A Real-world Study of Everolimus Plus Aromatase Inhibitor in Hormone Receptor-positive, HER2-negative Advanced Breast Cancer.

BACKGROUND/AIM: Everolimus in combination with exemestane was shown to offer benefit versus exemestane monotherapy in hormone receptor (HR)-positive, HER2-negative advanced breast cancer patients who progressed after aromatase inhibitor (AI) therapy. PATIENTS AND METHODS: The medical records of metastatic breast cancer patients, treated with everolimus, were retrospectively reviewed to generate real life safety and efficacy data. RESULTS: Sixty-eight percent of the patients had received chemotherapy (for early or metastatic disease) and 26% had received chemotherapy for metastatic disease. Among the 25 included patients, the most common adverse events were fatigue, neutropenia, epistaxis, stomatitis, and pneumonitis. Toxicity led to treatment discontinuation in 3 patients (12%). The median progression-free survival (PFS) was 7 months (95%CI=3.5-10.5). With a median follow-up of 73.3 months, the median overall survival was not reached. Twenty-five percent of the patients had received prior therapy with CDK4/6 inhibitors. Median PFS was significantly shorter in this subgroup (p=0.025). There was also a trend towards a longer PFS in patients with grade 3 breast cancer (p=0.085) and in patients receiving everolimus as first-line treatment (p=0.081). Some long responses were noted, with four patients exhibiting a PFS >5 years. CONCLUSION: These real-life data show that everolimus in combination with AI in patients with HER2-negative, HR-positive advanced breast cancer is an effective treatment with an acceptable toxicity profile.

Exploring the Use of a Digital Platform for Cancer Patients to Report Their Demographics, Disease and Therapy Characteristics, Age, and Educational Disparities: An Early-Stage Feasibility Study.

INTRODUCTION: The increasing burden of cancer, the development of novel therapies, and the COVID-19 pandemic have made cancer care more complex. Digital innovation was then pushed toward developing platforms to facilitate access to cancer care. Age, education, and other disparities were, however, shown to limit the use of the digital health innovation. The aim of this early-stage feasibility study was to assess whether Greek cancer patients would register at CureCancer and self-report their demographics, disease and therapy characteristics, and socioeconomic issues. The study was organized by the Hellenic Society of Medical Oncology. METHODS: Patients from nine cancer centers were invited to register on the CureCancer platform and complete an anonymous questionnaire on demographics, disease and therapy characteristics, and socioeconomic issues. Patients were also encouraged to upload, in a secure area for them, their medical files and share them with their physicians. They were then asked to comment on their experience of registration and how easy it was to upload their medical files. RESULTS: Of the 159 patients enrolled, 144 (90.56%) registered, and 114 of those (79.16%) completed the questionnaire, suggesting that the study is feasible. Users' median age was 54.5 years, and 86.8% of them were university and high school graduates. Most patients (79.8%) reported their specific type of cancer diagnosis, and all reported their therapy characteristics. Breast and lung cancers were the most common. A total of 87 patients (76.3%) reported being on active cancer therapy, 46 (40.4%) had metastatic disease, and 51 (44.7%) received supportive care medications. Eighty-one (71.05%) patients received prior cancer therapies, and twenty-seven recalled prior supportive care medications. All patients reported visiting non-oncology Health Care Professionals during the study. Nineteen of 72 (26.39%) patients who worked prior to cancer diagnosis changed work status; 49 (42.98) patients had children under 24 years; and 16 (14%) patients lived alone. Nine (7.9%) patients were members of patient associations. Registration was "much/very much" easy for 98 (86.0%) patients, while 67 (58.8%) had difficulties uploading their files. Patients commented on the well-organized data access, improved communication, feeling safe, medication adherence, interventions from a distance, and saving time and money. Over 80% of patients "preferred the digital way". DISCUSSION: A total of 114 patients succeeded in registering on the digital platform and reporting their demographics, disease and therapy characteristics, and socioeconomic issues. Age and educational disparities were disclosed and highlighted the need for educational programs to help older people and people of lower education use digital innovation. Health care policy measures would support patients' financial burden associated with work changes, living alone, and children under 24 years old at school or college. Policy actions would motivate patients to increase their participation in patient associations. According to the evidence DEFINED framework, the number of patients, and the focus on enrollment, engagement, and user experience, the study fulfills actionability level criterion 1.

