Douglas Zippel

Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma: Intent-to-Treat Analysis and Efficacy after Failure to Prior Immunotherapies

Purpose: Adoptive cell transfer (ACT) using autologous tumor-infiltrating lymphocytes (TIL) was reported to yield objective responses in about 50% of metastatic patients with melanoma. Here, we present the intent-to-treat analysis of TIL ACT and analyze parameters predictive to response as well as the impact of other immunotherapies. Experimental Design: Eighty patients with stage IV melanoma were enrolled, of which 57 were treated with unselected/young TIL and high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting conditioning. Results: TIL cultures were established from 72 of 80 enrolled patients. Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation. The overall response rate and median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2 months for treated patients. Five patients achieved complete and 18 partial remission. All complete responders are on unmaintained remission after a median follow-up of 28 months and the 3-year survival of responding patients was 78%. Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days of TIL in culture, and the total number of infused CD8+ cells as independent predictive markers for clinical outcome. Thirty-two patients received the CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the same overall response rate to ACT as other patients receiving TIL. No additional toxicities to TIL therapy occurred following ipilimumab treatment. Conclusion: Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed. Clin Cancer Res; 19(17); 4792–800. ©2013 AACR.

Sentinel lymph node involvement a predictor for axillary node status with breast cancer has the time come

AIMS Axillary node dissection for breast cancer is important for staging and its prognostic value. Sentinel nodes are defined as the first nodes into which the primary cancer drains. This study investigates whether identification, removal and pathological examination of these nodes indicates whether the completion of axillary lymphadenectomy is required. METHODS Using a vital dye injected at the primary tumour site, we were able to identify sentinel nodes in 96 out of 98 women examined. RESULTS An average number of 2.7 +/- 1.2 nodes per patient were identified as sentinel nodes. In 83% of cases there was a correlation between the involvement of the sentinel nodes and the rest of the axillary nodes. In 14% of patients the sentinel nodes were the only nodes involved with tumour. In three cases the sentinel nodes were negative, but other axillary nodes were tumour-positive. CONCLUSION The major problem in routine application of this method to the decision to perform axillary lymph node dissection (ALND) is the time needed for pathological identification of lymph node involvement by tumor.

Establishment and large-scale expansion of minimally cultured young tumor infiltrating lymphocytes for adoptive transfer therapy

Treatment of metastatic melanoma patients with adoptively transferred tumor infiltrating lymphocytes (TIL) has developed into an effective therapy. Various studies reported objective responses of 50% and more. The use of unselected, minimally cultured, bulk TIL (Young-TIL) has simplified the TIL production process and may therefore, allow the accessibility of this approach to cancer centers worldwide. This article describes the precise process leading to the large-scale production of Young-TIL for therapy. We have enrolled 55 melanoma patients and optimized their Young-TIL generation process. Young-TIL cultures were successfully established for 51 of 55 (93%) patients in 16.7±5.5 days. In a large-scale expansion procedure Young-TIL of 32 patients were further expanded to treatment levels, resulting in a final number of 4.5×1010 ±2.0×1010 TIL. Fifteen of 31 (48%) patients, who were evaluated, achieved a clinical response, including 4 complete and 11 partial responses. We confirmed the significant correlation between short culture duration, high number of infused cells, and tumor regression. A high percentage of CD8+ T cells in the infusion product was beneficial to achieve an objective response. All responding patients were treated with Young-TIL cultures established in <20 days. In summary, we describe here an efficient and reliable method to generate Young-TIL for adoptive transfer therapy, which may easily be adopted by other cancer centers and can lead to objective responses in 50% of refractory melanoma patients. In the future this approach may be used also in other types of malignancies.

Timing of sentinel lymph node biopsy in patients receiving neoadjuvant chemotherapy for breast cancer.

To address optimal timing of sentinel lymph node biopsy (SLNB) in breast cancer patients undergoing neoadjuvant treatment.

Positive margins of breast biopsy: Is reexcision always necessary?

Breast‐conserving surgery requires excision of all gross tumor and subsequent radiation therapy. It is generally accepted that the presence of microscopically positive margins requires reexcision. The goal of this study was to identify characteristics that distinguish breast biopsy specimens with positive margins that when reexcised are free from residual tumor. This population of patients may benefit from breast irradiation only, without the need for another surgical procedure.

Appendiceal carcinoid at a large tertiary center: pathologic findings and long-term follow-up evaluation

BACKGROUND Appendiceal carcinoid tumor is the most common type of primary appendiceal malignant lesion. Nonetheless; it is an exceedingly rare diagnosis; found in only about .3% to .9% of appendectomy specimens. We report the clinical and pathologic characteristics of carcinoids found with long-term follow-up evaluation. METHODS Data of patients who were histologically reported to have carcinoid tumor of the appendix; in a single center; during a 16-year period were collected retrospectively. In addition; patients were contacted for current follow-up information. RESULTS A total of 44 patients were diagnosed with appendiceal carcinoid during the study period. The median follow-up period for the cohort was 7 years. No evidence of any recurrent disease or other noncarcinoid neoplasm was found. CONCLUSIONS Our data confirm the good prognosis as seen in earlier reports. The long-term significance of having a carcinoid; and whether this poses a risk for future neoplasms; need even longer-term studies.

