Interacting Genetic Lesions of Melanoma in the Tumor Microenvironment: Defining a Viable Therapy.

Melanoma is the most aggressive form of skin cancer with an estimated 106,110 newly diagnosed cases in the United States of America in 2021 leading to an approximated 7180 melanoma-induced deaths. Cancer typically arises from an accumulation of somatic mutations and can be associated with mutagenic or carcinogenic exposure. A key characteristic of melanoma is the extensive somatic mutation rate of 16.8 mutations/Mb, which is largely attributed to UV exposure. Bearing the highest mutational load, many of them occur in key driver pathways, most commonly the BRAFV600E in the mitogen-activated protein kinase (MAPK) pathway. This driver mutation is targeted clinically with FDA-approved therapies using small molecule inhibitors of oncogenic BRAFV600E and MEK, which has greatly expanded therapeutic intervention following a melanoma diagnosis. Up until 2011, therapeutic options for metastatic melanoma were limited, and treatment typically fell under the spectrum of surgery, radiotherapy, and chemotherapy.Attributed to the extensive mutation rate, as well as having the highest number of neoepitopes, melanoma is deemed to be extremely immunogenic. However, despite this highly immunogenic nature, melanoma is notorious for inducing an immunosuppressive microenvironment which can be relieved by checkpoint inhibitor therapy. The two molecules currently approved clinically are ipilimumab and nivolumab, which target the molecules CTLA-4 and PD-1, respectively.A plethora of immunomodulatory molecules exist, many with redundant functions. Additionally, these molecules are expressed not only by immune cells but also by tumor cells within the tumor microenvironment. Tumor profiling of these cell surface checkpoint molecules is necessary to optimize a clinical response. The presence of immunomodulatory molecules in melanoma, using data from The Cancer Genome Atlas and validation of expression in two model systems, human melanoma tissues and patient-derived melanoma cells, revealed that the expression levels of B and T lymphocyte attenuator (BTLA), TIM1, and CD226, concurrently with the BRAFV600E mutation status, significantly dictated overall survival in melanoma patients. These molecules, along with herpesvirus entry mediator (HVEM) and CD160, two molecules that are a part of the HVEM/BTLA/CD160 axis, had a higher expression in human melanoma tissues when compared to normal skin melanocytes and have unique roles to play in T cell activation. New links are being uncovered between the expression of immunomodulatory molecules and the BRAFV600E genetic lesion in melanoma. Small molecule inhibitors of the MAPK pathway regulate the surface expression of this multifaceted molecule, making BTLA a promising target for immuno-oncology to be targeted in combination with small molecule inhibitors, potentially alleviating T regulatory cell activation and improving patient prognosis.

Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease.

Amylin, a pancreatic peptide, and amyloid-beta peptides (Aß), a major component of Alzheimer's disease (AD) brain, share similar ß-sheet secondary structures, but it is not known whether pancreatic amylin affects amyloid pathogenesis in the AD brain. Using AD mouse models, we investigated the effects of amylin and its clinical analog, pramlintide, on AD pathogenesis. Surprisingly, chronic intraperitoneal (i.p.) injection of AD animals with either amylin or pramlintide reduces the amyloid burden as well as lowers the concentrations of Aß in the brain. These treatments significantly improve their learning and memory assessed by two behavioral tests, Y maze and Morris water maze. Both amylin and pramlintide treatments increase the concentrations of Aß1-42 in cerebral spinal fluid (CSF). A single i.p. injection of either peptide also induces a surge of Aß in the serum, the magnitude of which is proportionate to the amount of Aß in brain tissue. One intracerebroventricular injection of amylin induces a more significant surge in serum Aß than one i.p. injection of the peptide. In 330 human plasma samples, a positive association between amylin and Aß1-42 as well as Aß1-40 is found only in patients with AD or amnestic mild cognitive impairment. As amylin readily crosses the blood-brain barrier, our study demonstrates that peripheral amylin's action on the central nervous system results in translocation of Aß from the brain into the CSF and blood that could be an explanation for a positive relationship between amylin and Aß in blood. As naturally occurring amylin may play a role in regulating Aß in brain, amylin class peptides may provide a new avenue for both treatment and diagnosis of AD.

