Alon Ben-Nun

Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients

Purpose: Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) has shown promising results in metastatic melanoma patients. Although objective response rates of over 50% have been reported, disadvantages of this approach are the labor-intensive TIL production and a very high drop-out rate of enrolled patients, limiting its widespread applicability. Previous studies showed a clear correlation between short TIL culture periods and clinical response. Therefore, we used a new TIL production technique using unselected, minimally cultured, bulk TIL (Young-TIL). The use of Young-TIL is not restricted to human leukocyte antigen (HLA)-A2 patients. The purpose of this study is to explore the efficacy and toxicity of adoptively transferred Young-TIL following lympho-depleting chemotherapy in metastatic melanoma patients, refractory to interleukin-2 and chemotherapy. Experimental Design: Young-TIL cultures for 90% of the patients were successfully generated, enabling the treatment of most enrolled patients. We report here the results of 20 evaluated patients. Results: Fifty percent of the patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including two ongoing complete remissions (20+, 4+ months) and eight partial responses (progression-free survival: 18+, 13+, 10+, 9, 6+, 4, 3+, and 3 months). All responders are currently alive. Four additional patients showed disease stabilization. Side effects were transient and manageable. Conclusion: We showed that lympho-depleting chemotherapy followed by transfer of short-term cultured TIL can mediate tumor regression in 50% of metastatic melanoma with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major effect on cell therapy of cancer. Clin Cancer Res; 16(9); 2646–55. ©2010 AACR.

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.

Video-Assisted Thoracoscopic Surgery for Recurrent Spontaneous Pneumothorax: The Long-term Benefit

BackgroundManagement of recurrent primary spontaneous pneumothorax by open surgery was considered the treatment of choice until recently. The major drawbacks of this management are the prolonged postoperative pain and cosmetic results. In the last decade, video-assisted thoracoscopic surgery (VATS) has replaced the routine use of open surgery. Most papers that compared limited open surgery to VATS addressed the early postoperative results, and studies that assessed the long-term results focused primarily on the rate of recurrence and pulmonary function tests. The aim of this study was to compare the outcome of minithoracotomy and VATS with emphasis on patients’ long-term, subjective perspective and satisfaction.MethodsMedical records of patients with recurrent primary spontaneous pneumothorax were retrospectively reviewed. Patients who underwent surgical treatment by limited thoracotomy (63 patients) or VATS (58 patients) more than 3 years ago were enrolled. Hospital medical charts were used to compare the early postoperative results. Outpatient clinic records and a telephone questionnaire were employed to evaluate long-term results.ResultsThere was no mortality or major morbidity in either group, and hospitalization time was similar. Patients in the thoracotomy group needed significantly higher doses of narcotic analgesia for a longer period. There were two cases of recurrence in the VATS group (3%). Seventy-eight percent of patients in the VATS and 21% in the thoracotomy group classified their pain as insignificant a month following the operation (P < 0.05). Three years following surgery, 97% of the VATS group patients considered themselves completely recovered from the operation compared with only 79% in the thoracotomy group (P < 0.05). Nineteen percent of the thoracotomy group and 3% of the VATS group suffered from chronic or intermittent pain necessitating use of analgesics more than once a month. Thirteen percent of patients from the open procedure group required services from the pain clinic. Patients in the VATS group were, in general, much more satisfied with their operation and with the surgical scars compared with patients from the thoracotomy group.ConclusionWe recommend video-assisted surgery as the first-line surgical treatment for patients with recurrent primary spontaneous pneumothorax. This recommendation is based on its somewhat favorable early postoperative course, the superior long-term outcome, and patient satisfaction.

Thoracic Endometriosis Syndrome is Strongly Associated With Severe Pelvic Endometriosis and Infertility

