Talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone for advanced melanoma: 5-year final analysis of a multicenter, randomized, open-label, phase II trial.

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor.

Vitamin D controls the capacity of human dendritic cells to induce functional regulatory T cells by regulation of glucose metabolism.

Tolerogenic dendritic cells (tolDCs) instruct regulatory T cells (Tregs) to dampen autoimmunity. Active vitamin D (1α,25-dihydroxyvitamin D; 1α,25(OH)D) imprints human monocyte-derived DCs with tolerogenic properties by reprogramming their glucose metabolism. Here we identify the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a critical checkpoint and direct transcriptional target of 1α,25(OH)D in determining the tolDC profile.

Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma.

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone.

Targeting the sugar metabolism of tumors with a first-in-class 6-phosphofructo-2-kinase (PFKFB4) inhibitor.

Human tumors exhibit increased glucose uptake and metabolism as a result of high demand for ATP and anabolic substrates and this metabolotype is a negative prognostic indicator for survival. Recent studies have demonstrated that cancer cells from several tissue origins and genetic backgrounds require the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4), a regulatory enzyme that synthesizes an allosteric activator of glycolysis, fructose-2,6-bisphosphate. We report the discovery of a first-in-class PFKFB4 inhibitor, 5-(n-(8-methoxy-4-quinolyl)amino)pentyl nitrate (5MPN), using structure-based virtual computational screening.

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.

Background: In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma.

Methods: In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors.

Gender-associated expression of tumor markers and a small gene set in breast carcinoma.

Breast carcinomas in both genders share pathological features, although differences in incidence, prognosis and survival are reported. Expression of 33 genes was investigated in male and female breast carcinomas in association with ER, PR, HER-2/neu and EGF-receptor. Among 98 male breast cancers, 82 were ER+ and 78 were PR+.

Ulceration as a predictive marker for response to adjuvant interferon therapy in melanoma.

Objective: This analysis was performed to investigate the hypothesis that ulceration predicts improved response to adjuvant interferon (IFN) therapy.

Summary Background Data: Several studies have demonstrated that adjuvant therapy for high-risk melanoma patients with IFN alfa-2b improves disease-free survival (DFS), although the impact on overall survival (OS) is controversial. Recent data have suggested that IFN therapy may preferentially benefit patients with ulcerated primary melanomas.

Cyclooxygenase-2 and epithelial growth factor receptor up-regulation during progression of Barrett's esophagus to adenocarcinoma.

Aim: To investigate the expression of cyclooxygenase-2 (COX-2) and epithelial growth factor receptor (EGFR) throughout the progression of Barretts esophagus (BE).

Methods: COX-2 and EGFR protein expressions were detected by using immunohistochemical method. A detailed cytomorphological changes were determined.

Formal training in advanced surgical technologies enhances the surgical residency.

Introduction: Surgeons have been consistently instructed to use better tools by which to improve upon a patient's medical care. Since the first laparoscopic cholecystectomy, the desire for advanced surgical technologies has continued. This surgical breakthrough has been one of many changes in modern surgical and medical therapy that now represents the standard of care.

Hepatoid carcinoma of the pancreas.

Extrahepatic hepatocellular carcinoma differentiation has been demonstrated in primary malignancies of the stomach. To date, only five cases of hepatocellular differentiation of the pancreas have been reported in the literature. An example of hepatoid carcinoma of the pancreas is reported in this study.

Current management of melanoma: benefits of surgical staging and adjuvant therapy.

Issues regarding appropriate management of stage I to III melanoma are addressed. Accurate surgical staging is critical to identifying patients who can benefit from therapeutic lymph node dissection and adjuvant therapy. Patients with primary tumors > or = 1 mm thick are appropriate candidates for sentinel lymph node biopsy, and node-positive patients benefit from therapeutic lymphadenectomy.

A short domain within Bcl-3 is responsible for its lymphocyte survival activity.

The NFkappaB factor Bcl-3 influences the survival of T cells when they are activated to take part in immune responses. Because treatment of mice with adjuvant results in the increased expression of Bcl-3 in T cells, where it has survival-promoting effects, Bcl-3 may be an important, limiting factor that is supplied to T cells only when they are contributing to an appropriate immune response to infection, and not when spuriously activated by self-antigens. Although Bcl-3 is a member of the NFkappaB/Rel/IkappaB family of transcription factors, the means by which it promotes T cell survival is not obvious because Bcl-3 is unique in having an ankyrin repeat domain, like inhibitory IkappaB proteins, while also possessing domains capable of transcriptional activation, like Rel proteins.