Molecular Epidemiology and Treatment Patterns of Patients With EGFR Exon 20-Mutant NSCLC in the Precision Oncology Era: The European EXOTIC Registry.

Introduction: Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking. Methods: We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models. Results: Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range: 29.7-87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range: 0%-95%) and mean tumor mutational burden was 7.06 (range: 0-18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767-771, 83.1%) and the far loop (codons 771-775, 13%) and only in 3.9% within the C helix (codons 761-766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival (p = 0.051) and overall survival (p = 0.03). Conclusions: EXOTIC represents the largest academic real-world evidence data set on EGFR exon 20-mutant NSCLC in Europe. Indirectly compared, treatment with new exon 20-targeting agents is likely to confer survival benefit than CT plus or minus IO.

Real-World Data on Cabozantinib in Advanced Osteosarcoma and Ewing Sarcoma Patients: A Study from the Hellenic Group of Sarcoma and Rare Cancers.

Advanced osteosarcomas (OSs) and Ewing sarcomas (ESs) tend to have poor prognosis with limited therapeutic options beyond first-line therapy. Aberrant angiogenesis and MET signaling play an important role in preclinical models. The anti-angiogenic drug cabozantinib was tested in a phase 2 trial of advanced OS and ES and was associated with clinical benefits. We retrospectively analyzed the off-label use of cabozantinib in adult patients with advanced OS and ES/primitive neuroectodermal tumors (PNETs) in three centers of the Hellenic Group of Sarcoma and Rare Cancers (HGSRC). Between April 2019 and January 2022, 16 patients started taking 60 mg of cabozantinib for advanced bone sarcoma or PNET. Median age at cabozantinib initiation was 31 years (17-83). All patients had received peri-operative chemotherapy for primary sarcoma and between 0 and 4 lines of treatment (median; 2.5) for advanced disease. The most common adverse effects included fatigue, anorexia, hypertransaminasemia, weight loss, and diarrhea. One toxic death was noted (cerebral hemorrhage). Dose reduction to 40 mg was required in 31.3% of the patients. No objective response was noted, and 9/16 patients exhibited stable disease outcomes. Progression-free survival varied from 1 to 8 (median; 5) months. Our study demonstrates that cabozantinib has antitumor activity in this population. In the real-life setting, we observed similar adverse events as in the CABONE study and in other neoplasms.

Association between Intratumoral CD8+ T Cells with FoxP3+ and CD163+ Cells: A Potential Immune Intrinsic Negative Feedback Mechanism for Acquired Immune Resistance.

Acquired immune resistance (AIR) describes a situation in which cancer patients who initially responded clinically to immunotherapies, after a certain period of time, progress with their disease. Considering that AIR represents a feedback response of the tumor against the immune attack generated during the course of immunotherapies, it is conceivable that AIR may also occur before treatment initiation as a mechanism to escape endogenous adaptive antitumor immunity (EAAI). In the present study, we assessed the EAAI in paraffin-embedded breast primary tumor tissue samples and drew correlations with the clinical outcomes. In particular, we analyzed densities of CD8+ cells as elements mediating antitumor cytotoxicity, and of CD163+ and FoxP3+ cells as suppressor elements. We found a direct correlation between the densities of CD8+ cells and of CD163+ and/or FoxP3+ cells in the vast majority of patients' tumors. Importantly, the vast majority of patients whose tumors were overpopulated by CD8+ cells developed AIR, which was characterized by high intratumoral CD163+ and/or FoxP3+ cell densities and reduced overall survival (OS). We also showed that AIR depends on the levels of CD8+ cell-ratios in the tumor center to the invasive margin. Our data suggest that tumors develop AIR only when under a robust endogenous immune pressure.

Serum Concentration of Selected Angiogenesis-Related Molecules Differs among Molecular Subtypes, Body Mass Index and Menopausal Status in Breast Cancer Patients.