Idiopathic granulomatous mastitis: experience at a New York hospital.

INTRODUCTION: Idiopathic granulomatous mastitis (IGM) often mimics breast cancer. Presentation includes pain, palpable mass, suppuration or suspicious imaging. Widely reported in Asia and the Middle East, IGM is diagnosed after excluding specific granulomatous mastitis (SGM). Aetiology remains unknown. Lactation, prolactinaemia, ethnicity, autoimmune disease and Corynebacteria are associated. Treatment is controversial and the prevalence rising. Surgery and non-operative treatments including antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, methotrexate and observation have advocates. METHODS: A retrospective chart review of 63 patients with IGM from 2008 to 2018 was undertaken focusing on birthplace, age, clinical presentation, wound cultures, imaging, treatments and outcomes. RESULTS: Sixty-one of 63 patients were Hispanic; 53 were Mexican-born women aged 23-46. Clinical presentation included pain, painful mass, painless mass, suppuration and abnormal imaging. Some 31/61 ultrasound examinations and 17/33 mammograms were deemed Breast Imaging Reporting and Data System (BI-RADS) score 4 or 5. Management included antibiotics (43), incision and drainage (24), NSAIDs (29), steroids (8), lumpectomy (18) and observation (12). Some 12/20 patients with painless masses resolved with observation, 3 received NSAIDs, 2 received steroids and 3 underwent lumpectomies. Antibiotics resolved 8/43 cases, 5 needed incision and drainage, 26 received NSAIDs, 6 received steroids and 5 underwent lumpectomies. Nineteen patients had indolent disease or recurrence. CONCLUSIONS: Excluding malignancy is critical, treatment challenging and recurrence common in IGM. A preponderance of patients were Mexican-born, similar to other reports from the USA. Over 50% of IGM cases had suspicious BI-RADS scores. Best management remains a challenge and ranges from observation to lumpectomy.

Fabrication and evaluation of a near-infrared hyperspectral imaging system.

This paper describes modifications to a hyperspectral imaging microscope that extend its capabilities into the near-infrared (950-1300 nm). The major changes include installing a grating, charge-coupled device camera, and lenses and filters appropriate for infrared wavelengths. Calibration of the system and validation with lead sulfide quantum dots of known emission wavelength is reported. Cells from the breast carcinoma cell line SkBr3 were scanned with lead sulfide quantum dots that emit at 1100 nm as the background and an image which contains the integrated spectral data is presented. We also demonstrate that this instrument is capable of detecting the photoluminescence spectra of single-walled carbon nanotubes dispersed in aqueous solution.

Immunotherapy as an adjuvant therapy in the management of advanced, surgically resected, melanoma.

Metastatic melanoma continues to be one of the most devastating of all cancers. It is a heterogeneous solid tumor whose treatment is challenging and difficult. It afflicts thousands of otherwise healthy patients annually, and clinicians have yet to discover an effective treatment for locally advanced disease. Over the years, much attention has been devoted to the development of an effective adjuvant treatment for patients with resected melanoma who remain at high risk for recurrence. The new advances in the understanding of melanoma's microenvironment and the complexity of its disease process, makes it clear that the treatment approach to this disease needs to be multi-directional. Numerous studies have tested various immunotherapeutic strategies in the treatment of advanced melanoma, in particular. These strategies include melanoma vaccines, interferon-alpha, interleukin-2 (IL-2), and dendritic cell vaccines. The Dr. Wallack's Surgery Research Laboratory has been studying melanoma vaccines for the past three decades. The first generation melanoma vaccine proposed by the Laboratory showed promising results in a subset of patients. Recently, the same Laboratory has produced a second generation melanoma vaccine (DC-Melvac) that consists of five human melanoma cell lines, a recombinant vaccinia virus that encodes for IL-2, as well as dendritic cells that have been programmed to recognize certain melanoma associated antigens. DC-MelVac was recently approved by the Food and Drug Administration for its use in Phase I clinical trials. These trials are expected to be underway in the near future. The ensuing review discusses many of the immunotherapeutic strategies that have been studied in the treatment of melanoma, including DC-MelVac.

