Impact of radiotherapy on survival in resected or unresectable anaplastic thyroid carcinomas, a Rare Cancer Network study.

PURPOSE: Anaplastic thyroid carcinomas (ATC) are a heterogenous group of tumors of overall dismal prognosis. We designed models to identify relevant prognostic factors of survival of irradiated ATC patients including radiotherapy modalities (field size, dose). MATERIAL AND METHODS: Between 2000 and 2017, 166 ATC patients' treatments were divided into surgery and postoperative radiotherapy (poRT) or definitive radiotherapy (RT). Multiple imputation approach was used for missing data. Prognostic factors were identified using Lasso-penalized Cox modelling and predicted risk scores were built. RESULTS: Patients undergoing RT (n=70) had more adverse patient and disease characteristics than those undergoing poRT (n=96). Corresponding median survival rates were 5.4 and 12.1 months, respectively. PoRT patients undergoing poRT more likely received extended-field radiotherapy with prophylactic nodal irradiation, but rather received platinum- vs. adriamycin-based chemoradiotherapy. Radiotherapy was conventionally fractionated, delivered >60Gy in 51.9% and 61.7% and used extended fields in 88.5% and 71.2% of patients with poRT or RT. Radiotherapy interruption rates for toxicity were similar in the two groups. The best poRT-group model identified age>45yo, PS≥1, pathologic tumor stage≥pT4b,>N1 and R2 resection as poor prognostic factors. The best RT-group model (C-index of 0.72) identified PS≥3,>N1 and extended-field radiotherapy with prophylactic nodal irradiation (as opposed to tumour-bed irradiation only) as poor prognostic factors. CONCLUSION: In patients undergoing poRT, radiotherapy parameters had little influence over their survival irrespective of patient, disease characteristics, and quality of resection. In patients undergoing RT, extended-field radiotherapy improved survival in addition to PS and nodal stage.

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.

Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study.

AIMS: To determine the role of total skin electron irradiation (TSEI) as a cause of second malignancies in mycosis fungoides patients. MATERIALS AND METHODS: Mycosis fungoides patients referred to TSEI were followed in a longitudinal study. Other diagnosed malignancies were obtained after cross-matching with the Israel National Cancer Registry database. RESULTS: Between 1974 and 2010, 197 patients were treated: 134 (68%) men, 63 (32%) women; mean age 58 ± 17years. Topical/systemic treatment was given to 134 (68%) patients. TSEI was given to 104 (68.9%) patients. Seven (4.6%) received sub-TSEI and 40 (26.5%) received focal electron irradiation fields. Forty-six (23%) patients did not receive radiotherapy. The second primaries rate was 6.7 times higher in male mycosis fungoides patients and 13.1 times higher in female mycosis fungoides patients than in the general Israeli population. Malignant melanoma developed in eight patients after radiotherapy, in one patient without irradiation. The skin-related cancer rate after irradiation versus no irradiation was higher (P = 0.018). Combination radiotherapy with psoralen + ultraviolet A and/or nitrogen mustard yielded 11 cases of skin cancer versus no cases without irradiation. CONCLUSIONS: Mycosis fungoides patients have a high incidence of sequential malignancies. TSEI is associated with higher 'skin-related cancer' rates. Close longitudinal follow-up of mycosis fungoides patients is obligatory.

Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression.

Bullous pemphigoid (BP) is considered to be a humorally mediated autoimmune disease, but autoreactive T-cells and T-regulatory cells (Tregs) have also been implicated in this disease. Tregs and the programmed death-1 (PD-1) : programmed death ligand (PD-L) pathway are both critical in terminating immune response, and elimination of either can result in breakdown of tolerance and development of autoimmunity. We report a patient with metastatic malignant melanoma (MM), who underwent pembrolizumab (anti-PD-1) therapy following unsuccessful treatment with ipilimumab [anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4]. The patient developed BP with increasing serum titres of anti-BP180 IgG autoantibodies and increasing disease severity during pembrolizumab therapy. High doses of corticosteroids and methotrexate were needed to control the BP. Following the termination of pembrolizumab therapy, imaging showed complete regression of all metastatic sites. This result may indicate a crucial role for T-cell suppressive activity in controlling and preventing BP.

Stepping from traditional to integrative medicine: perspectives of Israeli-Arab patients on complementary medicine's role in cancer care.

