Tumor Regression and Autoimmunity in Patients Treated With Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and Interleukin 2: A Phase I/II Study

Background Cytotoxic T lymphocyte–associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti–CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma. Methods Thirty-six patients received anti–CTLA-4 antibody every 3 weeks. Three patients per cohort received doses of .1, .3, 1.0, and 2.0 mg/kg. Twenty-four patients received 3.0 mg/kg. All patients received IL-2 therapy (720,000 IU/kg every 8 hours to a maximum of 15 doses). Results Eight patients (22%) experienced objective tumor responses (three complete and five partial), including metastases in the lungs, lymph nodes, mediastinum, and subcutaneous tissues. Six of the eight patients have ongoing objective responses at 11 to 19 months. Five patients (14%) developed grade III/IV autoimmune toxicities secondary to anti–CTLA-4 administration, including four patients with enterocolitis and one with arthritis and uveitis. Conclusions There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration, because the 22% objective response rate is that expected from the sum of these two agents administered alone. Durable cancer regressions were seen in patients treated with this combination.     

Development of immunotherapy in bladder cancer: present and future on targeting PD(L)1 and CTLA-4 pathways

Purpose

Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings.

Methods

A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: ‘urothelial carcinoma’ OR ‘bladder cancer’, and ‘immunotherapy’ OR ‘CTLA-4’ OR ‘PD-1’ OR ‘PD-L1’ OR ‘atezolizumab’ OR ‘nivolumab’ OR ‘ipilimumab’ OR ‘pembrolizumab’ OR ‘avelumab’ OR ‘durvalumab’ OR ‘tremelimumab’. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included.

Results

Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed.

Conclusions

Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L)1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies.

     

Evaluating Optimal Treatment for Melanoma: A Network Meta-Analysis

Background It is necessary to determine the optimal treatment for melanoma as the incidence of melanoma is increasing every year.In this study,we conducted a metaanalysis to compare the effectiveness of available treatments for melanoma.Methods The index keywords“melanoma”and“treatment”were used to search the PubMed,Cochrane Library,Web of Science,and Embase databases,and the articles were limited to randomized controlled trials.The search was filtered for articles published until February 2020,and articles were independently extracted by two reviewers.Network metaanalysis(Stata?14.0 software network package,StataCorp LLC,TX,USA)was used to compare the effectiveness of the mentioned treatments of melanoma.Results A total of 616 articles were screened of which 6 were selected for meta-analysis,involving 5 treatment measures and 2047 patients(those who were not followed up on were excluded).The treatment strategies reported for melanoma included tumor necrosis factor(L19-TNFα)and interleukin-2(L19IL2)in combination with dacarbazine(L19IL2+DTIC),DTIC,programmed cell death-1 plus cytotoxic T cell antigen-4(PD-1+CTLA-4),PD-1,and CTLA-4.Conclusion Among L19IL2+DTIC,DTIC,PD-1+CTLA-4,PD-1,and CTLA-4,CTLA-4 is found to be the best treatment method for melanoma.Our study findings provide a reference for the clinical treatment of melanoma and can clarify the direction for setting up controlled clinical trials.     

Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy for the treatment of prostate cancer

Costimulatory pathway ligands and receptors can deliver either positive or negative signals to help determine the ultimate fate of activated T lymphocytes. Cytotoxic T lymphocyte antigen-4 (CTLA-4) represents one of the most extensively studied receptors in the costimulatory pathway and has recently been shown to function as a potent inhibitor of T cell-mediated immunity. T-cell expression of CTLA-4 indirectly facilitates tumor progression by restraining host antitumoral immunity. In contrast, administration of a monoclonal antibody to block CTLA-4 function can alleviate restraints on T-cell activity to promote immune-mediated tumor regression. We review the preclinical and clinical experience with CTLA-4 blockade as a promising immunotherapeutic approach to treat patients with advanced prostate cancer.     