Transplantation immunity and cross-protection of two cultured murine colon lines.

Previous comparative investigations of the in vivo biology of two cultured colon tumors of BALB/c origin, C-C26 and C-C36, demonstrated different biologic activities. For elucidation of these differences, this report investigated the immunogenicity of these lines in providing protection to a subsequent challenge with different doses of tumor cells. Furthermore, the specificity of this protection was evaluated with cross-protection experiments. Our findings demonstrated these lines to be immunogenic and suggested the presence of cross-reactive tumor rejection-type antigens on these 2 cultured colon tumor lines. BALB/c mice immunized with these tumors developed resistance to challenge with the same tumor as well as to challenge with the other colon tumor lines. Further definition of these putative antigens could provide us with a better understanding for the diagnosis and treatment of colon tumors.

Characterization of tumorigenicity, mortality, metastasis, and splenomegaly of two cultured murine colon lines.

The murine colon tumors 26 and 36 have been adapted to culture in vitro from the parental, serially transplanted tumors. The biological activities of these cultured colon lines (C-C26 and C-C36) have been characterized in vivo by s.c. inoculation of serial doses of cells into syngeneic BALB/c mice. The C-C26 line is highly tumorigenic and has a low tendency (9.1%) for metastasis to the lungs. Moreover, mice inoculated with C-C26 exhibited high mortality and normal or atrophied spleens. In contrast, the C-C36 line is less tumorigenic and highly metastatic to the lungs (77.8%). Mortality was lower in animals inoculated with C-C36, and at autopsy, splenomegaly was frequently (72.2%) observed without any visible metastatic nodules in these spleens. Metastasis to the lungs was intimately associated with splenomegaly, and death followed closely. Our findings with the C-C26 and C-C36 lines agree with those reported for the parental tumors with respect to tumorigenicity, tumor growth, and mortality. However, they differ with respect to their metastatic potential, because previous reports showed this to be higher for the serially transplanted colon 26 than the colon 36 tumor cells. Furthermore, this work describes the remarkable splenomegaly observed in mice inoculated with C-C36 but not with C-C26. This finding may in turn provide us with the opportunity to compare the functional status of the spleen in these tumor-bearing animals.

Thoracoscopy in acquired immunodeficiency syndrome.

OBJECTIVE: The role of thoracic surgery in patients with acquired immunodeficiency syndrome (AIDS) continues to evolve. This review seeks to evaluate the outcome, morbidity, and mortality associated with video-assisted thoracoscopic surgery for empyema and pneumothorax in patients with AIDS. METHODS: A retrospective review was conducted of patients with AIDS in whom video-assisted thoracoscopic surgery was performed for empyema (group 1) or intractable pneumothorax (group 2). RESULTS: Twenty patients with AIDS (95% male, mean age 37.4 years, mean CD4 count 76 cells/ml3) underwent thoracoscopy. Surgery was performed for empyema (group 1) in 11 (55%) and intractable pneumothorax (group 2) in nine (45%). Three patients (15%) died within 30 days of the operation. At mean follow-up (29 months), overall survival was 55%. For those who survived the hospitalization and died within the follow-up period (35.3%), mean survival time was 8.2 months (range 1 month to 27 months). In group 1, surgical procedures were performed after 8 days of chest tube drainage and included pleural debridement and mechanical pleurodesis (n = 11) along with lung biopsy (n = 6). Survivals at 30 days and 29 months' follow-up were 90.9% and 45.4%, respectively. In group 2, significantly depressed CD4 counts (average 33.2 cells/ml3) were noted along with a more prolonged preoperative hospitalization (18.5 days) with 14.2 days spent with a chest tube before the operation. In this group, operative procedures included mechanical pleurodesis and talc poudrage (n = 9), bleb resection (n = 7), and lung biopsy (n = 1). Two deaths (22%) occurred within 30 days of the operation and survival at 29 months' follow-up was 66%. CONCLUSION: Video-assisted thoracoscopic surgery performed in patients with AIDS for the treatment of empyema and intractable pneumothorax is effective, can be performed with little operative morbidity and mortality, and is associated with acceptable long-term survival. Video-assisted thoracoscopic surgery is best performed soon after the diagnosis of intractable pneumothorax or empyema has been established.

