Case report: Immunotherapy inducing unexpected overall survival in choroidal melanoma: about a case.

Choroidal melanoma (CM) is the most common malignant ocular tumor in adults. The current treatment of metastatic CM is limited by the intrinsic resistance of CM to conventional systemic therapies. Immunotherapy alone or in association with cytotoxic treatment became a realist option treatment. Advancements in molecular biology have resulted in the identification of a number of promising prognostic and therapeutic targets. Herein, we report a rare case of 36-year-old patient with metastatic CM who presented a good long response to treatment with double immunotherapy reaching 3 years of overall survival, which has never been described in the literature.

Immunogenicity of radiotherapy on bone metastases from prostate adenocarcinoma: What is the future for the combination with radiotherapy/immunotherapy?

Bone metastatic prostate cancers (PCa) are resistant to usual immunotherapies such as checkpoint inhibitors. The main hypothesis related to this immunoresistance is the lack of antigens to stimulate anti-tumor immunity. External radiation is a potential inducer antigens presentation and thus to immunotherapy proprieties. The aim of this review is to describe the tumor microenvironment specificities, especially in bone metastasis and the immune modifications after radiation therapy on a metastatic castration-resistant PCa population. PCa microenvironment is immunosuppressive because of many tumor factors. The complex interplay between PCa cells and bone microenvironment leads to a 'vicious circle' promoting bone metastasis. Furthermore, the immune and bone systems, are connected through an osteoclastogenic cytokine: the Receptor Activator Nuclear Factor Kappa B ligand. Adapted doses of ionizing radiation play a dual role on the tumor. Indeed, radiotherapy leads to immunogenicity by inducing damage associated with molecular patterns. However, it also induces an immunosuppressive effect by increasing the number of immunosuppressive cells. Interestingly, the abscopal effect could be used to optimize immunotherapy potential, especially on bone metastasis. Radiotherapy and immunotherapy combination is a promising strategy, however further studies are necessary to determine the more efficient types of radiation and to control the abscopal effect.

OPN, BSP, and Bone Quality-Structural, Biochemical, and Biomechanical Assessment in OPN-/-, BSP-/-, and DKO Mice.

Osteopontin (OPN) and Bone Sialoprotein (BSP), abundantly expressed by osteoblasts and osteoclasts, appear to have important, partly overlapping functions in bone. In gene-knockout (KO, -/-) models of either protein and their double (D)KO in the same CD1/129sv genetic background, we analyzed the morphology, matrix characteristics, and biomechanical properties of femur bone in 2 and 4 month old, male and female mice. OPN-/- mice display inconsistent, perhaps localized hypermineralization, while the BSP-/- are hypomineralized throughout ages and sexes, and the low mineralization of young DKO mice recovers with age. The higher contribution of primary bone remnants in OPN-/- shafts suggests a slow turnover, while their lower percentage in BSP-/- indicates rapid remodeling, despite FTIR-based evidence in this genotype of a high maturity of the mineralized matrix. In 3-point bending assays, OPN-/- bones consistently display higher Maximal Load, Work to Max. Load and in young mice Ultimate Stress, an intrinsic characteristic of the matrix. Young male and old female BSP-/- also display high Work to Max. Load along with low Ultimate Stress. Principal Component Analysis confirms the major role of morphological traits in mechanical competence, and evidences a grouping of the WT phenotype with the OPN-/- and of BSP-/- with DKO, driven by both structural and matrix parameters, suggesting that the presence or absence of BSP has the most profound effects on skeletal properties. Single or double gene KO of OPN and BSP thus have multiple distinct effects on skeletal phenotypes, confirming their importance in bone biology and their interplay in its regulation.

Chemotherapy Primary Dose Reduction in Older Cancer Patients: A Retrospective Cohort.

Primary dose reduction (PDR) in the first course of chemotherapy is an empirical practice, commonly used in older population. Patients over 70 years old receiving a first course of chemotherapy for a solid tumor were enrolled. A total of 179 patients were included. Standard dose was used in 69.8% of patients, while 30.2% received PDR of chemotherapy. Only 29.6% received a standardized geriatric assessment. Patients receiving standard doses presented 83.2% of toxicities, while 68% of toxicities were reported in patients receiving PDR. The toxicity rate was significantly decreased in patients treated with reduced first-cycle dose of chemotherapy.

