CSPG4 expression in soft tissue sarcomas is associated with poor prognosis and low cytotoxic immune response.

BACKGROUND: Soft tissue sarcomas (STS) are heterogeneous and pro-metastatic tumors. Identification of accurate prognostic factors and novel therapeutic targets are crucial. CSPG4 is a cell surface proteoglycan with oncogenic functions. It recently emerged as a potential target for immunotherapy, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in STS. However, expression of CSPG4 is poorly known in STS so far. METHODS: We analyzed CSPG4 gene expression in 1378 localized STS clinical samples, and searched for correlations with clinicopathological data, including disease-free survival (DFS), and with tumor immune features. RESULTS: CSPG4 expression was heterogeneous across samples. High expression was associated with younger patients' age, more frequent undifferentiated pleomorphic sarcoma and myxofibrosarcoma pathological subtypes, more frequent internal trunk tumor site, and more CINSARC high-risk samples. No correlation existed with pathological tumor size and grade, and tumor depth. Patients with high CSPG4 expression displayed 49% (95% CI 42-57) 5-year DFS versus 61% (95% CI 56-68) in patients with low expression (p = 3.17E-03), representing a 49% increased risk of event in the "CSPG4-high" group (HR = 1.49, 95% CI 1.14-1.94). This unfavorable prognostic value persisted in multivariate analysis, independently from other variables. There were significant differences in immune variables between "CSPG4-high" and "CSPG4-low" tumors. The "CSPG4-low" tumors displayed profiles suggesting higher anti-tumor cytotoxic immune response and higher potential vulnerability to immune checkpoint inhibitors (ICI). By contrast, the "CSPG4-high" tumors displayed profiles implying an immune-excluded tumor microenvironment, potentially induced by hypoxia, resulting from an immature chaotic microvasculature, and/or the presence of contractile myofibroblasts. CONCLUSIONS: Patients with "CSPG4-high" STS, theoretically candidate for CAR.CIKs, display shorter DFS and an immune environment unfavorable to vulnerability to CAR.CIKs, which could be improved by combining anti-angiogenic drugs able to normalize the tumor vasculature. By contrast, "CSPG4-low" STS are better candidates for immune therapy involving ICI.

Bing-Neel syndrome, a rare complication of Waldenström macroglobulinemia: analysis of 44 cases and review of the literature. A study on behalf of the French Innovative Leukemia Organization (FILO).

Central nervous system involvement by malignant cells is a rare complication of Waldenström macroglobulinemia, and this clinicopathological entity is referred to as the Bing-Neel syndrome. There is currently no consensus on the diagnostic criteria, therapeutic approaches and response evaluation for this syndrome. In this series, we retrospectively analyzed 44 French patients with Bing-Neel syndrome. Bing-Neel syndrome was the first manifestation of Waldenström macroglobulinemia in 36% of patients. When Waldenström macroglobulinemia was diagnosed prior to Bing-Neel syndrome, the median time interval between this diagnosis and the onset of Bing-Neel syndrome was 8.9 years. This study highlights the possibility of the occurrence of Bing-Neel syndrome without any other evidence of progression of Waldenström macroglobulinemia. The clinical presentation was heterogeneous without any specific signs or symptoms. Biologically, the median lymphocyte count in the cerebrospinal fluid was 31/mm(3). Magnetic resonance imaging revealed abnormalities in 78% of the cases. The overall response rate after first-line treatment was 70%, and the overall survival rate after the diagnosis of Bing-Neel syndrome was 71% at 5 years. Altogether, these results suggest that Bing-Neel syndrome should be considered in the context of any unexplained neurological symptoms associated with Waldenström macroglobulinemia. The diagnostic approach should be based on cerebrospinal fluid analysis and magnetic resonance imaging of the brain and spinal axis. It still remains difficult to establish treatment recommendations or prognostic factors in the absence of large-scale, prospective, observational studies.

Role of Unit Physicians and Challenges Encountered in the Follow-up of Military Personnel with Cancer.