Aprotinin improves hemostasis after cardiopulmonary bypass better than single-donor platelet concentrate

Platelet transfusion and aprotinin administration improve platelet function and clinical hemostasis after extracorporeal circulation. To compare two methods of improving postoperative hemostasis, we preoperatively randomized 40 patients undergoing various open heart procedures into two groups. Group A included 20 patients who, immediately after bypass, received single-donor plateletpheresis concentrates collected from ABO-compatible donors (Baxter Autopheresis-C System). They were compared with 20 patients who received high-dose aprotinin (6 x 10(6) KIU) before and during cardiopulmonary bypass (group B). Group A patients showed significantly higher platelet count after single-donor plateletpheresis concentrate transfusion (157 +/- 36 x 10(9)/L compared with 118 +/- 42 x 10(9)/L (p < 0.05). However, platelet aggregation on extracellular matrix was better in group B (3.4 +/- 0.7 versus 2.8 +/- 0.9; p < 0.05). Total 24-hour blood loss and exposure to homologous blood products were significantly less in group B (396 +/- 125 mL and 1.1 +/- 1.6 units compared with 617 +/- 233 mL and 5.4 +/- 3.4 units; p < 0.01). Despite higher platelet count in patients after single-donor plateletpheresis concentrates transfusion, hemostasis in patients receiving aprotinin is better due to improved platelet function.

Retrievable Vena Cava Filters in Major Trauma Patients: Prevalence of Thrombus Within the Filter

The purpose of this study was to report the prevalence of thrombus within a retrievable vena cava filter inserted prophylactically in major trauma patients referred for filter extraction. Between November 2002 and August 2005, 80 retrievable inferior vena cava filters (68 Optease and 12 Gunther-Tulip) were inserted into critically injured trauma patients (mean injury severity score 33.5). The filters were inserted within 1 to 6 (mean 2) days of injury. Thirty-seven patients were referred for filter removal (32 with Optease and 5 with Gunther-Tulip). The indwelling time was 7 to 22 (mean 13) days. All patients underwent inferior vena cavography prior to filter removal. There were no insertion-related complications and all filters were successfully deployed. Forty-three (54%) of the 80 patients were not referred for filter removal, as these patients continued to have contraindications to anticoagulation. Thirty-seven patients (46%) were referred for filter removal. In eight of them (22%) a large thrombus was seen within the filters and they were left in place, all with the Optease device. The other 29 filters (36%) were removed uneventfully.We conclude that the relatively high prevalence of intrafilter thrombi with the Optease filter may be explained by either spontaneous thrombus formation or captured emboli.

Freehand Elastography for Determination of Breast Cancer Size Comparison With B-Mode Sonography and Histopathologic Measurement

Elastography assesses the strain of soft tissues and is used to enhance diagnostic accuracy in evaluating breast tumors, but minimal data exist on its ability to accurately assess tumor size. This study was performed to assess the preoperative accuracy of measuring the size of biopsyproven breast cancer lesions with elastography and conventional B‐mode sonography compared with the reference standard size measured by histopathologic examination.

A longitudinal study of CEACAM1 expression in melanoma disease progression

The present study characterized the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression profile in a longitudinal study during melanoma progression, in lesions obtained from the same patients: a primary skin lesion, a lymph node and a distant metastasis. The present study is expected to increase our understanding of the expression patterns of CEACAM1 in melanoma development. We identified 20 patients who could be analyzed for CEACAM1 expression over the course of disease progression. The pathology blocks were cut, and two slides were generated for each specimen. One underwent standard hematoxylin and eosin (H&E) staining and a corresponding slide underwent immunohistochemical staining for the detection of CEACAM1. For 13 patients who were able to be followed up serially from primary lesion, lymph node and distant metastasis, a borderline significant increase in the staining of the membrane was noted (P=0.06). In contrast, there was no equivalent increase in cytoplasmic CEACAM1 in the same group of patients. For the cohort of 20 patients with primary and distant metastasis, a significant increase in the membrane staining was noted (P=0.026) and again, no equivalent significant increase in cytoplasmic staining was observed. We report that CEACAM1 expression increases along the course of disease development and progression of a patient. CEACAM1 represents a novel area of research which may have profound influence in future methods of harnessing cellular immunity to combat this disease. The results of the present study confirm that CEACAM1 is potentially an extremely useful target in arresting melanoma progression.