COVID-19 Outbreak Impact on Cancer Multidisciplinary Team Meetings. A Multicenter French Experience.

Multidisciplinary team meeting (MDT) became a standard of care in cancer management. The COVID-19 epidemic induced unprecedented pressure on the health system. The impact of this health crisis on MDTs held within a regional French health structures was analyzed. A decrease in the total number of records discussed in hematological, digestive, thoracic, gynecological and genitourinary MDTs was observed following the 1st wave of the COVID-19 pandemic. This decrease was generally maintained during the 2nd and 3rd wave. MDTs activity back in order from the 4th wave. The COVID-19 pandemic has challenged MDTs settings. The implementation of virtual technologies offers an opportunity to improve MDTs organization.

Emergency radiation therapy in modern-day practice: Now or never, or never again ?

Radiation therapy plays a fundamental role in oncological emergencies such as superior vena cava syndrome (SVCS) and metastatic epidural spinal cord compression (MESCC). These are two examples of critical complications of metastatic cancer in terms of pain and functional impact (respiratory and/or neurological). The aim of this review is to explore the current indications, treatment options and outcomes for emergency radiotherapy regarding to these complications.Regarding SVCS, studies are mostly retrospective and unanimously demonstrated a beneficial effect of radiotherapy on symptom relief. Spinal cord compression remains an indication for urgent radiotherapy, and should be combined with surgery when possible. The innovative stereotactic body radiotherapy (SBRT) showed promising results, however this technique requires small volumes and more time preparation and therefore is often unsuitable for SVCS and MESCC emergencies.This review concluded that radiotherapy has a central role to play within a multimodal approach for SVCS and MESCC treatment. Further prospective studies are needed to confirm the effectiveness of radiation and establish the criteria for selecting patients to benefit from this treatment option.

The Impact of an Enrolment in Clinical Trial on Tolerance and Pathological Response for Patients Treated by Neoadjuvant MVAC Against an Invasive Bladder Cancer. A Retrospective Comparative Study.

INTRODUCTION: MVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) neoadjuvant chemotherapy a standard treatment for invasive bladder cancer is associated with mainly haematological toxicities. Randomized clinical trials remain a gold standard for treatment outcomes and efficacy assessment. Patients enrolled in clinical trials are selected and tend to benefit from a stricter follow-up unlike everyday clinical practice patients. Conversely, real-life observational studies better define the effectiveness of treatments in clinical routine practice. The aim of this study is to analyse the impact of clinical trial monitoring on MVAC-related toxicities. MATERIAL AND METHODS: Patients with an infiltrative localized bladder cancer treated by MVAC neoadjuvant chemotherapy between 2013 and 2019 were enrolled, and divided into 2 groups: patients included in a clinical trial namely "VESPER study" during their treatment and patients treated in clinical routine practice. RESULTS: Out of 59 patients were enrolled in this retrospective study, 13 patients were included in a clinical trial. Clinical characteristics were similar between the 2 groups. Comorbidities were more frequent in the nonclinical trial group (NCTG). Completed 6 cures treatment proportion was higher in the clinical trial group (CTG) (69.2% vs. 50%). Yet, in this group, patients had more doses reduction (38.5% vs. 19.6%). The proportion of complete pathologic response was higher in patients enrolled in clinical trial (53.8% vs. 39.1%). Statistically, the expected stricter monitoring due to clinical trial enrolment had no impact on the complete pathologic response and clinically relevant toxicities. DISCUSSION: When compared to conventional clinical practice, clinical trial enrolment induced no significant difference on the pathologic complete response or toxicity rate. Further large prospective studies are needed to confirm these data.

Evaluating video-based consultations in routine clinical practice at a comprehensive cancer center.