Factors Predictive of Acute Regional Toxicity After Isolated Limb Infusion with Melphalan and Actinomycin D in Melanoma Patients

Introduction  Isolated limb infusion (ILI) with cytotoxic drugs is a low-flow isolated limb perfusion (ILP) performed via percutaneous catheters without oxygenation to treat metastatic melanoma confined to a limb. Response rates and duration of response following ILI are similar to those after ILP. Previously we have shown that more significant limb toxicity is not associated with a higher response rate or improved patient outcome. In this study we sought to determine factors predicting toxicity following ILI. Methods  From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1992 and 2007 were identified. In all patients a cytotoxic combination of melphalan and actinomycin D was used. Drug circulation time was 20–30 min under mild hyperthermic conditions (38–39°C). Limb toxicity was assessed using the Wieberdink scale. Results  The average patient age was 74 years (range 29–93 years) and 62% were female. Most patients (134/185) had MD Anderson stage III disease (satellites and in-transit metastases). Toxicity grade I (no reaction) occurred in 3 patients, grade II (slight erythema and edema) in 105 patients, grade III (considerable erythema and edema ± blistering) in 72 patients, and grade IV (threatened or actual compartment syndrome) in 5 patients. No patient developed grade V toxicity (requiring amputation). On univariate analysis high peak and high final melphalan concentrations were found to be predictive factors for grade III/IV limb toxicity as well as the area under the curve of the melphalan concentration. Surprisingly, a greater rise in the CO₂ level during the procedure was associated with lower toxicity in the univariate analysis. Increased serum creatine phosphokinase (CK) postoperatively was related to higher toxicity score. In the multivariate analysis high final melphalan concentration and shorter tourniquet time were independent predictive risk factors for developing grade III/IV limb toxicity. Conclusions  ILI is a safe alternative to the more invasive and laborious ILP technique to treat melanoma confined to a limb. Regional acute toxicity following ILI is mild to moderate in most patients. Based on the predictive factors found in this series, altering melphalan dose and tourniquet time may allow further reductions in post-ILI toxicity without compromising effectiveness.     

黑色素瘤抗体治疗研究进展

黑色素瘤是一类起源于神经嵴黑色素细胞的高度恶性肿瘤,易发生远处转移,转移性黑色素瘤患者的预后很差。近年来,免疫治疗逐渐成为黑色素瘤治疗的新方向,越来越多的免疫药物被用于临床治疗。其中,对T细胞肿瘤免疫研究日益深入,多个有治疗意义的T细胞调节通路位点和共刺激分子被发现,并被用于加强对黑色素细胞瘤的免疫反应。本文就两种单克隆抗体,即程序死亡分子1(PD-1)和抗细胞毒性T淋巴细胞相关抗原4(CTLA-4),以及两种共刺激分子OX40和4-1BB在近年的研究进展进行综述。     

Immunotherapy Following Regional Chemotherapy Treatment of Advanced Extremity Melanoma

Purpose

Following regional chemotherapy (RC) for melanoma, approximately 75 % of patients will progress. The role of immunotherapy after RC has not been well established.

Methods

A prospective, single-institution database of 243 patients with in-transit melanoma (1995–2013) was queried for patients who had progression of disease after RC with melphalan and subsequently received systemic immunotherapy. Fifteen patients received IL-2 only, 12 received ipilimumab only, and 6 received IL-2 followed by ipilimumab. Fisher’s exact test was used to determine if there was a difference in number of complete responders after immunotherapy.

Results

With IL-2 alone, all patients progressed. After ipilimumab alone, three patients had a complete response and nine had progressive disease. Six additional patients received IL-2 first then ipilimumab. All six progressed on IL-2 but three went on to have a complete response to ipilimumab while three progressed. The use of ipilimumab at any time in patients who progressed after RC was associated with higher rate of complete response compared to use of IL-2 alone (33 vs. 0 %; p = 0.021).

Conclusions

Patients with progression after regional therapy for melanoma may benefit from immunologic therapy. In this group of patients, immune checkpoint blockade with ipilimumab has a higher complete response rate than T cell stimulation with IL-2, with no complete responders in the IL-2 only group. Furthermore, the complete response rate for ipilimumab in our cohort is higher than reported response rates in the literature for ipilimumab alone, suggesting that the effects of immunotherapy may be bolstered by previous regional treatment.     