BACKGROUND: Angiogenesis is a hallmark of breast cancer (BC) and is mediated by the vascular endothelial growth factor (VEGF) signaling axis. It is regulated by different proangiogenic factors, including platelet-derived growth factor-CC (PDGF-CC) and heparin-binding EGF-like growth factor (HB-EGF), as well as co-receptors, such as neuropilin-1, which could have prognostic implications in BC patients. PATIENTS AND METHODS: We assessed the serum levels of VEGF, HB-EGF, PDGF-CC and neuropilin-1 in 205 patients with early BC (invasive, n = 187; in situ, n = 18) and in 31 healthy donors (HD) and investigated the potential associations with clinical and histopathological parameters. RESULTS: VEGF serum levels were significantly higher in patients with invasive versus ductal carcinomas in situ. PDGF-CC serum concentrations varied among BC molecular subtypes. Furthermore, we observed a differential expression of most biomarkers between overweight/obese (body mass index (BMI) ≥ 25 kg/m2) and non-obese patients among the BC molecular subtypes. Finally, the classification of subjects according to menopausal status revealed a significant difference in specific biomarker levels between patients and HD. CONCLUSION: The serum concentrations of angiogenic molecules differ among breast cancer molecular subtypes and are affected by the BMI and menopausal status, which could have possible clinical or prognostic implications.

A Multicenter, Prospective, Observational Study to Assess the Clinical Activity and Impact on Symptom Burden and Patients' Quality of Life in Patients with Advanced Soft Tissue Sarcomas Treated with Trabectedin in a Real-World Setting in Greece.

This non-interventional, multicenter, prospective study aimed to evaluate the real-world activity of trabectedin, and its impact on symptom burden and quality of life in patients with advanced soft tissue sarcoma (aSTS) treated in routine clinical settings in Greece. Patients with histologically confirmed aSTS newly initiated on trabectedin were enrolled. The primary endpoint was progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS rate at 3 months, median PFS, objective response rate (ORR), disease control rate (DCR), overall survival (OS), and an assessment of the impact of treatment on health-related quality of life (HRQoL), cancer-related symptom burden and symptom interference with function, as well as all-cause treatment discontinuation rate. A total of 64 eligible patients from 13 Greek centers were evaluated. Patients received a median of three trabectedin cycles per patient (interquartile range [IQR]: 2.0-6.0). Median PFS was 6.6 months with 67.9% and 51.2% of patients free from progression at 3 and 6 months, respectively. ORR was 7.8% and DCR 21.9%. Median OS was 13.1 months. No significant changes from enrolment were noted in HRQoL scores. In total, 30 patients (46.9%) had at least one trabectedin-related adverse drug reaction (ADR) and 9 (14.1%) at least one serious ADR. The treatment discontinuation rate due to toxicity was 9.4%. These results suggest that trabectedin is an active treatment with clinically meaningful benefits in patients with aSTS with no new safety signals.

The addition of the immunomodulator mifamurtide to adjuvant chemotherapy for early osteosarcoma: a retrospective analysis.

BACKGROUND: Current treatment recommendations for high grade non-metastatic osteosarcoma include perioperative chemotherapy and surgery. Despite this intensive protocol, approximately 40% of patients will relapse. The addition of the immunomodulator mifamurtide to adjuvant cytotoxic chemotherapy was associated with a significant improvement in 6-year overall survival (OS) in young patients with resectable osteosarcoma, leading to its approval in Europe and other countries. Very limited real-world data are reported on its use. METHODS: We retrospectively evaluated data from osteosarcoma patients who received mifamurtide in the adjuvant setting. Data were obtained from medical records in 2 high-volume bone sarcoma centers. The aim of this study was to collect real-world data on mifamurtide safety and efficacy in Greece. RESULTS: We identified 15 patients with completely resected osteosarcoma who received mifamurtide from September 2015 to January 2020. Median age at diagnosis was 24 years old (16-76). Osteosarcoma arose in the lower extremities (n = 12), in the upper extremities (n = 2) or in the ilium (n = 1). The majority of patients (n = 13) received cisplatin/doxorubicin/methotrexate as perioperative chemotherapy and the remaining patients cisplatin/doxorubicin. After a median follow-up of 46.9 months (range, 32.8-61.1), the median recurrence-free survival was 58.7 months (range, 18.5-98.8) and the median OS 64.1 months (range, 25.6-102.6). Except for fever and chills, the only adverse event probably related to mifamurtide was pericarditis (n = 1). CONCLUSIONS: Mifamurtide was well tolerated in a Greek osteosarcoma population, including patients older than 30 years. The small sample size and the non-comparative design do not allow drawing conclusions on the drug benefit in terms of survival.