INTRODUCTION: Integrating telemedicine into cancer care remains a major challenge. There are little clinical evidence for teleconsultation efficacy and safety in daily oncology practice. This study as a pioneering experience, aimed to analyze patient and physician opinions regarding the implementation of telemedicine consultations, and to identify major limitations of telehealth spread in an oncology institute. MATERIAL AND METHODS: During COVID-19 lockdown, patients and physicians who took part to at least one video-based teleconsultation between March and May 2020, were enrolled in this observational study. All eligible patients received an anonymous online questionnaire. On the other hand, all physicians eligible to participate were asked through email to complete a questionnaire. RESULTS: In this study, 31 physicians and 304 patients consented to participate in this study by answering the questionnaire and were included. Regarding telemedicine satisfaction, 65.8% of patients were satisfied. The lack of clinical examination was the major limitation reported by 77% of patients. Patients belonging to a high socio-professional category were statistically more dissatisfied with the relationship with their doctor (OR = 2.31 and 95% CI [1.12; 4.74]). CONCLUSION: This study showed promising results of incorporating video-based teleconsultations into cancer patient management. Randomized clinical trials are needed in order to accelerate the digital implementation in clinical practice.

Pelvic insufficiency fractures after intensity modulated radiation therapy combined with chemotherapy for cervix carcinoma: Incidence and impact of bone mineral density.

Background and Purpose: The aim of this study was to evaluate the incidence and predictive factors of Pelvic Insufficiency Fractures (PIFs) occurring after Intensity Modulated Radiation Therapy (IMRT) combined with chemotherapy for locally advanced cervical cancer (CC). Material and methods: Medical records of patients receiving radio-chemotherapy with IMRT between 2010 and 2020 for advanced CC were reviewed. PIFs were detected during follow-up on pelvic Magnetic Resonance Imaging (MRI) or Computed Tomography (CT). The cumulative incidence rate of PIFs and its confidence interval were calculated at 2 and 5 years of follow-up. Pre-therapeutic Bone Mineral Density (BMD) (g/cm3) was evaluated on CT simulation for sacrum and the fourth lumbar (L4) vertebrae. Sacrum dosimetric parameters (V30Gy, V40Gy, D50%, Dmean) were analyzed. Results: 136 patients were included. The median follow-up was 4.4 years. Median dose of D50% and V40Gy sacrum were 35.2 Gy (20.6-46.4) and 32.2% (7.2-73.4) respectively. The 2-year and 5-year cumulative incidence rates were 15.7% (95% CI: 9.88-22.71) and 22% (95% CI: 14.58-30.45) respectively. Median time interval between RT completion and PIFs' detection was 11.5 months (IQR: 7.4-22.3). Univariate analysis showed that older age (p < 0.01), postmenopausal status at baseline (p < 0.01), and lower sacral and spinal BMD at baseline (respectively p < 0.001 and p < 0.01) were significantly associated to all sites of PIFs, and lower sacral BMD with sacral fractures (p < 0.001). Conclusion: Post-IMRT PIFs were detected in 18.4% of patients with locally advanced CC. Individual predisposing factors as older age, postmenopausal status, decreased bone density on the CT simulation were mainly predictive.

Impact of Medical Specialties on Diagnostic and Therapeutic Management of Elderly Cancer Patients.

The management (diagnostic and therapeutic) of cancer in the geriatric population involves a number of complex difficulties. The aim of this study was to assess the impact of a medical specialty on the diagnostic and therapeutic management of elderly cancer patients. Four clinical scenarios of cancer in the geriatric population, with a dedicated survey to gather information regarding each clinical case's diagnostic and therapeutic approaches, as well as the different criteria influencing physicians' therapeutic decisions, were exposed to geriatricians, oncologists, and radiotherapists in Saint-Etienne. The surveys were filled out by 13 geriatricians, 11 oncologists, and 7 radiotherapists. There was a homogeneity of responses regarding the confirmation of cancer diagnostics in the elderly. There were strong disparities (inter- and intra-specialties) for several clinical situations regarding the therapeutic management of cancer. There were significant disparities in terms of surgical management, the implementation of a chemotherapy protocol, and the adaptation of the chemotherapy dosage. Contrary to oncologists, who primarily consider the G8 and the Karnofsky score, geriatric autonomy scores and frailty with cognitive assessment were the key factors determining diagnostic/therapeutic therapy for geriatricians. These results raise important ethical questions, requiring specific studies in geriatric populations to provide the homogenous management of elderly patients with cancer.