Serologic response to human melanoma lines from patients with melanoma undergoing treatment with vaccinia melanoma oncolysates.

Specific active tumor immunotherapy methods offer the possibility of increasing the immunogenicity of tumor cells. One of these methods is viral oncolysis, in which tumor cells are modified by viral infection. We prepared vaccinia melanoma oncolysates (VMO) from human melanoma lines infected with vaccinia virus. In a preliminary trial at Washington University, sera from 12 patients with melanoma with stage I and II disease were obtained before and during treatment with VMO. The reactivity of these sera to melanoma lines was examined with a Staphylococcus protein A assay that detects most human IgGs. Our data demonstrate that, during treatment with VMO, sera from all 12 patients developed reactivity to melanoma lines. Selected sera were also tested in a double blind study by the C3-mixed hemadsorption assay, which detects mostly IgM. Results from this assay were in complete agreement with those obtained by the Staphylococcus protein A assay: Pretreatment sera were generally negative and sera obtained during treatment were positive. The specificity of these responses is presently under investigation. Our findings indicate that, as a consequence of treatment with VMO, a reactivity develops in the patients' sera. This reactivity is probably due to both IgG and IgM antibodies and its directed toward antigens expressed on human melanoma lines.

Crohn's disease of the appendix.

Crohn's disease limited to the appendix is uncommon. The disease may mimic acute appendicitis with fever, leukocytosis, right lower quadrant pain, and occasionally a palpable mass. When Crohn's disease affects the appendix, it typically has a longer clinical period in which the patient has symptoms than do most cases of acute appendicitis. The most common preoperative diagnoses are acute appendicitis and appendiceal abscess. A review of the literature is presented along with our experience in three additional cases of Crohn's disease limited to the appendix. We suggest that Crohn's disease be included in the preoperative differential diagnosis and that extensive intraoperative examination of the gastrointestinal tract be made in any case of suspected appendicitis that has had a protracted preoperative course.

Positive relationship of clinical and serologic responses to vaccinia melanoma oncolysate.

In this phase Ia/Ib trial, vaccinia melanoma oncolysate (VMO) is a virus-augmented melanoma cell membrane vaccine that has been shown to be safe and to stimulate the production of antimelanoma antibodies in high-risk melanoma patients treated in a surgical adjuvant setting. One patient with stage I and 38 patients with stage II melanoma were entered in the study between December 1984 and October 1985, with a mean follow-up of approximately 17 months. Each patient received a smallpox booster injection followed one week later by the first of 13 weekly intradermal injections of 2.0 mg of VMO. At the end of 13 weeks, injections were given every other week for 12 months or until recurrence. Clinical results show that 25 of the 39 patients had no evidence of disease as of December 1986. Moreover and more importantly, statistical comparison of patients in this study with 39 matched controls shows a significant increase in disease-free survival for the patients treated with VMO. Serum obtained prior to treatment and at three-month intervals during treatment was tested in a Staphylococcus protein A rosette assay for reactivity with melanoma cell lines. All pretreatment samples (39/39) were negative, and 64% became positive by 12 months after appropriate dosage escalations. Moreover, enzyme-linked immunosorbent assay showed a positive correlation between anti-melanoma IgG antibody titer and disease-free survival.

Perfusion therapy for extremity melanoma.

Because of their initial appearance on extremities, malignant melanomas lend themselves to isolated chemotherapeutic perfusions. Perfusion is attractive because one can deliver effective cytotoxic drugs without systemic toxicity. We are reviewing 20 patients treated between 1960 and 1973 with isolated perfusion. Melphalan (L-phenylalanine mustard) was the drug of choice. Eleven of the 20 patients had previous surgical treatment. Three of the 11 patients are still alive from 27 to 72 months postperfusion. Eight died after an average survival time of 33 months. Of the seven patients who underwent perfusion as primary therapy, four patients are alive from 25 to 76 months postperfusion, and three died after an average survival time of 34 months. There is direct correlation between stages and levels of melanoma, and perfusion and prolonged survival time.

