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.

Pazolimus: pazopanib plus sirolimus following progression on pazopanib, a retrospective case series analysis.

BACKGROUND: To explore the activity of pazopanib (P) + sirolimus (S) in patients who progressed after previous clinical benefit on pazopanib. METHODS: Eight patients with progressing metastatic high grade soft tissue sarcoma (STS) whose disease advanced on P following a response duration of at least 4 months were offered re-challenge of P supplemented by off-label S and a single patient with progressing metastatic chondrosarcoma was offered the combination as compassionate treatment. Patients were treated in two centers: Hadassah Medical Center and Tel Aviv Medical Center. Patients received oral P 200-600 mg once a day supplemented by S 3-4 mg taken separately, 12 h after the P dose. RESULTS: Patients received treatment from December 2012 to February 2016. Four progressed on the combination and their treatment was terminated. Two patients were undergoing treatment when data was summarized. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: one partial response (PR), four stable disease (SD), and four progressive disease (PD), corresponding to five PR and four PD on the Choi criteria. Median progression free survival was 5.5 months (range 4-17). CONCLUSIONS: Our series showed that the combination of P + S has activity in STS patients selected by previous response to P and in a patient with chondrosarcoma, suggesting this can serve as a mechanism to reverse resistance to P and extend the chemotherapy-free window.

Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.

Synovial sarcoma of the extremities and trunk: a long-lasting disease.

Synovial sarcoma (SS) of an extremity or trunk is relatively rare and is approached by limb sparing surgery (LSS), radiation therapy (RT) and chemotherapy. We conducted a retrospective analysis of the clinical and histopathological data of 73 patients with proven SS. At a median follow-up time of 6 years, local recurrence was seen in 17.8 and systemic recurrence 35.6% of patients (local-only, 6.8; systemic-only, 24.6; combined, 11%). The 10-year local recurrence-free survival (LRFS), systemic recurrence-free survival (SRFS) and overall survival (OS) rates were 78, 68 and 61%, respectively. LRFS was significantly better in patients treated with isolated limb perfusion (ILP); SRFS was influenced by the delay until diagnosis. The practical aspects of our observations are the need for long-term follow-up in order to diagnose recurrences, the fact that not all local or distant recurrences are necessarily associated with a shortening of OS time and the important role of induction ILP with TNF in cases of extremity SS.

Decreased prevalence of asymptomatic choroidal metastasis in disseminated breast and lung cancer: argument against screening.

AIM: To determine the frequency of visually asymptomatic choroidal metastases in patients with disseminated breast and lung carcinomas in order to establish optimal patient management policies. METHODS: All patients with confirmed metastatic disease treated in our institution between January 2002 and December 2003 were invited to undergo a funduscopic examination and a B-scan ultrasound evaluation. RESULTS: Of the 169 study participants, 77 had breast cancer (64 with metastases in one organ and 13 with multiple-organ involvement) and 92 had lung cancer (85 with metastases in one organ and 7 with multiple-organ involvement). No patient with metastatic breast cancer and two patients with metastatic lung disease (each with multiple-organ involvement) were found to have choroidal metastases. The choroidal metastases were detected by both the funduscopic and ultrasound examinations. CONCLUSIONS: The 2.17% incidence of choroidal metastasis in disseminated lung cancer and the 0% incidence in disseminated breast cancer speaks against the practicality of screening for early detection of choroidal metastasis among these patients, even though it would lead to early implementation of appropriate, often vision saving, therapeutic management. Its low incidence probably testifies to progress achieved by enhanced systemic oncological treatment policies that have been introduced into routine patient management over the past few years.

Liposarcoma in adult limbs treated by limb-sparing surgery and adjuvant radiotherapy.

Between December 1995 and March 2003, 38 adult patients with intermediate or high-grade liposarcoma in a limb were treated by limb-sparing surgery and post-operative radiotherapy. The ten-year local recurrence-free survival was 83%, the ten-year metastasis-free survival 61%, the ten-year disease-free survival 51% and the ten-year overall survival 67%. Analysis of failure and success showed no association with the age of the patients, gender, the location of the primary tumour, the type of liposarcoma and the quality of resection. Our results indicate that liposarcoma may recur even ten years after the end of definitive therapy and may spread to unexpected sites as for soft-tissue sarcoma.