Results of a Multimodal Therapy in Patients with Stage IV Barrett’s Adenocarcinoma

Background  Locally advanced and metastatic Barrett’s carcinomas account for the majority of this tumor entity at the time of diagnosis. Many studies have shown that a multimodal therapy concept consisting of neoadjuvant chemotherapy followed by resection can result in improved long-term survival in patients responding to chemotherapy. The benefit of a multimodal therapy concept in patients with stage IV disease remains unclear. Methods  A total of 178 patients with Barrett’s carcinoma who underwent multimodal therapy with resection of the tumor were reviewed. The pathological staging and the clinical course of patients with metastatic disease, who were treated equally, were compared to patients with locally advanced tumors. Results  As expected, postoperative pathological staging showed that patients with metastatic disease have a more advanced T- and N-status. Moreover, the histopathological response according to Becker showed a chemoresistence in 84% of cases with metastatic disease, whereas 54% of patients with locally advanced carcinomas had a good response rate. Overall survival was poor, with 9 months in the metastatic group. Conclusions  This is the first study to compare the outcome of a modern multimodal therapy concept in patients with metastatic Barrett’s carcinoma in comparison to patients with the locally advanced form of the disease. There are profound differences in the two groups with regard to survival time and response rates. Because of the poor outcome to date, multimodal therapy with resection of the tumor in stage IV disease cannot be recommended.     

Immunological Insights from Patients Undergoing Surgery on Ipilimumab for Metastatic Melanoma

Background

The tumor microenvironment after treatment with ipilimumab is not well described. Furthermore, the safety of surgery for patients being treated with ipilimumab for metastatic melanoma has not been well reported. This study analyzed the safety of surgery and the immune phenotype of tumors resected while on ipilimumab.

Methods

From our prospective melanoma database, we identified patients undergoing surgery for any indication within 30 days of receiving a dose of induction ipilimumab or while on maintenance ipilimumab therapy. Surgical toxicity was graded 1–5 by the Clavien classification. Tumor-infiltrating lymphocytes were classified by flow cytometry and compared with peripheral blood.

Results

23 patients were identified who underwent 34 operations a median of 27 weeks after initiation of ipilimumab (1–123 weeks). Subcutaneous resections were the most frequent, followed by intra-abdominal and nodal procedures. Grade 1 or 2 wound complications were seen in 22 % of patients. No Grade 3–5 complications were seen. Analysis of the T cell infiltrate and matched peripheral blood from ten patients showed an elevated % of CD4⁺FOXP3⁺ T-regulatory cells and a 2.8-fold lower ratio of CD8⁺/CD4⁺FOXP3⁺ in the tumor compared with blood (p = 0.02). In addition, all CD8⁺ T cells had a higher expression of PD-1 in the tumor, compared with peripheral blood.

Conclusions

Surgery for patients on ipilimumab is safe. This study highlights the immunosuppressive phenotype in tumors not responding to immunotherapy. The high percentage of T-regulatory cells and low T-effector cells in progressive tumors suggests a possible mechanism of immune escape.     

Good-risk-advanced germ cell tumors: historical perspective and current standards of care

Outcomes for patients with metastatic germ cell tumors have improved dramatically over the last 30 years with today’s cure rates approaching 80%. A critical contribution to the treatment of metastatic disease was the development of the universally accepted international germ cell cancer collaborative group (IGCCCG) outcome prediction model. With this system, patients are classified into good, intermediate, and poor-risk groups, each with a significantly different likelihood of cure. Not only are outcomes more favorable in the good-risk group, the intensity of treatment required to achieve these outcomes is also less. Therefore, the physician’s goal in treating good-risk patients is to minimize the short- and long-term therapy-related toxicities, while maintaining the excellent cure rates. Through well-conducted clinical trials, four cycles of etoposide + cisplatin (EP×4) and three cycles of bleomycin + etoposide + cisplatin (BEP×3) have emerged as the two optimal treatment regimens for good-risk patients. Cure rates with either regimen with or without surgery approximate to 90%. Attempts to further diminish the toxicity of either regimen have been unsuccessful due to the resulting reductions in efficacy. The authors discuss the trials which led to the establishment of EP×4 and BEP×3 as today’s treatment standards as well as the development of the IGCCCG prognostic model.     