The role of tracheostomy in acquired immunodeficiency syndrome.

BACKGROUND: Tracheostomy tube (TT) insertion for respiratory failure in patients with acquired immunodeficiency syndrome has been associated with an early mortality rate of 100%. We have reviewed our experience with tracheostomy to determine if there is a role for this procedure among certain subgroups. METHODS: A retrospective review was conducted of 47 patients diagnosed with acquired immunodeficiency syndrome who underwent tracheostomy from 1988 to 1995. Patients were divided into three groups based on indications for tracheostomy: group 1, Pneumocystis carinii pneumonia (PCP); group 2, non-PCP pneumonia; and group 3, others (including neurosyphilis, endocarditis, and trauma). RESULTS: All groups were similar with regard to demographic details and laboratory values (mean age, 38 +/- 1.4 years; 95% male; CD4 count = 21.8 +/- 3.6 cells/microL). In the vast majority of cases the decision to place a TT was elective. Forty-three percent of all patients had signed do not resuscitate orders before endotracheal tube intubation. The mean time from endotracheal tube to TT insertion was 14.1 +/- 1.6 days. Early mortality after TT placement was dismal (91%) for group 1 patients but significantly better (47%) in group 2 patients (p = 0.04). Early mortality usually occurred within 3 weeks of TT placement (range, 1 to 54 days). The cause of pneumonia (PCP versus non-PCP) was the only statistically significant variable in predicting outcome. For those who survived to TT removal (26%), the average time to removal of TT was 67 +/- 11 days. Long-term survival was noted in 8 group 2 patients (mean, 584 days) and in 2 group 1 patients (450 days). CONCLUSIONS: Outcome after tracheostomy in patients with AIDS is generally poor. Patients with PCP should not undergo TT placement; however, patients with non-PCP pneumonia have a reasonable expected survival and should undergo the operation.

Pacemaker leads: a simple atraumatic method for replacing pacemaker electrodes.

Early dislodgment or malfunction of pacemaker leads can result in significant morbidity and therefore must be corrected promptly. We describe a method of changing pacemaker leads that is atraumatic, maintains central venous access, and eliminates the need for venipuncture. Our technique is simple, highly reproducible, and can be performed with standard operating room instruments.

The surgeon's database for AIDS: a collective review.

BACKGROUND: The human immunodeficiency virus infection and acquired immunodeficiency syndrome have had a dramatic effect on the practice of surgery. Critical issues include quantifying the risk encountered by surgeons when operating on infected patients, the benefits of chemoprophylaxis after injury by a health care worker, the likelihood of infected surgeons transmitting human immunodeficiency virus to patients, and the debate over mandatory testing. STUDY DESIGN: Literature review of English-language publications. RESULTS: The incidence of human immunodeficiency virus infection ranges from 1.3 percent of patients hospitalized at sentinel hospitals to 1.5/1,000 patients in lower risk environments. The rate of percutaneous injury during an operation is 5 percent to 6 percent, and human immunodeficiency virus transmission after percutaneous injury with a needle contaminated with the human immunodeficiency virus is 0.3 percent. Here, we review current Public Health Service recommendations for chemoprophylaxis after percutaneous injury and address the debate over mandatory human immunodeficiency virus testing for patients and surgeons in the context of new information regarding the test for the human immunodeficiency virus. CONCLUSIONS: Controversial issues regarding acquired immunodeficiency syndrome and the human immunodeficiency virus infection must be addressed by all surgeons on the basis of objective information.

Appendicitis in patients with acquired immunodeficiency syndrome.