BACKGROUND: Limited research is available on the perspectives of patients with cancer regarding integration of complementary medicine (CM) in conventional supportive cancer care. The purpose of this study was to explore patients' perspectives concerning CM integration within conventional oncology settings. PATIENTS AND METHODS: A 27-item questionnaire was constructed and administered to a convenient sample of Arab patients receiving cancer care in three oncology centers in northern Israel. RESULTS: Of the 324 respondents (94.7% response rate), 124 of 313 (39.6%) reported the use of CM for cancer-related outcomes. A logistic regression model indicated that CM was used with active chemo- or radiotherapy treatment [EXP [B], 2.926, 95% confidence interval (CI) 1.276-6.708; P=0.011] and a higher degree of spiritual quest (EXP [B], 3.425, 95% CI 1.042-11.253; P=0.043). Herbal medicine was the leading CM modality (87.9% of CM users), which included the use of 28 plants and traditional remedies, of which 17 were used to improve QOL, with 5 of the herbs having potential interactions with chemotherapy. 83.1% of respondents stated that they would consult with a CM provider if CM were to be integrated into the oncology department. Patients' expectation of CM consultation was clearly associated with expectations of QOL improvement, coping with cancer, and alleviating chemotherapy's side-effects when compared with expectations of cancer cure (P<0.0001). The three leading concerns which patients expected to be improved by integrative CM treatment were gastrointestinal symptoms (63.2%), fatigue (51.9%), and pain (40.5%). CONCLUSIONS: Integrative CM consultations should focus on the improvement of QOL concomitant with safety concerns regarding potential drug-herb interactions. The need to integrate a nonjudgmental yet evidence-based CM consultation service may also be applicable to oncology institutions challenged with culturally diverse populations with a high prevalence of traditional medicine use.

Osteosarcomas of the mandible: multidisciplinary management of a rare tumor of the young adult a cooperative study of the GSF-GETO, Rare Cancer Network, GETTEC/REFCOR and SFCE.

BACKGROUND: Mandibular osteosarcomas (MOS) mostly affect young adults. Their treatment is extrapolated from that of extragnathic osteosarcomas. MATERIAL AND METHODS: A retrospective multicooperative group study was conducted to determine the impact of chemotherapy, adjuvant radiation therapy and surgery on outcomes and to identify prognostic factors. This ethical committee-approved study included a centralized review of histology slides and operative reports. RESULTS: Of 111 patients, 58.6% were male, median age 35 years (13%, ≤18 years). Histology was osteoblastic, chondroblastic, fibroblastic, conventional not otherwise specified and others in 39.6%, 30.6%, 8.1%, 12.6% and 8.0%, respectively. Pathological World Health Organisation grades were low, intermediate and high grade in 6.4%, 11.8% and 81.8%, respectively. Surgery was carried out for 94.5% of patients. Neoadjuvant chemotherapy (mixed protocols) was carried out in 93.1% of patients. Postoperative chemotherapy and radiotherapy were carried out in 54.7% and 23.8%, respectively. Median follow-up was 59.6 months (range). Five-year local control, metastasis-free, disease-free and overall survival rates were 64.6%, 68.9%, 53.2% and 69.2%, respectively. Survival was significantly associated with age, tumor size and surgery. Wide surgery with clear margins and free flap reconstruction was the strongest prognostic factor. Neoadjuvant chemotherapy improved disease-free and metastatic-free survival and increased clear margins rates from 50% to 68%. Intermediate grades behaved like high grades in terms of metastatic-free and disease-free survival. CONCLUSION: This homogeneous series is the largest to date and emphasizes the major impact of clear margins and multidisciplinary management. Neoadjuvant chemotherapy improves disease-free survival and should be recommended for both high and intermediate grade MOS.

Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications.

Curcumin, commonly called diferuloyl methane, is a hydrophobic polyphenol derived from rhizome (turmeric) of the herb Curcuma longa. Extensive research over the last half century has revealed important functions of curcumin. In vitro and in vivo research has shown various activities, such as anti-inflammatory, cytokines release, antioxidant, immunomodulatory, enhancing of the apoptotic process, and anti-angiogenic properties. Curcumin has also been shown to be a mediator of chemo-resistance and radio-resistance. The anti-cancer effect has been seen in a few clinical trials, mainly as a native chemoprevention agent in colon and pancreatic cancer, cervical neoplasia and Barrets metaplasia. Some clinical studies with healthy volunteers revealed a low bioavailability of curcumin, casting doubt on the use of curcumin only as food additive. Our clinical experience with curcumin, along with the anti-metabolite gemcitabine in the treatment of patients with advanced pancreatic carcinoma, produced an objective response in less than 10% of patients, with a minor effect on survival. However, the safety of this combination was proved. Curcumin's potent anti-proliferative activity interacting with several intracellular signal transduction pathways may potentiate the anti-tumor effect of gemcitabine. The preclinical data lead to various, but still scarce, clinical studies (some on-going) that demonstrated the possible efficacy of this treatment as a chemopreventive or chemotherapeutic agent. This review will focus on the clinical evidence, including our experience with curcumin as a chemopreventive and therapeutic agent and the in vitro background results.

Heparanase expression in nasopharyngeal carcinoma inversely correlates with patient survival.

AIMS: To determine the expression and prognostic significance of heparanase in nasopharyngeal carcinoma (NPC). METHODS: Immunohistochemistry was performed on formalin-fixed paraffin-embedded sections of 46 patients with NPC. Clinical and immunohistochemical data were correlated with gender, age, histological type, Epstein-Barr virus (EBV) status, stage and survival. RESULTS: Heparanase immunoreactivity was found in 35% (16/46) of specimens. The cumulative survival of patients diagnosed as heparanase negative (n = 30) at 10 years was 70%. In contrast, the cumulative survival of patients diagnosed as heparanase positive (n = 16) at 10 years was 25%, differences that are highly statistically significant (P = 0.03). No significant correlations were found between heparanase immunoreactivity and gender, age, EBV status, tumour histology or tumour stage. CONCLUSION: Heparanase expression is inversely correlated with survival of NPC patients, clearly indicating that heparanase is a reliable prognostic factor for this malignancy, and further supports the notion that heparanase is a valid target for the development of anti-cancer drugs.

