Phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (cKS).

BACKGROUND: Classical Kaposi sarcoma (cKS) is a rare human herpesvirus 8-associated sarcoma with limited treatment options. We evaluated the efficacy and safety of nivolumab in combination with ipilimumab in patients with previously treated progressive cKS. PATIENTS AND METHODS: cKS patients with progressive disease after one or more lines of systemic therapy and measurable disease by positron emission tomography/computed tomography and/or physical examination received nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until progression or toxicity for a maximum of 24 months. The primary endpoint was overall response rate; secondary endpoints included 6-month progression-free survival (PFS) rate and safety. Immune correlates were explored using immunohistochemistry, DNA sequencing (596/648 genes) and RNA sequencing (whole transcriptome hybrid capture) of tumor specimens and matched blood. RESULTS: Eighteen male patients (median age 76.5 years) were enrolled between April 2018 and December 2020. At a median follow up of 24.4 months, overall response rate by RECIST v1.1 was 87%. Metabolic complete response as assessed by positron emission tomography/computed tomography was observed in 8 of 13 (62%) assessable patients. Some 6/13 achieved pathological complete response after treatment. In two patients, palliative limb amputation was prevented. Median PFS was not reached. The 6- month and 12-month PFS rate was 76.5% and 58.8%, respectively. Only four patients (22%) experienced grade 3-4 adverse events. The most frequent genomic alteration was biallelic copy number loss of the FOX1A gene. The majority of tumors carried a low tumor mutational burden, were microsatellite stable, mismatch repair proficient, did not express programmed death-ligand 1, and displayed only low lymphocytic infiltrates, rendering them immunologically 'cold'. CONCLUSIONS: This prospectively designed phase II study of nivolumab and ipilimumab demonstrates promising activity of this combination in progressive cKS representing a new treatment option in this population.

Pancreatic panniculitis and carcinoma of the pancreas.

Pancreatic panniculitis is a rare complication of carcinoma of the pancreas, most often accompanying the rare acinar cystadenocarcinoma. It presents with painful erythematous subcutaneous nodules typically located on the leg. We present a case of a 79-year-old man with neuroendocrine carcinoma of the pancreas and liver metastasis, who developed painful subcutaneous nodules on his shins. Laboratory values included a raised lipase level with normal amylase level and peripheral eosinophilia. The patient was treated with nonsteroidal anti-inflammatory drugs, dexamethasone and antibiotics, with resolution of the dermatological symptoms.

Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients.

BACKGROUND: Exclusive liver metastases occur in up to 40% of patients with uveal melanoma associated with a median survival of 2-7 months. Single agent response rates with commonly available chemotherapy are below 10%. We have investigated the use of fotemustine via direct intra-arterial hepatic (i.a.h.) administration in patients with uveal melanoma metastases. PATIENTS AND METHODS: A total of 101 patients from seven centers were treated with i.a.h. fotemustine, administered intra-arterially weekly for a 4-week induction period, and then as a maintenance treatment every 3 weeks until disease progression, unacceptable toxicity or patient refusal. RESULTS: A median of eight fotemustine infusions per patient were delivered (range 1-26). Catheter related complications occurred in 23% of patients; however, this required treatment discontinuation in only 10% of the patients. The overall response rate was 36% with a median overall survival of 15 months and a 2-year survival rate of 29%. LDH, time between diagnosis and treatment start and gender were significant predictors of survival. CONCLUSIONS: Locoregional treatment with fotemustine is well tolerated and seems to improve outcome of this poor prognosis patient population. Median survival rates are among the longest reported and one-third of the patients are still alive at 2 years.

Effects of cisplatin on olfactory function in cancer patients.

A prospective analysis of olfaction was performed in 21 patients receiving cisplatin. A reduction in olfactory function was noted in only one patient. Hearing impairment was documented in nine patients, none of whom had impaired sense of smell. We conclude that cisplatin has no major deleterious effect on olfactory function at doses which cause hearing impairment.

Targeting pulmonary metastases of renal cell carcinoma by inhalation of interleukin-2.

INTRODUCTION: Pulmonary metastases of renal cell carcinoma (RCC) are associated with poor prognosis. Inhalation therapy with interleukin-2 (IL-2) is thus an appealing method for palliation. This multicenter study summarizes the national experience of IL-2 inhalation in patients with lung metastases of RCC. PATIENTS AND METHODS: Forty patients (median, 66.5 years of age) with radiologically documented progressing pulmonary metastases were enrolled. All patients had to be able to comply with inhalation technique, and were not candidates for other treatment options. Twenty-eight patients were systemic treatment-naïve. The protocol included three daily inhalations of IL-2 to a total dose of 18 MU. Treatment had to be continued until one of the following occurred: progression; a complete response; a life threatening toxicity; or patient refusal. Response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) system. RESULTS: The disease-control rate reached 57.5%, with a partial response rate of 2.5% and a disease stabilization rate of 55%. Median time to progression was 8.7 months. The main side-effects were cough and weakness. CONCLUSIONS: Inhalation of IL-2 for the treatment of pulmonary metastases in RCC is feasible, tolerable and beneficial in controlling progressive disease for considerable periods of time. The definition of response of biological therapy may need to be re-assessed and modified: stable disease should be regarded as a favorable response.

Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma.