Induction of apoptosis in non-small lung carcinoma cell line (H1299) by combination of anti-asthma drugs with gemcitabine and cisplatin.

Gemcitabine and cisplatin are commonly used in chemotherapy, however, these drugs may cause severe cytotoxic side effects. Theophylline and aminophylline are commonly used as anti-asthma drugs and can block anti-phosphodiesterase activity. We examined whether these methylxanthins could effect lung cancer cell survival and synergise with gemcitabine and cisplatin to induce apoptosis. We found that theophylline induced apoptosis in the cultured H1299 cell line already at concentrations of 30 microg/ml, reaching an ED50% at 100 microg/ml. In contrast, aminophylline induced apoptosis at concentrations of 300 microg/ml and 17% apoptosis was evident at concentrations as high as 900 microg/ml, which is a lethal dose for in vivo treatment. Cisplatin induced apoptosis with ED50% of 0.8 microg/ml, while gemcitabine induced apoptosis with ED50% of 20 ng/ml. Using a combination of 20 microg/ml of theophylline (calculated as an effective but not toxic anti-asthma drug) with 10 ng/ml gemcitabine or with 0.3 microg/ml cisplatin significantly elevated incidence of apoptosis compared to gemcitabine or cisplatin alone at similar concentrations. In contrast, an observed synergistic effect between aminophylline and gemcitabine was evident only at concentrations of 80 microg/ml and 10 ng/ml respectively. However, no effect was apparent in combination doses of aminophylline (80 microg/ml) with cisplatin (0.3 microg/ml). The combined treatments involved reduction in the intracellular level of the anti-apoptotic Bcl-2 gene product. This corresponded with the extent of apoptosis induced by the various drug combinations. Thus, theophylline is significantly more effective than aminophylline in increasing the sensitivity of the H1299 lung cancer cells to the induction of cell death by gemcitabine and cisplatin. Thus, combination of theophylline with these drugs may permit a reduction in the effective dose needed in chemotherapy treatment of lung cancer patients.

Interferon-related mental deterioration and behavioral changes in patients with renal cell carcinoma.

Five out of 38 patients (13%) with metastatic renal cell carcinoma had mental deterioration 3 weeks to 13 months after the start of treatment with recombinant interferon alpha-C. Metastatic spread to the brain, paraneoplastic effect of the tumor on the central nervous system and other causes of dementia were excluded. Computed tomography of the brain in these patients was normal and the width of the cerebral sulci and ventricles did not correlate with the severity of dementia. Specific patterns of atrophy were not seen. General deterioration, assessed by the change in Karnofsky performance status, was associated with dementia. The dementia may have been caused by a neurotoxic effect of interferon.

Serial serum MCA measurements in the follow-up of breast cancer patients.

Mucin-like carcinoma-associated antigen (MCA) was serially assayed in 58 women with histologically proven breast cancer after their treatment for primary disease. MCA sensitivity and specificity were 87.5% and 76.9%, respectively, and the positive predictive value 82.4%. 10 patients had elevated MCA and no evidence of disease (NED) during their follow-up, of whom 4 finally developed overt metastases. The 4 had a mean (S.D.) MCA value of 46.48 (18.26) U/ml during the lead time, versus 18.76 (2.69) U/ml in the other 6, who are still at high risk for developing overt metastases. Raised levels of MCA in patients with NED create a dilemma of "treat" versus "wait and see". Early treatment of patients with serially uprising MCA levels should be evaluated in a prospective randomised study to assess its ability to prevent or delay the development of overt metastatic disease and influence survival.

ErbB-4 expression in limb soft-tissue sarcoma: correlation with the results of neoadjuvant chemotherapy.