Challenges in radiobiology - technology duality as a key for a risk-free α/ß ratio.

Since radiotherapy discovery, prediction of biological response to ionizing radiation remains a major challenge. Indeed, several radiobiological models appeared through radiotherapy history. Nominal single dose so popular in the 1970s, was tragically linked to the dark years in radiobiology by underestimating the late toxicity of the high-dose fractions. The actual prominent linear-quadratic model continues to prove to be an effective tool in radiobiology. Mainly with its pivotal α/ß ratio, which gives a reliable estimate of tissues sensitivity to fractions. Despite these arguments, this model experiences limitations with substantial doubts of α/ß ratio values. Interestingly, the story of radiobiology since X-ray discovery is truly instructive and teaches modern clinicians to refine fractionation schemes. Many fractionation schemes have been tested with successes or dramas. This review retraces radiobiological models' history, and confronts these models to new fractionation schemes, drawing a preventive message.

hTERT and IGF-1R Proteins Expression in Response to Treatment in Patients with HPV Alpha 9-Positive Cervical Cancer.

Human papillomavirus (HPV) infection is strongly associated with cervical cancer (CC). Genomic alterations caused by viral infection and subsequent dysregulation of cellular metabolism under hypoxic conditions could influence the response to treatment. We studied a possible influence of IGF-1Rb, hTERT, HIF1a, GLUT1 protein expression, HPV species presence and relevant clinical parameters on the response to treatment. In 21 patients, HPV infection and protein expression were detected using GP5+/GP6+PCR-RLB and immunohistochemistry, respectively. The worse response was associated with radiotherapy alone compared with chemoradiotherapy (CTX-RT), anemia and HIF1a expression. HPV16 type was the most frequent (57.1%) followed by HPV-58 (14.2%) and HPV-56 (9.5%). The HPV alpha 9 species was the most frequent (76.1%) followed by alpha 6 and alpha 7. IGF-1Rb (85.7%), HIF1a (61.9%), GLUT1 (52.3%), and hTERT expression [cytoplasm and nucleus (90.4%)] were detected. The MCA factorial map showed different relationships, standing out, expression of hTERT and alpha 9 species HPV, expression of hTERT and IGF-1Rb expression [Fisher's exact test (P = 0.04)]. A slight trend of association was observed between, GLUT1 and HIF1 a expression, hTERT and GLUT1 expression. A noteworthy finding was the subcellular localization of hTERT in the nucleus and cytoplasm of CC cells and its possible interaction with IGF-1R in presence of HPV alpha 9 species. Our findings suggest that the expression of HIF1a, hTERT, IGF-1Rb and GLUT1 proteins that interact with some HPV species may contribute to cervical cancer development, and the modu lation of treatment response.

Approaches to Oligometastatic Renal Cell Carcinoma.

PURPOSE OF REVIEW: This study aims to gather the current state of the literature about therapeutic approaches and management of oligometastatic renal cell carcinoma. RECENT FINDINGS: Two recent stereotactic body radiotherapy (SBRT) studies gained attention and offered a promising outcome alone or in association with antineoplastic drugs especially in oligometastatic renal cell carcinoma. If one can consider evidence-based medicine as the sole therapeutic option, many unresolved questions are still pending. Thus, therapeutic approaches in oligometastatic renal cell carcinoma are still working. Further phase III clinical trials are urgently needed to validate the last 2 phase II involving SBRT and improve knowledge for defining the right care to the right patient at the right time. In addition, a discussion in a disciplinary consultation meeting remains essential to validate the arrangement between systemic treatments and focal treatments that will best benefit the patient.

Nectin-4: a Tumor Cell Target and Status of Inhibitor Development.