Prophylaxis of cancer-associated venous thromboembolism with low-molecular-weight heparin-tinzaparin: Real world evidence.

Thromboprophylaxis, as a preventive measure for cancer-associated thrombosis (CAT), may be beneficial for patients with active cancer and high-risk for thrombosis. The present post hoc analysis include a total of 407 patients enrolled in the Greek Management of Thrombosis study, who received thromboprophylaxis with tinzaparin. The objectives of the present analysis were: i) To obtain sufficient evidence for the administration of prophylaxis in patients with active cancer, irrespective of Khorana risk assessment model score; ii) to identify the selection criteria for both dose and duration of tinzaparin; and iii) to evaluate the efficacy and safety of tinzaparin administered for CAT prophylaxis. The main tumor types for the patients included in the present study were as follows: Lung (25.1%), pancreatic (14.3%), breast (9.1%), stomach (8.4%), colorectal (7.9%) and ovarian (7.6%). Furthermore, metastatic disease was observed in 69.5% of the patients. High thrombotic burden agents (HTBAs) were administered to 66.3% of the patients, and 17.4% received erythropoietin. A total of 43.7% of the patients exhibited a Khorana score <2. The results of the present study demonstrated that both the presence of metastatic disease and the use of HTBAs seemed to influence oncologists' decisions for the use of thromboprophylaxis in patients with active cancer, regardless of Khorana score. Tinzaparin, in dose expressed in the standard notation for heparins, i.e., anti-Xa factor international units (Anti-Xa IU), was administered at an intermediate dose (InterD; 8,000-12,000 Anti-Xa IU; once daily) to 52.4% of patients, while the remaining patients received a prophylactic dose (ProD; ≤4,500 Anti-Xa IU; once daily). The average duration of thromoprophylaxis was 5 months. Furthermore, a total of 14 (3.4%) thrombotic events and 6 (1.5%) minor bleeding events were recorded. A total of four thrombotic events were observed following an InterD treatment of tinzaparin, while 10 thrombotic events were observed following ProD treatment. The present study also demonstrated that an InterD of tinzaparin was administered more frequently to patients with a body mass index >30 kg/m2, a history of smoking and a history of metastatic disease, along with administration of erythropoietin. InterD tinzaparin treatment was found to be potentially more efficacious and without safety concerns. The present study is a registered clinical trial (ClinicalTrials.gov code, NCT03292107; registration date, September 25, 2017).

Front-Line Bevacizumab plus Chemotherapy with or without Maintenance Therapy for Metastatic Breast Cancer: An Observational Study by the Hellenic Oncology Research Group.

Front-line bevacizumab (BEV) in combination with taxanes offers benefit in progression-free survival (PFS) in metastatic breast cancer (mBC). The medical records of mBC patients, treated with front-line BEV-based chemotherapy, were retrospectively reviewed in order to generate real life safety and efficacy data. Patients with human epidermal growth factor receptor 2 (HER2)-negative mBC treated with front-line BEV in combination with chemotherapy were eligible. Maintenance therapy with BEV and/or hormonal agents was at the physicians' discretion. Among the 387 included patients, the most common adverse events were anemia (61.9%, mainly grade 1), grade 3/4 neutropenia (16.5%), grade 1/2 fatigue (22.3%), and grade 1/2 neuropathy (19.6%). Dose reductions were required in 164 cycles (7.1%) and toxicity led to treatment discontinuation in 21 patients (5.4%). The median PFS and the median overall survival (OS) were 13.3 (95% CI: 11.7-14.8) and 32.3 months (95% CI: 27.7-36.9), respectively. Maintenance therapy, with hormonal agents (ET) and/or BEV, was associated with longer OS versus no maintenance therapy (47.2 versus 23.6 months; p < 0.001) in patients with hormone receptor (HR)-positive disease and BEV maintenance offered longer OS versus no maintenance in patients with HR-negative disease (52.8 versus 23.3; p = 0.023). These real-life data show that front-line BEV-based chemotherapy in HER2-negative mBC patients is an effective treatment with an acceptable toxicity profile. The potential benefit of maintenance treatment, especially ET, is important and warrants further research.

