Eric D. Whitman

gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma

BACKGROUND Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freunds adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).

Comparative analysis of laparoscopic versus open splenectomy

BACKGROUND Laparoscopic splenectomy (LS) has been used to treat a variety of splenic disorders. However, there have been few direct comparisons of this approach with open splenectomy (OS). METHODS Results and outcomes were compared retrospectively in 46 consecutive patients treated by laparoscopic (n = 26) or open splenectomy (n = 20) from January 1990 through March 1996. The two groups were similar in age, sex, and American Society of Anesthesiology classification. Splenectomy was performed for a variety of indications, and the majority of patients in both groups had normal or near-normal size spleens. All data are expressed as mean +/- standard deviation. RESULTS Laparoscopic splenectomy was successfully completed in all 26 attempted cases. Operative times were significantly longer for LS (202 +/- 55 minutes) than for OS (134 +/- 43 minutes) (P < 0.001); however, operative times in the last 13 LS cases (176 +/- 48 minutes) averaged 51 minutes less than in the first 13 cases (227 +/- 51 minutes). Estimated operative blood loss was less for LS (222 +/- 280 mL) than for OS (376 +/- 500 mL) (P = not significant). A mean of 2.0 units of red blood cells was transfused in 4 (15%) of 26 patients during LS vs 1.0 unit transfused in 2 (10%) of 20 patients who had OS (P = NS). Patients who underwent LS required significantly less parenteral pain medications, had a more rapid return to regular diet, and were discharged sooner than patients who had OS. Complication rates were similar in the two groups. CONCLUSIONS These results suggest that LS is technically safe and has several advantages over OS. Laparoscopic splenectomy should become the procedure of choice for the removal of normal and near-normal size spleens.

A phase 2 study of high-dose Allovectin-7 in patients with advanced metastatic melanoma.

Allovectin-7, a bicistronic plasmid encoding human leukocyte antigen-B7 and β-2 microglobulin formulated with a cationic lipid system, is an immunotherapeutic agent designed to express allogeneic major histocompatibility complex class I antigen upon intralesional administration. A phase 2 dose-escalation study (VCL-1005-208) was conducted to evaluate the safety and efficacy of Allovectin-7 in patients with metastatic melanoma. Eligible patients had stage III or IV metastatic melanoma recurrent or unresponsive to prior therapy, an Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients with brain or visceral (except lung) metastases, abnormal lactate dehydrogenase, or any lesion greater than 100 cm2 were excluded. Patients received six weekly intralesional injections followed by 3 weeks of observation and evaluation. Overall response was assessed using Response Evaluation Criteria in Solid Tumors guidelines. Patients with stable or responding disease were eligible to receive additional cycles of Allovectin-7. All 133 patients were evaluated for safety and 127 patients (2 mg, high dose) were evaluated for efficacy. Fifteen patients (11.8%, 95% confidence interval: 6.2–17.4) achieved an objective response with median duration of response of 13.8 months (95% confidence interval: 8.5, not estimable). A histological examination of tissue from two responding patients who had their lesions resected has shown no evidence of melanoma. Median time-to-progression in this study was 1.6 months. In conclusion, these results indicate that high-dose Allovectin-7 seems to be an active, well-tolerated treatment for selected stage III/IV metastatic melanoma patients with injectable cutaneous, subcutaneous, or nodal lesions.

Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database.

BackgroundNumerous predictive factors for cutaneous melanoma metastases to sentinel lymph nodes have been identified; however, few have been found to be reproducibly significant. This study investigated the significance of factors for predicting regional nodal disease in cutaneous melanoma using a large multicenter database.MethodsSeventeen institutions submitted retrospective and prospective data on 3463 patients undergoing sentinel lymph node (SLN) biopsy for primary melanoma. Multiple demographic and tumor factors were analyzed for correlation with a positive SLN. Univariate and multivariate statistical analyses were performed.ResultsOf 3445 analyzable patients, 561 (16.3%) had a positive SLN biopsy. In multivariate analysis of 1526 patients with complete records for 10 variables, increasing Breslow thickness, lymphovascular invasion, ulceration, younger age, the absence of regression, and tumor location on the trunk were statistically significant predictors of a positive SLN.ConclusionsThese results confirm the predictive significance of the well-established variables of Breslow thickness, ulceration, age, and location, as well as consistently reported but less well-established variables such as lymphovascular invasion. In addition, the presence of regression was associated with a lower likelihood of a positive SLN. Consideration of multiple tumor parameters should influence the decision for SLN biopsy and the estimation of nodal metastatic disease risk.