A Single-Institution Validation of the AJCC Staging System for Stage IV Melanoma

Background  Survival of patients with stage IV melanoma is poor. In the current American Joint Committee on Cancer (AJCC) staging system, site of distant disease and lactate dehydrogenase (LDH) are the only prognostic factors included for stage IV disease. We sought to validate the current AJCC staging system in a contemporary, prospectively collected cohort of patients and explore additional factors that may influence prognosis. Methods  Our prospective database was searched to identify patients with stage IV melanoma; only patients seen at our institution before developing stage IV disease were included (n = 589). Demographic, clinical, and tumor characteristics were abstracted. Univariate and multivariate assessment of prognostic factors associated with survival were performed by Cox regression. Results  Overall median survival was 9 months. Differential survival by AJCC substage was observed (P < .001). For each site of disease described within the AJCC staging system, an abnormal LDH level was associated with a poorer prognosis. By multivariate analysis, older age at diagnosis (as a continuous variable, hazard ratio [HR] 1.02, 95% confidence interval [95% CI]) 1.01–1.02), an abnormal LDH (HR 1.42, 95% CI 1.11–1.82), site of disease (lung HR 1.22, 95% CI .89–1.66; other viscera 1.61, 95% CI 1.18–2.21), more than one organ involvement (HR 1.27, 95% CI 1.01–1.60), and more than one metastasis (HR 2.27, 95% CI 1.65–3.14) were independently associated with poorer survival. Sex, antecedent stage, and disease-free interval were not statistically significant. Conclusion  In our patient cohort, the AJCC staging system was valid. The strongest predictor of survival—the number of metastases present at the diagnosis of stage IV disease—represents a variable to consider in future staging systems. Presented in part at the American Society Clinical Oncology annual meeting, June 2007.     

Cervical Nodal Metastasis from Intrathoracic Esophageal Squamous Cell Carcinoma is not Necessarily an Incurable Disease

Background  It remains controversial if metastatic cervical lymph nodes in patients with intrathoracic esophageal cancer signify distant metastases and are therefore incurable or if they should be regarded as regional spread with a potential for cure. Material and Methods  Patients with intrathoracic esophageal squamous cell carcinoma managed from 1995 to 2007, in whom metastatic cervical lymph node spread was confirmed by fine needle aspiration cytology, were studied. Treatment strategies and outcome were reviewed. Results  There were 109 patients, of whom 98 were men. Median age was 62 years (range, 34–88). Excluding those who underwent primarily palliative treatments, there were two main groups: 22 who had upfront chemoradiation therapy and subsequent esophagectomy ± cervical lymphadenectomy and 46 who had chemoradiation only. Significant downstaging occurred in 29 of the 68 patients (42.6%), of whom eight (11.8%) had complete pathological/clinical response. There was no mortality after esophagectomy. Median survival of patients with chemoradiation plus esophagectomy was 34.8 months compared to those with no surgery at 9.9 months, (p < 0.001). Patients with stage IV disease at presentation by virtue of nodal disease survived longer than those with the same stage because of systemic organ metastases: 9.3 vs. 3 months, (p < 0.001). Conclusions  Prognosis of patients with metastatic cervical nodes was not uniformly dismal. Up to 20% had reasonable survival after chemoradiation and surgical resection. Stage IV disease should be revised to segregate those with nodal and systemic metastases.     

Outcomes Following Isolated Limb Infusion for Melanoma. A 14-Year Experience

Background  Isolated limb infusion (ILI) is a minimally invasive technique for delivering regional chemotherapy in patients with advanced and metastatic melanoma confined to a limb. It is essentially a low-flow isolated limb perfusion (ILP) performed via percutaneous catheters without oxygenation. Methods  From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1993 and 2007 were identified. In all patients a cytotoxic drug combination of melphalan and actinomycin-D was used. Drug circulation time was 20–30 min under mild hyperthermic conditions (38–39°C). Results  The majority of patients (62%) were female. Their average age was 74 years (range 29–93 years). Most patients had MD Anderson stage III disease (134/185). The overall response rate was 84% [complete response (CR) rate 38%, partial response rate 46%]. Median response duration was 13 months (22 months for patients with CR; P = 0.01). Median follow-up was 20 months and median survival was 38 months. In those patients with a CR, the median survival was 53 months (P = 0.005). CR rate and survival time decreased with increasing stage of disease. On multivariate analysis significant factors for a favorable outcome were achievement of CR, stage of disease, thickness of primary melanoma, the CO₂ level in the isolated circuit, and a Wieberdink limb toxicity score of III (considerable erythema and edema). Conclusion  The response rates and duration of response after ILI are comparable to those achieved by conventional ILP. ILI is a minimally invasive alternative to the much more complex and morbid conventional ILP technique for patients with advanced metastatic melanoma confined to a limb.     