Safety and Efficacy of RAD001 (Everolimus) Administered Upon Relapse During or After Adjuvant Treatment in Post-menopausal Women With Hormone Receptor Positive, HER2/neu Negative Locally Advanced or Metastatic Breast Cancer (CRAD001JGR08 "MELPOMENI" study).

BACKGROUND/AIM: This study aimed to provide real-world safety and effectiveness data of everolimus (EVE) plus exemestane (EXE) in estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced breast cancer (aBC). PATIENTS AND METHODS: This prospective observational study was conducted by 19 hospital-based oncologists in Greece. Eligible patients were treated with EVE+EXE in the first-line setting; EVE was initiated according to the approved label. RESULTS: Overall, 75 eligible patients (mean age: 66.9 years; visceral metastases: 49.3%; bone-only metastases: 37.3%) were included in the effectiveness analyses. Over a median (interquartile range) of 12.1 months (range=4.2-20.5 months) of EVE treatment, the median progression-free survival was 18.0 months and the overall response rate was 22.7%. Among patients that received ≥1 EVE dose (n=80), the incidence of EVE-related adverse events was 72.5% (serious: 55.0%); stomatitis (22.5%), fatigue (22.5%), pneumonitis (18.8%); and cough (18.8%) were the most common. CONCLUSION: In the routine care in Greece, EVE demonstrates clinical benefit and a predictable safety profile.

Exploring Essential Issues for Improving Therapeutic Cancer Vaccine Trial Design.

Therapeutic cancer vaccines have been at the forefront of cancer immunotherapy for more than 20 years, with promising results in phase I and-in some cases-phase II clinical trials, but with failures in large phase III studies. After dozens of clinical studies, only Dendreon's dendritic cell vaccine Sipuleucel-T has succeeded in receiving US FDA approval for the treatment of metastatic castrate-resistant prostate cancer. Although scientists working on cancer immunotherapy feel that this is an essential breakthrough for the field, they still expect that new vaccine regimens will yield better clinical benefits compared to the four months prolonged median overall survival (OS) Sipuleucel-T demonstrated in the IMPACT phase III clinical trial. Clinical development of cancer vaccines has been unsuccessful due to failures either in randomized phase II or-even worse-phase III trials. Thus, rigorous re-evaluation of these trials is urgently required in order to redefine aspects and optimize the benefits offered by therapeutic cancer vaccines. The scope of this review is to provide to the reader our thoughts on the key challenges in maximizing the therapeutic potentials of cancer vaccines, with a special focus on issues that touch upon clinical trial design.

Real-World Data on Thromboprophylaxis in Active Cancer Patients: Where Are We? Are We Getting There?

Background: Cancer patients are at high risk for cancer-associated thrombosis (CAT). CAT is the second leading cause of death in these patients but it can be preventable with thromboprophylaxis. Patients and Methods: An observational, prospective, multicenter study aiming to record CAT management in clinical practice was conducted by the Hellenic Society of Medical Oncology (HeSMO). Results: A total of 426 active cancer patients (mean age 65.3 years, mean BMI: 26.1 kg/m2) who received thromboprophylaxis, were included from 18 oncology units. Tumor types were lung 25.1%, pancreas 13.9%, breast 8.7%, stomach 8.5%, ovarian 7.8%, and others 36%, while 69% had metastases. A total of 71% had a Khorana score ≤2 and 61% received High Thrombotic Risk Chemotherapy Agents (HTRCAs, e.g., platinum). For thromboprophylaxis patients received mainly Low Molecular Weight Heparins (LMWHs), on higher than prophylactic doses in 50% of cases. Overall, 16 (3.8%) thrombotic events and 6 (1.4%) bleeding events were recorded. Notably, patients on higher doses of LMWHs compared to patients who received standard prophylactic doses had 70% lower odds to develop thrombotic events (OR: 0.3, 95% CI: 0.10-1.0, p = 0.04). Conclusion: CAT is an important issue in oncology. Along with the Khorana score, factors as metastasis and use of HTRCAs should also be taken into consideration. Thromboprophylaxis for active cancer patients with LMWHs, even on higher doses is safe and efficient.