Prevalence and relevance of EBV latency in nasopharyngeal carcinoma in Israel.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is frequently associated with Epstein-Barr virus (EBV). The incidence of NPC in Western countries is lower than in the Far East, and EBV latency in NPC is less prevalent. Israel, as a part of the Mediterranean area, is one of the countries with an intermediate risk for NPC. METHODS: Immunohistochemistry (IHC) for latent membrane protein 1 (LMP-1) and in situ hybridisation (ISH) for EBV encoded RNA (EBER) were used to evaluate the prevalence and possible prognostic value of EBV latency among Israeli patients with NPC. Forty five patients with different NPC histologies were studied. RESULTS: LMP-1 IHC was positive in six samples only, all with undifferentiated histology. EBER ISH was positive in 40 of the 45 samples. According to histological type, three of five patients with squamous cell carcinoma were EBV positive and 37 of 40 non-keratinising and undifferentiated carcinoma cases were positive. Although EBV was more prevalent in patients with non-squamous carcinoma, the difference was not significant, probably because of the small number of patients with keratinising carcinoma. With regard to the clinical categories and survival, no significant difference could be detected between patients who were positive or negative for EBER ISH. No association was found between EBV latency and patient sex, age, origin, stage, or survival. CONCLUSIONS: NPC in Israel is highly associated with EBV latency as detected by EBER ISH. LMP-1 IHC is considerably less sensitive in detecting EBV latency in NPC among the same patient group.

Expression of HER2 and C-KIT in nasopharyngeal carcinoma: implications for a new therapeutic approach.

We sought to determine the expression and prognostic significance of HER2 and c-KIT proteins in nasopharyngeal carcinoma (NPC). In this retrospective study, immunohistochemical stains for HER2 and c-KIT were performed on formalin-fixed paraffin-embedded sections from 49 patients with NPC who were treated at our hospital from 1971 to 2000. The clinical and immunohistochemical data were correlated, including gender, ethnic origin, age, histological type, EBV status (EBER in situ hybridization), stage, and overall survival. HER2 expression was not found in the tested samples. C-KIT overexpression was found in 33% (16/49) of the patients. Nine of the 16 samples (56%) were strongly positive for c-KIT protein (staining of >50% of the tumor cells). C-KIT expression was associated with younger age. C-KIT was not found in patients with squamous carcinoma or in those with negative EBV status, although these two groups consisted of only five patients each. Although c-KIT-positive cases tended to be associated with slightly better survival, this was not statistically significant. C-KIT protein was expressed in one third of the NPC patients in this study, only in EBV-positive, undifferentiated, or nonkeratinizing carcinoma patients. Further study is needed to check whether c-KIT expression is correlated with c-KIT DNA mutations and to test the possibility of treatment with imatinib mesylate (Gleevec). HER2 protein was negative in the same tested specimens.

Etoposide, doxorubicin and cisplatin alternating with 5-fluorouracil, doxorubicin and high-dose methotrexate in patients with advanced adenocarcinoma of the stomach or the gastroesophageal junction.

Both the etoposide, doxorubicin, cisplatin (EAP) and 5-fluorouracil, doxorubicin, high-dose methotrexate (FAMTX) schedules have been reported to be active in advanced gastric cancer. Since these regimens include non-cross resistant agents, a regimen that consists of EAP alternating with FAMTX may have an advantage over each regimen alone. We undertook a phase II trial to evaluate EAP/FAMTX in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction. Of the 56 patients treated, an objective response was observed in 34%, including complete response in 7%. Median response duration was 8 months and median survival for the entire group was 9 months. The main toxicity was myelosuppression. Hospitalization for granulocytopenic fever was required in 32% of patients and 34% required red blood cells (RBC) transfusion. Non-hematological toxicity was moderate. There were three drug-related deaths associated with granulocytopenic fever. We conclude that the alternating EAP/FAMTX regimen is associated with occasional lethal events and has no obvious advantage over either regimen alone.

Primary osteogenic sarcoma arising from the dura mater: case report.

A 42-year-old woman who sought treatment for left drop foot was found to have a right frontoparietal parasagittal mass. Gross total resection of the tumor was performed and pathologic analysis revealed high grade osteoblastic osteosarcoma. The patient received adjuvant chemotherapy and continues to do well with no evidence of metastases or local recurrence 3 years after initial presentation.

Gemcitabine-induced radiation recall dermatitis: case report.

A 65-year-old male with lung adenocarcinoma received radiotherapy to the mediastinum and right upper lobe, followed by chemotherapy with gemcitabine. Radiation recall dermatitis developed in the area corresponding to the radiotherapy portal. This is one of just a few cases reported recently concerning radiation recall dermatitis stemming from gemcitabine.