Immunosuppressive Dendritic and Regulatory T Cells are Upregulated in Melanoma Patients

Background Immunologic therapies for melanoma rarely succeed, suggesting a persistent counter-regulatory immune modulation. Regulatory T cells (T_regs) and plasmacytoid subpopulations of dendritic cells (pDCs) inhibit the immune response. We hypothesize that melanoma upregulates T_regs and subpopulations of immunosuppressive dendritic cells (DCs). Methods Peripheral blood mononuclear cells (PBMCs) were obtained from healthy controls, stage I and stage IV melanoma patients. T_regs were identified as CD4+ and CD25^hi. Dendritic cells were identified using a DC cocktail of antibodies including CD11c+ myeloid dendritic cells (mDCs) and CD123+ pDCs. Serum transforming growth factor-β (TGF-β), interleukin-4 (IL-4) and interleukin-10 (IL-10) levels were determined by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using analysis of variance (ANOVA). Results Stage IV melanoma patients had a doubling of regulatory T cells compared to both normal subjects and stage I melanoma patients. There was a significantly higher number of DCs in all melanoma patients compared to normal subjects. Stage I melanoma patients had a significantly higher number of pDCs than normal subjects, and all melanoma patients had a higher concentration of mDCs than controls. Serum IL-4 and IL-10 were not detectable but serum TGF-β levels were significantly higher in stage I and stage IV melanoma patients compared to normal controls. Conclusion Advanced melanoma is associated with increased numbers of circulating dendritic cells and regulatory T cells. These data suggest that melanoma induces immunosuppressive DCs and regulatory T cells in the systemic circulation.     

Superior inhibition of alloantibody responses with selective CD28 blockade is CTLA-4 dependent and T follicular helper cell specific

Anti-donor antibodies cause immunologic injury in transplantation. CD28 blockade with CTLA-4-Ig has the ability to reduce the incidence of these donor-specific antibodies (DSA), but its mechanism is suboptimal for the inhibition of alloimmunity in that CTLA-4-Ig blocks both CD28 costimulation and CTLA-4 coinhibition. Thus selective CD28 blockade that spares CTLA-4 has potential to result in improved inhibition of humoral alloimmunity. To test this possibility, we utilized a full allogeneic mismatch murine transplant model and T follicular helper (Tfh):B cell co-culture system. We observed that selective blockade with an anti-CD28 domain antibody (dAb) compared to CTLA-4-Ig led to superior inhibition of Tfh cell, germinal center, and DSA responses in vivo and better control of B cell responses in vitro. CTLA-4 blockade enhanced the humoral alloresponse and, in combination with anti-CD28 dAb, abrogated the effects of selective blockade. This CTLA-4-dependent inhibition was Tfh cell specific in that CTLA-4 expression by Tfh cells was necessary and sufficient for the improved humoral inhibition observed with selective CD28 blockade. As CD28 blockade attracts interest for control of alloantibodies in the clinic, these data support selective CD28 blockade as a superior strategy to address DSA via the sparing of CTLA-4 and more potent targeting of Tfh cells.     

Status of Involved Lymph Nodes and Direction of Metastatic Lymphatic Flow Between Submucosal and T2-4 Thoracic Squamous Cell Esophageal Cancers

Background  Three-field lymph node dissection for thoracic esophageal cancer is associated with high morbidity and reduced quality of life after surgery. Consequently, minimized lymphadenectomy would be desirable, if appropriate. In the present study, we retrospectively analyzed the status of involved nodes and the direction of metastatic lymphatic flow from tumors into involved nodes to determine whether submucosal squamous cell esophageal cancers are potential candidates for minimized lymphadenectomy. Methods  We enrolled 199 patients who received esophagectomy with extensive lymph node dissection between 1989 and 2005 and retrospectively analyzed their prognoses, distribution of solitary metastatic lymph nodes, and the direction of metastatic lymphatic flow from the tumor, taking into consideration tumor location and depth. Results  Of these patients with submucosal cancers, 83% had 1 or 2 involved nodes, and their esophageal cancer-specific 5-year survival rate was 66%. Solitary lymph node metastasis did not occur in neck lymph nodes in lower thoracic submucosal esophageal cancers, and the direction of metastatic lymphatic flow from the tumor was almost always in one direction. By contrast, T2–4 cancers with 2–4 involved nodes had bidirectional metastatic lymphatic flow from the tumor. Conclusions  There was a difference in the status of lymph node metastasis and the direction of metastatic lymphatic flow from tumors into involved nodes between submucosal and T2–4 thoracic squamous cell esophageal cancers. This analysis may be useful for developing an approach to minimized lymphadenectomy for thoracic esophageal cancers.     