PURPOSE OF REVIEW: This study aims to gather the current state of the literature about anti-Nectin-4 innovative associations in solid tumors and to investigate underlying resistance mechanisms. RECENT FINDINGS: Antibody-drug conjugate (ADC) targeting Nectin-4 efficacy gained attention and offers a promising association with other antineoplastic drugs especially in urothelial carcinoma. The heterogeneity of Nectin-4 expression across the molecular subtypes was highlighted especially in urothelial cancers. A unique study using preclinical models demonstrated an upregulation of P-gp expression, which may explain the anti-Nectin-4 resistance mechanisms. Further studies are urgently needed to understand anti-Nectin-4 sensitivity and resistance phenomenon. The growing therapeutic associations of enfortumab vedotin offer optimistic opportunities in management and treatment of wide range of solid tumors including rare aggressive malignancies.

Impact of Radiation Therapy on Biological Parameters in Cancer Patients: Sub-analysis from the RIT Prospective Epidemiological Study.

Scarce data investigate the impact of radiotherapy (RT) on biology markers. An analysis of ancillary study of RIT (Radiation Impact on Thromboembolic events) prospective trial was carried out. All patients with non-metastatic solid tumors and treated with radiotherapy and/or brachytherapy in curative and consenting to have blood samples were included. A significant decrease in white blood count, (i.e. lymphocytes, monocytes, neutrophils and basophils) and platelet counts was observed after RT and maintained at 6 months. Whereas, eosinophils, D-dimers and hemoglobin levels were affected respectively 3 months and 6 months after RT initiation. Conversely, red cells count and CRP level were not affected by RT. This study is an advocacy to develop an understanding of basic immune system in relation with RT.

COVID-19 Vaccine-Related Adverse Events in Solid Cancer Patients Treated with Immunotherapy.

Little data are available regarding the effects of COVID-19 vaccine in cancer patients undergoing immunotherapy. Thereby, COVID-19 vaccine-related adverse events were monitored through a short questionnaire in solid cancer patients receiving immunotherapy. A total of 95 patients were included in this study. Two doses of vaccines were administered to cancer patients which mainly received Pembrolizumab (51.1%). Respectively 78.2% and 62.2% of patients reported no adverse events after the first and the second dose regardless of the type of vaccine used. Considering the high mortality rate due to COVID-19 among cancer patients, this study demonstrated the good tolerance of COVID-19 vaccine.

Preservation of organs related to future sexual function during prostate stereotactic body radiotherapy: feasibility analysis through a re-optimization process.

Preserving the quality of life and sexual function of patients with a localized prostate cancer remains a challenge for physicians and a major issue for patients. The present study aimed at demonstrating the feasibility of a dosimetric preservation of the sexual organs during prostate stereotactic radiotherapy planning. Patients from a single centre were retrospectively included in the RPAH-2 trial and randomized in Arm B if they presented with either a low- or intermediate- risk prostate cancer. A 37.5Gy in 5 fractions stereotactic body radiotherapy was delivered on the prostate gland. The corpus cavernosum, penile bulb and internal pudental arteries were retrospectively delineated before a re-optimization process. During this process, RPAH-2 trial dose constraints were respected on Gross Tumor Volume (GTV), Planning Target Volume and usual organs at risk. Pre-defined dose setting delivered to corpus cavernosum, penile bulb and internal pudental arteries were collected and compared before and after the re-optimization process. Nine patients were included in the study. A decrease of the median of each investigated dose setting (except D90% for corpus cavernosum) was reported after the re-optimization for corpus cavernosum, penile bulb and internal pudental arteries. Our study demonstrated the feasibility of a dosimetric preservation of structures considered as relevant to preserve sexual function after prostate stereotactic radiotherapy.

Dose to pelvic lymph nodes in locally advanced cervical cancer during high-dose-rate brachytherapy with tandem-ring applicators.