STUDY OBJECTIVE To evaluate the clinical and surgical features of thoracic endometriosis syndrome (TES) represented by catamenial pneumothorax and pelvic endometriosis and to describe their association with infertility. DESIGN Retrospective clinical study (Canadian Task Force classification: II-2). SETTING Academic tertiary referral endometriosis center. PATIENTS Seven patients who had undergone surgery because of thoracic and pelvic endometriosis between 2004 and 2010. INTERVENTIONS Thoracic and pelvic exploration and treatment and fertility treatment. MEASUREMENTS AND MAIN RESULTS Concurrently, thoracic and pelvic endometriosis, and subsequent fertility were determined during long-term follow-up after combined surgical and pharmacologic interventions. The most frequent thoracic finding was diaphragmatic implants. Except for 1 patient with recurrent pleurodesis at 1 month after video-assisted thoracoscopy, no patients experienced recurrence of thoracic symptoms during a median (range) follow-up of 31.4 (1-61) months. Severe pelvic endometriosis was diagnosed in 6 patients with notable urologic and gastrointestinal tract involvement. Only 1 patient with catamenial pneumothorax had no macroscopic pelvic lesions. There was a considerable delay between the onset of pelvic symptoms and diagnosis. Median postoperative follow-up was 31.5 (7-84) months. Most patients who tried to conceive had primary infertility. CONCLUSION Thoracic endometriosis syndrome, represented by catamenial pneumothorax, was strongly associated with severe pelvic endometriosis and a high rate of infertility. Inasmuch as many patients with thoracic endometriosis syndrome are treated by thoracic surgeons using video-assisted thoracoscopy, it is desirable to involve an experienced gynecologist who can diagnose and treat concurrent pelvic endometriosis.

Detection of Lung Cancer and EGFR Mutation by Electronic Nose System

Introduction: Early detection of lung cancer (LC) has been well established as a significant key point in patient survival and prognosis. New highly sensitive nanoarray sensors for exhaled volatile organic compounds that have been developed and coupled with powerful statistical programs may be used when diseases such as LC are suspected. Detection of genetic aberration mutation by nanoarray sensors is the next target. Methods: Breath samples were taken from patients who were evaluated for suspicious pulmonary lesions. Patients were classified as those with benign nodules, as patients with LC with or without the EGFR mutation, and according to their smoking status. Breath prints were recognized by nanomaterial‐based sensor array, and pattern recognition methods were used. Results: A total of 119 patients participated in this study, 30 patients with benign nodules and 89 patients with LC (16 with early disease and 73 with advanced disease). Patients with LC who harbored the EGFR mutation (n = 19) could be discriminated from those with wild‐type EGFR (n = 34) with an accuracy of 83%, sensitivity of 79%, and specificity of 85%. Discrimination of early LC from benign nodules had 87% accuracy and positive and negative predictive values of 87.7 and 87.5% respectively. Moderate discrimination (accuracy of 76%) was found between LC of heavy smokers and that of never‐smokers or distant past light smokers. Conclusions: Breath analysis could discriminate patients with LC who harbor the EGFR mutation from those with wild‐type EGFR and those with benign pulmonary nodules from those patients with early LC. A positive breath print for the EGFR mutation may be used in treatment decisions if tissue sampling does not provide adequate material for definitive mutation analysis.

Nonsteroidal Antiinflammatory Medications: Efficient and Safe Treatment Following Video-Assisted Pleurodesis for Spontaneous Pneumothorax

BackgroundRecurrent spontaneous pneumothorax is widely treated by video-assisted thoracoscopic (VATS) bullectomy and pleurodesis. Treatment of postoperative pain with nonsteroidal antiinflammatory drugs (NSAIDs) is controversial as many surgeons believe that it reduces the efficacy of pleurodesis and increases the pneumothorax recurrence rate.MethodsIn this retrospective study, we reviewed the hospital records for patients following VATS pleurodesis for recurrent spontaneous pneumothorax. The patients were divided into two groups: (1) NSAID group: patients were treated with NSAIDs for more than a week following surgery and (2) control group: patients did not receive NSAIDs. Data regarding short- and long-term outcomes were compared.ResultsThe study cohort included 105 patients: 48 in the NSAID group and 57 in the control group. During the early postoperative period the average daily requirement of narcotic analgesia and the incidence of narcotic-related side effects were lower in the NSAIDs group. No difference was found in the long-term recurrence rate: two of 48 (4%) in the NSAID group and three of 57 (5%) in the control group. There was one case of early recurrence in the NSAID group. Both groups had similar length of stay with no cases of mortality or major morbidity.ConclusionsNSAIDs for postsurgical pleurodesis pain obviates the need for narcotics without increasing the pneumothorax recurrence rate. Prospective randomized controlled studies are needed to further investigate this issue.

Fluorodeoxyglucose—positive internal mammary lymph node in breast cancer patients with silicone implants: is it always metastatic cancer?