BACKGROUND: Previous reports evaluating appendicitis in patients with human immunodeficiency virus/ acquired immunodeficiency syndrome have detailed unusual pathology, atypical clinical presentations, and poor outcomes. These reports have described small groups of patients and are inconsistent with larger surveys. STUDY DESIGN: A retrospective design was used to evaluate patients diagnosed with human immunodeficiency virus or acquired immunodeficiency syndrome undergoing appendectomy from 1986 to 1995. RESULTS: Fifty-five patients were evaluated (mean age 33.4 +/- 8.2 years, 98 percent male, 90 percent clinical acquired immunodeficiency syndrome, CD4 count 144.45 +/- 34 cells/mL3). Presenting symptoms included right lower quadrant pain (91 percent), nausea and vomiting (41 percent), diarrhea (22 percent), and generalized abdominal pain (24 percent). Significant findings on examination included right lower quadrant tenderness (91 percent), rebound (74 percent), fever (54 percent), abdominal distention (7 percent), and generalized abdominal tenderness (9.3 percent). Computed tomography was performed in 26 percent and findings were suggestive of appendicitis in 93 percent of cases. Operative findings included acute inflammation (83.3 percent), appendiceal rupture (24 percent), gangrene (29 percent), and normal-appearing appendices (5.5 percent). Unusual findings included Mycobacterium tuberculosis (1.8 percent), atypical mycobacterium (1.8 percent), and chronic appendicitis (3.7 percent). Thirty-day survival was 100 percent. Significant postoperative fevers were noted in 33 percent and lasted 4.63 +/- 1.2 days. The presence of prolonged postoperative fever was linked to lower CD4 counts (p = .05). Follow-up (mean time to follow-up, 1,656 +/- 970 days) was complete in 43 percent. Survival at follow-up was noted in 57.1 percent (mean length of survival after surgery, 837 +/- 155 days). CONCLUSIONS: Appendectomy in patients with human immunodeficiency virus/acquired immunodeficiency syndrome is associated with little morbidity or mortality. Atypical pathology is rarely identified. A higher than expected rate of rupture may be linked to delays before hospitalization or to impaired immune status.

The role of cholecystectomy in acquired immunodeficiency syndrome.

BACKGROUND: Hepatobiliary disease is a common manifestation of acquired immunodeficiency syndrome, although the role of surgical intervention in the spectrum of therapy is unclear. STUDY DESIGN: A retrospective review was designed to evaluate the characteristics of patients given a diagnosis of human immunodeficiency virus infection or acquired immunodeficiency syndrome and undergoing cholecystectomy between January 1, 1986, and November 1, 1995. RESULTS: The study included 40 patients (35 men, 5 women; mean age, 42 +/- 9 years), 33 (82.5 percent) with acquired immunodeficiency syndrome; their mean preoperative T-helper (CD4) cell count was 163/mL3. Gross pathologic findings included acute (n = 9, 22.5 percent) and chronic (n = 31, 77.5 percent) cholecystitis. Gallbladder specimens were positive for cholelithiasis in 28 (70 percent), Cryptococcus organisms in 5 (12.5 percent), cytomegalovirus in 3 (7.5 percent), and lymphoma in 2 (5 percent). The median follow-up time was 48 months (range, 6 to 63 months). The percentage survival was 92.5 percent (n = 37) at 30 days, and 57.5 percent (n = 23), 37.5 percent (n = 15), and 25 percent (n = 10) at 12, 24, and 36 months, respectively. The mean survival time was 25.1 months. The likelihood of survival was directly linked to the CD4 cell count. The mean survival period was 25 months for patients with CD4 cell counts less than 200/mL3 compared with 48 months for those with CD4 cell counts greater than 200/mL3. CONCLUSIONS: Although the pathologic changes identified in patients with acquired immunodeficiency syndrome may occasionally be atypical, the clinical presentation, indications for operation, and pathologic findings identified are quite common. Patients tolerate cholecystectomy well with good long-term outcome and minimal infectious complications. Even in patients with the most compromised immune status, a 2-year survival after operation is acceptable. Cholecystectomy has a clear role in the spectrum of treatment for biliary disease relative to acquired immunodeficiency syndrome.

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.

Surgical management of melanoma.

The incidence of melanoma is rising more rapidly than any other malignancy. More conservative margins of excision have been established and the role of elective node dissection awaits determination by prospective randomized trials. Lymphoscintigraphy has clarified lymphatic drainage from watershed areas. Lymphatic mapping and sentinel node biopsy may lead to acceptance of selective lymphadenectomy, and also allows for more sensitive staging. Further advances in outcome require the development of effective systemic adjuvant therapies. Until such time, surgery continues to play a pivotal role in all stages.

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.