Purpose: The present study aimed to assess the correlation between dose to pelvic lymph nodes and to point B with tandem-ring (TR) applicators for intra-cavitary brachytherapy treatment of locally advanced cervical cancer. Material and methods: Cervical cancer patients treated at brachytherapy department of Lucien Neuwirth Cancer Center, from 2015 to 2018, were included. Target delineation was performed in compliance with GEC-ESTRO guidelines. Revised American Brachytherapy Society (ABS) point A was determined (ARN (right) and ALN (left)) as well as Manchester point B. Prescription dose was 25-35 Gy in 5 fractions. Pelvic lymph nodes were delineated, then dose to points A and B, and dose-volume histogram (DVH) parameters of delineated lymph nodes were extracted. Significant relationships or correlations between lymph nodes reference points, dosage to points B, and their DVH parameters were investigated. Results: The mean dose and mean percentage of the prescription dose to the left and right points B were 4.6 ±0.18 Gy and 82.08 ±0.72%, respectively. Pearson correlation coefficient R = 0.81 (p-value = 0.00) between dose to ARN and ALN points and prescription dose was obtained. Negative correlation between CTVHR volume and difference between French and ABS prescription points was found. Conclusions: Dose to point B can be a moderate surrogate for maximum, minimum, and median dose to the internal iliac and presacral lymph node, but cannot be for maximum dose to the obturator lymph node. Points B cannot be a reliable substitute for common and external iliac chains.

Cardiovascular Diseases Following Breast Cancer: Towards a Case-by-Case Assessment Through a Prediction Risk Score Model in 943 Patients.

OBJECTIVES: To identify patients at high risk of developing cardiovascular disease through the identification of risk factors among a large population of breast cancer women and to assess the performance of Abdel-Qadir risk prediction model score. MATERIALS AND METHODS: The medical records and baseline characteristics of all patients/tumors diagnosed with breast cancer from 2010 to 2011 in a French comprehensive cancer center were collected. Cardiovascular events were defined as arterial and cardiac events, atrial fibrillation and venous thromboembolism occurring during the 5-year follow-up. Abdel-Qadir multivariable prediction model for major adverse cardiovascular events were used with the concordance index (c-index) score to assess calibration by comparing predicted risks to observed probabilities. RESULTS: Among the 943 breast cancer patients included, 83 patients (8.8%) presented with at least one cardiovascular event, leading to a cumulative incidence of 0.07 at 5 years (95% confidence interval [CI], 0.055-0.088). The cumulative incidence of atrial fibrillation at 5 years was 0.01 (95% CI, 0.005-0.018). Factors associated with the occurrence of cardiovascular events were pre-existing cardiovascular diseases including high blood pressure (hazard ratio [HR]=1.78, 95% CI=1.07-2.97, P=0.028), acute coronary syndrome (HR=5.28, 95% CI: 2.16-12.88, P<0.05) and grade 3 Scarff-Blool-Richardson (HR=1.95, 95% CI: 1.21-3.15, P=0.006). With a c-index inferior to 0.7, the Abdel-Qadir score was not fully validated in our population. CONCLUSION: These findings call for the assessment of the performance of risk prediction models such as Abdel-Qadir score coupled with other factors such as Scarff Bloom and Richardson grading in order to identify patients at high risk of experiencing cardiotoxicity.

The Anti-Nectin 4: A Promising Tumor Cells Target. A Systematic Review.

The Nectin cell adhesion protein 4 (Nectin-4) is overexpressed in multiple human malignancies. Such aberrant expression is correlated with cancer progression and poor prognostic. Nectin-4 has emerged as a potential biomarker and promising targeted therapy. This review aimed to gather the current state of the literature about Nectin-4 relevance in preclinical tumor models and to summarize its clinical relevance regarding cancer. A systematic assessment of literature articles was performed by searching in PUBMED (MEDLINE) from the database inception to May 2021, following PRISMA guidelines. Preclinical models unanimously demonstrated membrane and cytoplasmic location of the Nectin-4. Furthermore, Nectin-4 was overexpressed whatever the location of the solid tumors. Interestingly, a heterogeneity of Nectin-4 expression has been highlighted in bladder urothelial carcinoma. High serum Nectin-4 level was correlated with treatment efficiency and disease progression. Finally, generated anti-drug-conjugated targeting Nectin-4 induced cell death in multiple tumor cell lines. Nectin-4 emerges as a promising target for anticancer drugs development because of its central role in tumorigenesis, and lymphangiogenesis. Enfortumab vedotin targeting Nectin-4 demonstrated encouraging results and should be extended to other types of solid tumors.