Acute Leriche Syndrome in Pancreatic Adenocarcinoma: A Case Report.

INTRODUCTION: Coexistance of pancreatic carcinoma and Leriche syndrome is an extremely rare pathological condition. Leriche syndrome is defined as occlusion of the distal aorta at the bifurcation into the common iliac arteries. CASE REPORT: We report the case of a 57-year old male patient with a locally advanced pancreatic tumor that during chemotherapy presented Leriche syndrome. Four months after the diagnosis and although the initial staging by MRI had only revealed a few atheromatic lesions of the abdominal aorta, the patient complained about claudication of the legs and hypoesthesia. Angiography with multi-detector computed tomography (MDCTA) was performed using aortography protocol and three-dimensional reconstruction of the images followed, demonstrating the relationship between pancreatic carcinoma and Leriche syndrome. CONCLUSION: Review of the literature revealed that acute abdominal thrombosis is rare in cancer patients. To our knowledge, complete occlusion of the aorta in a patient with pancreatic cancer has not been reported yet.

Cerebral metastasis from osteosarcoma: "Bone" in the brain.

Although brain metastases from bone and soft tissue sarcoma are uncommon, advances in sarcoma treatment have led to an increasing incidence of them. We present a 23-year-old male with a history of metastatic femoral osteosarcoma, who presented with headache and unsteady gait and was diagnosed with a cerebellar metastasis. CT scan revealed a mass in the left cerebellar parenchyma with large intralesional central calcification and perilesional edema. Corticosteroid treatment led to neurological symptoms resolution, with a rapid tapering. The patient had also lung metastases and we opted to administer systemic treatment with the tyrosine kinase inhibitor cabozantinib. Given the relative radioresistance of osteosarcomas, the patient did not receive radiation therapy.

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence.

PURPOSE: AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. METHODS: In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. RESULTS: 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275-1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499-1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114-1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142-0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG. CONCLUSIONS: This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.

Alveolar bone histological necrosis observed prior to extractions in patients, who received bone-targeting agents.

OBJECTIVE: We reported the alveolar bone histology prior to dental extractions in cancer patients, who received bone-targeting agents (BTA). SUBJECTS AND METHODS: Fifty-four patients were included. Patients underwent extractions, and bone biopsies were taken. RESULTS: Extractions were performed due to pain, swelling, purulence, fistula, and numbness, not responding to treatment, in 40 patients (group A); extractions due to asymptomatic, non-restorable teeth, were performed in 14 patients (group B). Complete alveolar jaw bone histological necrosis was observed in 28 of 40 (70%) patients of group A and none of group B (p < .001). The development of clinical osteonecrosis (MRON) was assessed in 44 patients; 10 patients, who were also treated with Low Level Laser Treatments-LLLT, were excluded from this analysis, as the alternative therapies were a confounding factor. Twelve patients, with alveolar bone histological necrosis prior to extraction, developed medication-related osteonecrosis of the jaw (MRONJ) compared with two patients with vital or mixed vital/non-vital bone (p < .0007). BTAs >1 year and concurrent targeted therapy were also significantly associated with MRONJ (p = .016 and p = .050). CONCLUSION: Pain, swelling, purulence, fistula, and numbness were significantly associated with complete bone histological necrosis prior to extractions and increased MRONJ development. Research is justified to explore whether histological necrosis represents an early stage of osteonecrosis.

Management of Cancer-associated Thrombosis (CAT): Symptomatic or Incidental.

