa-2a (ASCO 15 (1996) 437). The analysis was carried out comparing the disease-free interval (DFI) and overall survival (OS). The analysis shows that the VMO results are fairly comparable to the results of the treatment arms from the ECOG and Mayo trials at the 5-year mark; percent DFI 0.37, 0.37, and 0.4, percent OS 0.48, 0.46, 0.47, respectively. In some cases, VMO DFI is superior to the observation arms from other studies; ECOG, Mayo, and WHO; 0.37 versus 0.26, 0.3, 0.27 (4 years), respectively. These comparative results suggest that the vaccinia arm is not a true observation arm in the VMO trial, and the VMO could have shown an enhanced efficacy had the trial included a no-treatment observation control arm.