ErbB-4 is a recently described growth factor receptor. Relatively little is known about its expression in human tumours. In this study, we assessed the possible role of erbB-4 as a tissue marker for soft-tissue sarcomas (STS) and its correlation with the response to chemotherapy. The histological specimen of 29 patients with STS of a limb who had received preoperative doxorubicin (ADR)-based chemotherapy were studied for the degree of necrosis and the expression of erbB-4 (by an avidin-biotin-peroxidase technique). ErbB-4 expression in the preoperative tissue samples was compared with the expression in the postchemotherapy resected tumour. The true objective response rate to preoperative chemotherapy was 34%. Wide resection of the tumour was done in 12 patients, marginal in 14, amputation in 2 and no surgery in 1. The tumour necrosis was above 90% in 9 patients, 60-90% in 12, and less than 60% in 7 patients. An increase in erbB-4 expression was more common in cases with no response to chemotherapy, while no change or a decrease in erbB-4 was more common in responsive tumours (P=0.004). No correlation could be found between the degree of necrosis or the chemotherapeutic regimen and the change in expression of erbB-4. The median disease-free survival (DFS) was longer for patients with a decrease or no change in expression of erbB-4 than for patients with increased expression. It is believed that postchemotherapy new expression or no downregulation of the erbB-4 molecule represents tumour aggressiveness and increased capability of growth and spread.

Postoperative high dose-rate intravaginal brachytherapy combined with external irradiation for early stage endometrial cancer: a long-term follow-up.

PURPOSE: To evaluate the long-term control of disease and cure rate, complications, second malignancy, and survival of early-stage endometrial cancer patients treated with surgery, high dose-rate brachytherapy, and external beam radiation therapy. METHODS AND MATERIALS: From 1969 through 1979, 300 patients with clinically staged Stage I-II endometrial cancer underwent total abdominal hysterectomy and bilateral salpingo-oopherectomy, followed by high dose-rate intravaginal radiation, 7 Gy x 3 to 0.5 cm from the mucosal surface, using a remote afterloading technique. External beam radiation therapy, 40 Gy to midplane in 4 weeks, was delivered to high risk patients through AP/PA and lateral fields. RESULTS: The patients were followed for 5-24 years (median 12). The actuarial progression-free survival rate was 96.6%. Post-treatment grade 1-2 actuarial complication rate was 9.5%, including cystitis (4.5%), vaginal stenosis (2.5%), proctitis (1.5%), vaginal necrosis (0.5%), and partial bowel obstruction (0.5%). Neither grade 3-4 complications nor additional late complications were observed in any of our patients. Relapse rate was only 3.7%, of which 45.5% were local, 45.5% were distant, and 9% were mixed. All the patients with relapse were postmenopausal, age range of 58-77 years, with tumor grade 2-3 in 64%. Second primary cancer rate was 12.8% (mostly breast and colon). Factors that were associated with improved prognosis were young age, premenopausal, low grade, no extrauterine disease, and a histology of adenocarcinoma (adenocarcinoma with squamous metaplasia). CONCLUSION: High dose rate intravaginal radiation therapy combined with surgery and external beam radiation therapy achieved a high cure rate small number of minor complications. No long-term treatment-related complications were noted in any of the patients. This treatment combination may be safely applied to patients with early stage endometrial cancer.

Autoimmunity and cancer - Beneficial relationships.

Autoimmune diseases are the consequence of the immune system attack on the self. Autoimmunity, sometimes, is reflected through the production of autoantibodies to various self antigens leading to cellular malfunction or destruction. In the current study we employ such autoantibodies for the treatment of cancer originated from the respective normal cells. This concept is wide and entails many autoimmune disorders and diversity of malignant conditions. To illustrate the therapeutic and practical potential we depicted four examples: vitiligo and melanoma - vitiligo is considered dermatologic autoimmune disorder presented as depigmented skin areas. The destruction of the pigmented cells (melanocytes) is mediated by autoantibodies. We have purified these anti-melanocyte antibodies from patients with vitiligo and showed their cytotoxic effect towards malignant melanoma cells in vitro and in vivo; anti-phospholipid syndrome (APLS) and cancer-cancer cells differ from normal cells by the expression of phosphatydilserine (PS) on their outer membrane surface. We have used such anti-PS autoantibodies, derived from patients with APLS, as effective treatment for melanoma in a murine system; Autoimmune hemolytic anemia (AIHA) and hematological malignancies - in patients with AIHA, the red blood cells (RBC) destruction is mediated by binding of autoantibodies to RBC. We have shown the specific binding of these anti-RBC autoantibodies to RBC and to malignant cells of the erythroid lineage. Thus, these autoantibodies may have diagnostic/therapeutic potential for conditions such as erythroleukemia and polycythemia vera; anti-lymphocyte antibodies and lymphoproliferative diseases - in SLE and other systemic autoimmune conditions autoantibodies directed against lymphocytes can be found. These cytotoxic antibodies can be targeted against lymphocytes of lymphoproliferative diseases such as chronic lymphocytic leukemia, or lymphoma. The diversity of autoimmune diseases provides a great source for human preformed highly specific autoantibodies which can be used as an effective immunotherapy by themselves, for diagnostic purposes, as a cell specific carrier conjugated to other cytotoxic agents and in combined therapy in the combat against cancer.