BACKGROUND: Cancer-associated thrombosis (CAT), the second leading cause of death in patients with cancer can be treated with low molecular weight heparin (LMWH) according to guidelines. PATIENTS AND METHODS: A multicenter prospective observational study was carried out to record anti-thrombotic treatment practice, assess thrombosis recurrence and bleeding, and identify potential risk factors. Adult patients from 18 Oncology Departments throughout Greece were followed-up for 12 months. RESULTS: A total of 120 patients with CAT receiving anticoagulant treatment were enrolled (35% incidental); 85% were treated for more than 6 months, 95.8% were treated with tinzaparin and smaller percentages with other agents. Thrombosis recurred in three patients and there was minor bleeding in four patients. Bleeding was associated with high body mass index (>35 kg/m2), trauma history, renal insufficiency and bevacizumab use. CONCLUSION: Incidental thrombosis contributes significantly to CAT burden. Long-term use of LMWH seems to be effective and safe. Several risk factors associated with bleeding should be considered during anti-coagulation therapy planning.

Nivolumab in patients with rare head and neck carcinomas: A single center's experience.

Immunotherapy (IO) with anti-PD1 inhibitors is available for the treatment of recurrent/metastatic squamous cell carcinomas of the head and neck (SCCHD) since 2016. Both nivolumab and pembrolizumab were tested in phase 3 randomized trials in adults progressing on or after platinum-based therapy and were found to confer an overall survival benefit compared to investigator's choice. However, very limited data exist concerning IO use in rare subtypes of head and neck carcinoma, like salivary gland carcinoma. We retrospectively collected clinical data of all patients diagnosed with rare subtypes of head and neck carcinoma, who were treated with immune checkpoint inhibitors in our department during the last 5 years. We analyzed safety and efficacy of these therapies. We identified six patients who received nivolumab for recurrent or metastatic head and neck carcinomas, between 31 and 57 years old. All patients had received at least one line of platinum-chemotherapy, as well as radiation therapy. Treatment was administered every 2 weeks, at a dose of 3 mg per kilogram of body weight. Number of nivolumab cycles varied between 2 and 18. Progression-free survival varied from 1 to 12 months and overall survival from 4 to 24 months. Tolerance was very good, except for one case of diabetes and hypothyroidism requiring medication. There is currently insufficient evidence regarding the optimal treatment of the rare non-squamous cell carcinoma of the head and neck. Our case series supports a role for immunotherapy in these patients. However, larger collaborative studies are needed to evaluate this treatment.

Primary squamous cell carcinoma of the ovary. Review of the literature.

PURPOSE: Primary squamous cell carcinoma (SCC) of the ovary is rare. Most cases arise from a cystic teratoma or less frequently from Brenner tumor or endometriosis. We reviewed 36 cases of primary ovarian SCC reported in the literature including a case diagnosed and treated in our institution. METHODS: Data was collected by using the key-words "primary squamous cell carcinoma" and "ovary" on Google Scholar and PubMed in April 2018. All reviewed cases were analyzed according to diagnosis, surgical approach, adjuvant therapy and outcome. RESULTS: To date 23 articles presenting 36 cases of primary ovarian SCC are reported. Nine patients had stage I, 8 stage II, 11 stage III and 5 stage IV disease, whereas 3 patients had in situ carcinoma. All patients underwent surgery (mainly hysterectomy with bilateral salpingo-oophorectomy). Adjuvant therapy was reported in 24 patients, 15 of which received chemotherapy, 6 radiotherapy and 3 a combination of both. Chemotherapy regimens were similar to the ones used in ovarian carcinoma (more often platinum plus paclitaxel). Follow-up period was in general short and survival varied between 9 days and 14 years, depending on the stage at diagnosis. CONCLUSIONS: Primary ovarian SCC is a rare entity with poor prognosis, compared to serous carcinoma. Treatment is usually extrapolated from classical ovarian carcinoma algorithms, including surgical management combined with adjuvant chemotherapy with or without radiotherapy. Further investigations are needed to define optimal treatment, such as chemotherapy regimens and the role of radiotherapy and lymph node dissection.