OBJECTIVES Patients with breast cancer following mastectomy and silicone implant reconstruction may have enlarged internal mammary lymph nodes with pathological uptake on positron emission tomography with (18)F-fluorodeoxyglucose. This lymphadenopathy is usually considered as metastatic in nature, but has also been reported to be related to other conditions, including silicon migration. The purpose of this study was to determine the rate of metastatic disease in this unique group of patients. METHODS A retrospective comparative study of 12 female patients with breast cancer with silicone implants referred for biopsy due to isolated internal mammary lymph node fluorodeoxyglucose uptake on positron emission tomography. RESULTS Five patients (41.6%) had histological findings related to silicone (n = 4) or non-specific inflammation (n = 1). The remaining 7 (58.3%) had histological evidence of cancer recurrence. There was no significant difference in the fluorodeoxyglucose-standardized uptake value between the two groups. CONCLUSIONS Fluorodeoxyglucose-positive mammary lymph nodes in patients with breast cancer following silicone implant reconstruction may be due to metastatic deposits, non-specific inflammation or silicone migration. Clinical and imaging characteristics are insufficient in differentiating between these conditions. Biopsy is recommended prior to initiation of further treatment.

Electric Suction-Lavage Device for Video-Assisted Thoracoscopic Surgery Treatment of Empyema and Hemothorax

We describe the use of an electric trigger-controlled suction-lavage device for the evacuation of empyema or clotted hemothorax. Wound debridement systems provide efficient irrigation and debris removal. It is frequently used for orthopedic procedures or infected wound rinsing. Internet search of the literature did not result in any paper describing the use of this technique for thoracic surgery. We present our experience with an electrical wound-washing device in video-assisted thoracoscopic surgery for thoracic empyema or clotted hemothorax.

A simple method of using a foley catheter to drain pleural effusion

Pleural effusion is a common problem, and various techniques of pleural fluid drainage have been described. We report our experience of using a Foley-type catheter to drain pleural effusion. After the injection of local anesthesia, the catheter is inserted, usually through the 7th intercostal space, with the patient sitting upright. The size of the catheter is selected according to the predicted fluid characteristics, and ranges from 18 to 24 F. Once the catheter is positioned in the pleural space, the balloon is inflated with diluted soluble contrast material and connected to a urine collection bag. During the last 10 years, we have used 3500 catheters for this purpose. The catheter site can be used as a port for various procedures, including needle biopsy of the parietal pleura, talc-slurry pleurodesis, and intra-pleural fibrinolysis. This method of pleural drainage is simple, reliable, and inexpensive.

Focal fluorine-18 fluorodeoxyglucose-avid parotid findings in patients with lung cancer: prevalence and characteristics.

ObjectiveCorrect interpretation of incidental tumors is important to plan an appropriate treatment. We assessed the incidence and imaging characteristics of fluorine-18 fluorodeoxyglucose (18F-FDG)-avid focal parotid findings (FPFs) in patients with lung cancer. Patients and methodsFPFs in PET-computed tomography reports of cancer patients were searched. Those with known parotid malignancies, lymphoma, and diffuse 18F-FDG uptake in the entire parotid gland were not included in the analysis. ResultsFPFs were detected in 38/3120 cancer patients (1.23%), observed as a soft tissue mass with a mean diameter 1.6±0.5 cm (range 0.8–2.7 cm) and a mean maximum standardized uptake value of 7.7±3.7 (range 2.5–17.8). FPFs were observed in 23/604 (3.8%) patients with lung cancer, compared with 6/1366 (0.4%) with breast cancer and 5/842 (0.6%) with gastrointestinal malignancies. We assessed FPFs appearances in 23 patients with lung cancer (18 men, mean age 72.8±9.2); 20 (87%) were current or past smokers. There was no correlation between the stage or histopathological type of the lung cancer and the prevalence of parotid lesions. In four patients with histopathology, no malignancy was detected. For an additional 11 patients with available imaging and clinical follow-up (mean follow-up 15.5±13.5 months, range 3–42 months), FPFs were consistent with benign lesions. ConclusionFPFs were more prevalent among patients with lung cancer than in patients with other malignancies. As 18F-FDG avidity was moderate to high, FPFs may mimic distant metastases. It is important to consider FPFs in the interpretation of a focal parotid lesion as misinterpretation may result in denial of appropriate therapy.