Postoperative 5-fluorouracil plus levamisole combined with radiation therapy for high risk rectal cancer patients.

Adjuvant chemotherapy in rectal cancer patients is aimed at decreasing the relapse rate of the disease, increasing the disease-free and the overall survival of the patients. The combinations of radiation therapy and several drugs have been tested, but the efficacy of 5-fluorouracil plus levamisole in rectal cancer is not determined yet. Sixty-two consecutive Dukes' B2 or C rectal cancer patients were enrolled into a prospective phase II study. Within 4 to 6 weeks following en-block resection of the tumor and lymphatics, adjuvant chemotherapy had to be started. Combination of 5-FU 375 mg/m(2)/day was given intravenously over 15-20 min for 5 consecutive days, every 4 weeks for 1 year. Levamisole 50 mg t.i.d. was administered orally during the first 3 days of each course of chemotherapy. Radiation therapy included 50 Gy, given by a linear accelerator 8 MV, to a pelvic BOX field. Dose per fraction was 1.8-2.0 Gy daily, administered for 5 consecutive days a week. Follow-up time of the whole group ranges from 7 to 53 months (median 18). Failure rate was 32.3%. The most common site for first relapse was the liver followed by recurrence in the pelvis or the surgical bed. Age, sex, tumor grade and number of involved lymph nodes were not associated with rate nor with site of relapse. Fifty-five percent of the relapses were observed in patients during the year of the adjuvant treatment. Toxicity included diarrhea (33.9%), nausea and vomiting (19.4%), weakness and mucositis. The disease-free survival rate for a median follow-up of 18 months in our study is 75%. The 3.5 year disease-free survival is 67% for the whole group. Our phase II study results point to the feasibility and acceptable toxicity of post-operative combination of 5-FU plus low-dose levamisole and radiation therapy in rectal cancer patients.

Mononuclear cells release low molecular weight factors with anti-cancer activity: A lower level of production by cells of cancer patients.

Following the clinical observations that tumor metastases are extremely rare in striated muscles we defined recently a low molecular weight factor which is released by muscle cells (muscle factor, MF) and possesses specific anti-proliferative activity against tumor cells. we demonstrate that peripheral blood mononuclear cells constitutively release low molecular weight factor (LMF) similar to the MF which is capable of inhibiting in vitro the proliferation of carcinoma, melanoma, leukemia and lymphoma cell lines. The proliferation of normal cells such as bone marrow or fibroblasts was not inhibited but slightly stimulated following incubation with the LMF. Biochemical purification of this factor by several HPLC steps revealed that the inhibitory activity against tumor cells was concentrated within two definitive peaks. The LMF affects tumor cell growth by arresting them in the G0/G1 of the cell cycle and its activity is species and tumor non-specific. In vivo studies in melanoma- bearing mice revealed that the LMF inhibited melanoma growth when given either intraperitoneally or orally. Mononuclear cells from cancer patients with different malignancies (non-Hodgkin lymphoma, malignant melanoma, colon carcinoma and carcinoma of the rectum) secreted lower level of LMF in comparison to healthy subjects. The capability of the LMF to inhibit tumor cell growth and promote normal cell proliferation combined with its bioavailability in vivo may lead to its potential therapeutic and diagnostic use.