Adverse Outcomes Associated with Noncompliance with Melanoma Treatment Guidelines

Background  Clinical practice guidelines have been developed to improve melanoma patient care. However, it is unclear whether failure to comply with these standards (either excessive or inadequate treatment) increases morbidity or relapse rates. Therefore, we undertook this study to evaluate the effect of variance from National Comprehensive Cancer Network (NCCN) recommendations on postoperative complication rates and disease recurrence. Methods  We retrospectively reviewed our institutional cancer registry data on 327 clinically node-negative melanoma patients and assessed compliance with NCCN guidelines, complication rates, and outcome. Data were confirmed by chart, pathology report, and operative note review. Statistical analysis was performed by using the SAS statistical software package. Results  Postoperative complications were documented in 17% of patients and were 3.4-fold higher for patients treated in a margin-noncompliant fashion and 2.4-fold higher for patients treated in a lymph-node-noncompliant manner (P < 0.001 for both). After mean follow-up of 51 months, disease recurred in 58 patients (18%) at a mean of 33 months (range 4–93 months). Locoregional disease alone as the first site of relapse was seen in 24% of margin-noncompliant versus 6% of margin-compliant cases and in 33% of lymph-node-noncompliant versus 6% of lymph-node-compliant cases (P < 0.0001). Conclusion  While there are valid reasons for variance from treatment algorithms, these data suggest that compliance with NCCN guidelines improves outcome and decreases morbidity in clinically node-negative melanoma patients.     

Pancreatic Resection of Isolated Metastases from Nonpancreatic Primary Cancers

Background  The goal of this study is to report the safety and efficacy of pancreatic resection for isolated metastatic cancers from nonpancreatic primary disease. Methods  We retrospectively identified patients from a single institution’s prospectively gathered pancreaticobiliary database from 1970 to 2007 who underwent a pancreatic resection for metastatic disease. Results  Forty-nine patients were identified with metastatic lesions to the pancreas. Pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy were performed in 31, 14, and 4 patients, respectively. Pathology distribution was as follows: 21 renal cell carcinoma (RCC), 6 gallbladder cancer, 4 lung cancer, 4 ovarian cancer, 4 sarcoma, 3 melanoma, 2 colon cancer, 1 breast cancer, 1 hepatocellular carcinoma, 1 seminoma, 1 Langerhans cell histiocytosis, and 1 nonpancreatic endocrine cancer. Postoperative morbidity was 48%. There were no perioperative deaths. A statistically significant difference in survival was found between cancer types (P = .007) with median survivals ranging from 4.8 years for RCC to .9 years for melanoma. Univariate analysis demonstrated a survival disadvantage for patients with perineural (hazard ratio [HR] = 5.4, P = .004) and vascular invasion (HR = 4.4, P = .002). The most commonly resected metastatic lesion of the pancreas was RCC. Eighteen of the 23 patients with RCC had a metachronous lesion with a median length between initial operation and pancreatic resection of 9.3 years. Metachronous lesions had a survival similar to that of synchronous lesions (HR = 1.0, P = .98). Vascular invasion (HR = 2.4, P = .007) and lymph node metastases (HR = 24.1, P = .01) were associated with greater mortality. Conclusion  Long-term survival can be achieved in patients undergoing resection of isolated metastases to the pancreas. Presented at the Society of Surgical Oncology Annual Cancer Symposium, Chicago, Illinois, March 13–16, 2008.     

20 Years Experience of TNF-Based Isolated Limb Perfusion for In-Transit Melanoma Metastases: TNF Dose Matters

Background  

Approximately 5–8% of melanoma patients will develop in-transit metastases (IT-mets). Tumor necrosis factor-α (TNF) and melphalan-based isolated limb perfusion (TM-ILP) is an attractive treatment modality in melanoma patients with multiple IT-mets. This study reports on a 20 years experience and outlines the evolution and major changes since the introduction of TNF in ILP.