Endocrine Surgical Diseases of Elderly Patients

The causes, evaluation, and preoperative and postoperative care of primary hyperparathyroidism and thyroid nodules in the elderly patient population have been described. Primary hyperparathyroidism is easily diagnosed and is almost always curable by surgery. Elderly patients with asymptomatic disease are candidates for nonoperative, expectant management. If they become symptomatic, surgery should be performed. Postoperative care of the elderly patient who has undergone parathyroid exploration is potentially complicated by the patients other medical problems, including cardiac and pulmonary difficulties, variable severity of symptoms of hypocalcemia, and sensitivity to medications. Thyroid nodules in the elderly may present later than in younger patients and are more likely to contain malignant tissue. Tissue diagnosis preoperatively, usually by FNA testing, is mandatory. Anaplastic thyroid carcinoma and thyroid lymphoma are both treated nonoperatively. Thyroid surgery in the elderly is usually well tolerated, although other medical conditions, as mentioned above, may complicate postoperative care. Thyroid carcinoma in the elderly carries a worse prognosis than in younger patients and should always be treated with postoperative adjuvant (radioablative) therapy. Although this does not affect survival (from the thyroid cancer), it does extend the disease-free interval. As the number of elderly patients increases, the frequency with which these disorders are encountered will also rise. It is important to realize that almost all elderly patients can both tolerate and benefit from surgical correction of these two disorders, if appropriate preoperative evaluation is coupled with excellent intraoperative and postoperative care.

Comparison of diagnostic specimens and methods to evaluate infected venous access ports

BACKGROUND Implanted venous access port infection can be difficult to diagnose and treat. If device removal is necessary, confirming port infection is problematic. MATERIALS AND METHODS Culture specimens from three sites, catheter tip (Tip), port pocket, and the material within the reservoir (Inside), were sent from ports removed for potential infection. The results of these cultures were compared to preremoval peripheral and central blood cultures. RESULTS Forty-five ports were removed for suspected infection. Confirmed port infection was defined as positive culture(s) from one or more experimental specimen(s). In 29 evaluable cases, the Inside specimens were completely predictive. Tip specimens were less accurate, even with a lower diagnostic threshold. In 7 of 19 confirmed infections, only the Inside culture was diagnostic. CONCLUSION The most predictive culture specimen in a potentially infected port is the thrombotic material inside the reservoir.

Construction and expression in tumor cells of a recombinant vaccinia virus encoding human interleukin-1β

AbstractBackground: Human interleukin-1β (hIL-1β) injected intratumorally has demonstrated growth inhibition of transplanted subcutaneous tumors in mice, regression of metastatic lesions, resistance to tumor rechallenge, and increased survival. Vaccinia virus (VV) can be genetically engineered to produce cytokines and may be an effective vector for gene therapy of cancer. This study was designed to (a) construct a VV expressing hIL-1β, (b) assess tumor cell infection in vitro with this construct, (c) measure hIL-1β production, and (d) assess the bioactivity of the secreted cytokine. Methods: The hIL-1β gene was amplified from a plasmid clone using polymerase chain reaction (PCR) and then cloned into a homologous recombination (HR) and expression vector, which was used to insert the hIL-1β gene into the VV genome. Selection of the recombinant VV (vMJ601hIL-1β) was based on inactivation of viral TK and expression of β-galactosidase. vMJ601hIL-1β infectivity and cytokine production was assessed by infecting tumor cell lines and analyzing culture supernatants for hIL-1β. Bioactivity of the hIL-1β produced was demonstrated using an IL-1 dependent T helper cell line. Results: The hIL-1β gene was successfully cloned into the VV genome by HR, which was confirmed by PCR. vMJ601hIL-1β efficiently infected tumor cells, as shown by increased hIL-1β secretion (0 to >500 ng/ml) and morphologic evidence of viral cytopathic effect. vMJ601hIL-1β-infected cells secreted large amounts of hIL-1β (mean 772 ng/106 cells/24 h). The secreted hIL-1β was bioactive (mean bioactivity 6.8×108 U/mg of hIL-1β). Conclusions: (a) hIL-1β can be cloned into VV, (b) vMJ601hIL-1β retains its infectivity, (c) a large amount of hIL-1β is secreted, and (d) the secreted hIL-1β is bioactive. Recombinant VV may allow in situ cytokine gene delivery and expression in established tumors.

Role of sentinel lymphadenectomy in thin cutaneous melanomas with positive deep margins on initial biopsy

Breslow thickness (BRES) on initial melanoma biopsy determines need for sentinel lymph node (SLN) biopsy. In presence of positive deep margins, BRES is indeterminate. We hypothesized that thin (BRES <0.76 mm) melanomas with positive deep margins and thicker melanomas (BRES 0.76–2.0 mm) have statistically similar risk of SLN metastasis.

An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0

BackgroundCancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available.MethodsTo address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. ResultsThe Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma.ConclusionThese clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.

Vemurafenib treatment for patients with locally advanced, unresectable stage IIIC or metastatic melanoma and activating exon 15 BRAF mutations other than V600E.

BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAFV600E-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety. Planned (V600K vs. non-V600K mutations) subgroup analyses were carried out. Thirty-one patients were enrolled; 13 (42%) had V600K mutations and 18 (58%) had other mutations. Investigator-assessed confirmed that the best overall response rate was 23% (95% confidence interval=10–41%) in the overall population, and was similar between patients with V600K mutations (23%; 95% confidence interval=5–54%) versus other mutations (22%; 95% confidence interval=6–48%). Responses were observed in patients with V600K (n=3), V600E2 (n=1), V600R (n=1), L597S (n=1) and D594G (n=1) mutations. No new safety signals were reported. Vemurafenib showed activity in patients with advanced melanoma with rarer BRAF mutations.