This paper is a report of response rate (RR) and survival of 34 metastatic melanoma patients who received a dinitrophenyl (DNP)-modified autologous melanoma cell vaccine. In all, 27 patients started the vaccine as a primary treatment for metastatic melanoma and seven started it as an adjuvant, with no evidence of disease at the time, but had developed new metastases. Interleukin-2 (IL-2) was administered in 24 out of the 34 patients: 19 who progressed on vaccine alone and five who had the combination from start. Interleukin-2 was administered in the intravenous, bolus high-dose regimen (seven patients) or as subcutaneous (s.c.) low-dose treatment (17). Overall response for the entire group was 35% (12 patients out of 34), 12% having a complete response (CR) and 23% a partial response (PR). However, only two patients had tumour responses while on the vaccine alone, whereas the other 10 demonstrated objective tumour regression following the combination with IL-2 (two CR, eight PR), lasting for a median duration of 6 months (range 3-50 months). Of the 12 responding patients, 11 attained strong skin reactivity to the s.c. injection of irradiated, unmodified autologous melanoma cells. None of the patients with a negative reactivity experienced any tumour response. Patients with positive skin reactions survived longer (median survival - 54 months). The results suggest enhanced RRs to the combination of IL-2 and autologous melanoma vaccine. Skin reactivity to unmodified autologous melanoma cells may be a predictor of response and improved survival, and therefore a criterion for further pursuing of immunotherapeutic strategies.

Pulmonary embolism-the initial manifestation of renal cell carcinoma in a young woman.

We report a case of massive pulmonary embolus demonstrated on CT in a young woman presenting with dyspnea, with no known risk factors for embolism. Abdominal CT on further investigation showed a renal tumor invading the left renal vein and the inferior vena cava as the cause of the pulmonary embolus. In a patient presenting with pulmonary artery embolism without venous thrombosis, the differential diagnosis should include an occult tumor as the cause of the embolus.

Autologous cell vaccine as a post operative adjuvant treatment for high-risk melanoma patients (AJCC stages III and IV). The new American Joint Committee on Cancer.

This study evaluates the overall survival and disease free survival of melanoma patients that were treated with an autologous melanoma cell vaccine, administered as a post-operative adjuvant. Included are 43 patients with totally resected metastatic melanoma (28-AJCC stage III, 15-AJCC stage IV), with a median follow up of 34 months (6-62). The treatment consisted of eight doses of a vaccine made of 10-25x10(6) autologous melanoma cells either released from the surgical specimen or grown in cell cultures. Tumour cells were conjugated with hapten dinitrophenyl, mixed with Bacille Calmette Guérin and irradiated to 110 Gy. Both disease free survival and overall survival were found to be correlated with intensity of evolving delayed type hypersensitivity to subcutaneous injection of unmodified melanoma cells. Patients with a delayed type hypersensitivity reaction of > or =10 mm had a median disease free survival of 17 months (mean 35 months) and a mean overall survival of 63 months (median not reached). In contrast, patients with a negative or weak delayed type hypersensitivity had a median disease free survival of 9 months (relative risk of recurrence=4.5, P=0.001), and a median overall survival of 16 months (relative risk of death=15, P=0.001). Stage III patients with a positive delayed type hypersensitivity reaction had an improved disease free survival of 16 months and a mean overall survival of 38 months, whereas patients with a negative delayed type hypersensitivity had a median disease free survival of 7 months (relative risk=4.5, P=0.02) and a median overall survival of 16 months (relative risk=9.5, P=0.005). The adjuvant administration of autologous melanoma vaccine was associated with improved disease-free and overall survival to selected patients who successfully attained anti-melanoma reactivity as detected by positive delayed type hypersensitivity reactions to unmodified melanoma cells.

[Testicular cancer--self-awareness and testicular self-examination in soldiers and physicians in the Israeli army].

Testicular cancer is the most common malignancy in young men. To evaluate knowledge and awareness of that cancer, and of the practice of testicular self-examination (TSE), we developed a questionnaire which was distributed to 717 male soldiers and 200 of their military physicians. 21% of the soldiers had received some explanation of the importance of TSE, but only 16% were actually instructed how to perform TSE, and only 2% practiced it regularly. 24% had never examined their testicles before, 185 only rarely, and 6% often. With increased age, TSE frequency increased, but previous education, type of military unit, and ethnic origin had no affect. 99% of military physicians had been taught how to examine breasts, but only 70% had been taught routine testicular examination. 22% performed it, but 27% never did. 84% had never taught their soldiers the importance of TSE, although 51% taught female soldiers breast self-examination. There was a significant lack of awareness of the importance of regular practice of TSE among both soldiers and their army physicians.

[Multidisciplinary approach to the treatment of musculo-skeletal tumors].

Tumors of the musculoskeletal system are relatively rare. They occur mostly in the young, while in older age groups metastases and myeloma are more prevalent. Treatment has undergone major change in the past 20 years with the introduction of neoadjuvant treatment protocols. According to recent reports 5-year survival rates have increased from 20% to 60-70%. These new protocols involve the use of modern imaging modalities, immunohistochemical pathological analysis and improved surgical technics. This has required establishment of multidisciplinary teams of experts to escort the patient through all the steps of current treatment.

Radiation pneumonitis complicating mediastinal radiotherapy postpneumonectomy.

Radiation pneumonitis is a well-characterized clinicopathological syndrome. The severity of radiation-induced lung injury correlates, among other factors, with the extent of lung volume incorporated within the field of radiation. The present article describes the cases of two patients with radiation pneumonitis following pneumonectomy and mediastinal radiotherapy. Postpneumonectomy pulmonary-mediastinal shift of the remaining lung towards the operated side, with inclusion of lung parenchyma within the "mediastinal" radiation portals, resulted in a substantial (albeit clinically unsuspected) radiation pneumonitis. Chest computed tomography in the postpneumonectomy patient may be helpful to evaluate the degree of pulmonary-mediastinal shift and optimization of the radiotherapy field.