Optimal use of sentinel lymph node biopsy versus axillary lymph node dissection in patients with breast carcinoma: a decision analysis.

Background: There are no data available from randomized controlled trials that compare the efficacy of sentinel lymph node (SLN) biopsy with Level I/II axillary lymph node dissection (ALND) in patients with breast carcinoma. We performed a formal decision analysis to determine whether SLN biopsy is appropriate, compared with ALND, for patients with T1, T2, and T3 tumors and to quantify the relative value of these two procedures in the management of patients with breast carcinoma.

Methods: All clinically relevant outcomes were modeled for both SLN biopsy and ALND.

The effect of prior breast biopsy method and concurrent definitive breast procedure on success and accuracy of sentinel lymph node biopsy.

Background: It has been suggested that sentinel lymph node (SLN) biopsy for breast cancer may be less accurate after excisional biopsy of the primary tumor compared with core needle biopsy. Furthermore, some have suggested an improved ability to identify the SLN when total mastectomy is performed compared with lumpectomy. This analysis was performed to determine the impact of the type of breast biopsy (needle vs.

Utility of intraoperative frozen section analysis of sentinel lymph nodes in breast cancer.

Background: Intraoperative frozen section pathologic analysis of sentinel lymph node (SLN) may guide immediate (single-stage) completion axillary dissection for patients with nodal metastases.

Methods: The results of 203 consecutive patients undergoing SLN biopsy who had intraoperative pathology consultation between January 1998 and September 2000 were reviewed. SLN were analyzed by standard frozen section procedures.

The use of cytokeratin staining in sentinel lymph node biopsy for breast cancer.

Background: Controversy exists regarding the routine use of cytokeratin immunohistochemistry (IHC) in the histopathologic examination of breast cancer sentinel lymph nodes (SLN) because the clinical significance of micrometastases detected by IHC is unclear. This analysis was performed to determine the frequency of IHC-detected micrometastases.

Methods: All patients underwent SLN biopsy, followed by completion axillary dissection.

Reliable lymphatic drainage to axillary sentinel lymph nodes regardless of tumor location within the breast.

Background: This analysis was performed in order to determine whether primary tumor location in breast cancer affects the axillary sentinel lymph node (SLN) identification (ID) rate, the false negative (FN) rate, incidence of axillary nodal metastases, or the number of SLN identified.

Methods: In this prospective multi-institutional study, SLN biopsy was performed on clinical stage T1-2, N0 breast cancer patients using blue dye alone or in combination with radioactive colloid, followed by completion axillary LN dissection.

Results: Central tumor location was associated with an improved FN rate, which may be related to reliable drainage from the subareolar lymphatic plexus.

The Sunbelt Melanoma Trial.

The Sunbelt Melanoma Trial is a prospective randomized trial to evaluate the role of lymph node dissection and adjuvant interferon alfa-2b for patients with early lymph node metastases.

Defining the optimal surgeon experience for breast cancer sentinel lymph node biopsy: a model for implementation of new surgical techniques.

Objective: To determine the optimal experience required to minimize the false-negative rate of sentinel lymph node (SLN) biopsy for breast cancer.

Summary Background Data: Before abandoning routine axillary dissection in favor of SLN biopsy for breast cancer, each surgeon and institution must document acceptable SLN identification and false-negative rates. Although some studies have examined the impact of individual surgeon experience on the SLN identification rate, minimal data exist to determine the optimal experience required to minimize the more crucial false-negative rate.

Dermal injection of radioactive colloid is superior to peritumoral injection for breast cancer sentinel lymph node biopsy: results of a multiinstitutional study.

Objective: To determine the optimal radioactive colloid injection technique for sentinel lymph node (SLN) biopsy for breast cancer.

Summary Background Data: The optimal radioactive colloid injection technique for breast cancer SLN biopsy has not yet been defined. Peritumoral injection of radioactive colloid has been used in most studies.

Predicting the status of the nonsentinel axillary nodes: a multicenter study.

Background: Sentinel lymph node (SLN) biopsy is a minimally invasive procedure that provides accurate nodal staging information. The need for completion axillary dissection after finding a positive SLN for breast cancer has been questioned.

Hypothesis: The presence of nonsentinel node (NSN) metastases in the axillary dissection specimen correlates with tumor size, the number of SLNs removed, and the number of positive SLNs.