INTRODUCTION: General practitioners (GPs) play a central role in the management and coordination of care of patients with malignant tumors and blood diseases. Civilian GPs encounter certain difficulties during the care of such patients. The practice of unit medicine in a military environment differs from that in a civilian context through expertise in fitness to serve and to deployment and the target population. We identified the difficulties encountered by "unit" physicians during and after cancer treatment. MATERIALS AND METHODS: We conducted a multicenter cross-sectional descriptive study from July 2, 2021, to September 30, 2022, targeting all military GPs belonging to the French Armed Forces Health Service. We sent a questionnaire consisting of 1 open- and 16 closed multiple-choice questions describing the population of unit physicians and their patients (questions 1-5), the difficulties encountered by physicians in the follow-up of military personnel with cancer (Questions 6, 7, 11, 12, and 13), and the potential information networks accessible to physicians (questions 8-10, 14, and 17). RESULTS: Three hundred and ninety physicians completed the questionnaires. Among the 700 military GPs, 390 physicians responded to the questionnaire and 327 completed it exhaustively. The questionnaire response rate was 55%. Of the responding physicians, 49% and 70% reported following patients with an "active" malignant tumor and a malignant tumor pathology in remission, respectively. Thirty-one percent of the physicians encountered difficulties with these patients as follows: 26% concerning fitness for duty, 17% in medical follow-up, 14% in addressing the psychological aspect, 11% concerning specialist accessibility for advice, 10% in managing deconditioning to effort, 9% in addressing the social aspect, 7% in medical management, and 6% concerning other issues. CONCLUSIONS: Difficulties in the follow-up of patients with cancer affect military doctors. They mainly concern fitness for duty and medical follow-up.

Prognostic and Predictive Value of LIV1 Expression in Early Breast Cancer and by Molecular Subtype.

BACKGROUND: LIV1 is a transmembrane protein that may become a new therapeutic target through the development of antibody-drug conjugates (ADCs). Few studies are available regarding the assessment of LIV1 expression in clinical breast cancer (BC) samples. METHODS: We analyzed LIV1 mRNA expression in 8982 primary BC. We searched for correlations between LIV1 expression and clinicopathological data, including disease-free survival (DFS), overall survival (OS), pathological complete response to chemotherapy (pCR), and potential vulnerability and actionability to anti-cancer drugs used or under development in BC. Analyses were performed in the whole population and each molecular subtype separately. RESULTS: LIV1 expression was associated with good-prognosis features and with longer DFS and OS in multivariate analysis. However, patients with high LIV1 expression displayed a lower pCR rate than patients with low expression after anthracycline-based neoadjuvant chemotherapy, including in multivariate analysis adjusted on grade and molecular subtypes. LIV1-high tumors were associated with higher probabilities of sensitivity to hormone therapy and CDK4/6 inhibitors and lower probabilities of sensitivity to immune-checkpoint inhibitors and PARP inhibitors. These observations were different according to the molecular subtypes when analyzed separately. CONCLUSIONS: These results may provide novel insights into the clinical development and use of LIV1-targeted ADCs by identifying prognostic and predictive value of LIV1 expression in each molecular subtype and associated vulnerability to other systemic therapies.

Fast Track Management of Primary Thyroid Lymphoma in the Very Elderly Patient.

A rapid growing cervical mass mobile while swallowing is the most common clinical presentation of severe thyroid malignancy. A 91-year-old female patient with a history of Hashimoto thyroiditis presented with clinical compressive neck symptoms. The patient had gastric Maltoma diagnosed that was surgically resected thirty years ago. A straightforward process was needed to reach full histological diagnosis and initiate prompt therapy. Ultrasound (US) showed a 67 mm hypoechoic left thyroid mass with reticulated pattern without signs of locoregional invasion. Percutaneous trans isthmic US-guided 18G core needle biopsy (CNB) disclosed diffuse large B cell lymphoma of the thyroid gland. FDG PET revealed two distinct thyroid and gastric foci (both SUVmax 39.1). Therapy was initiated rapidly to decrease clinical symptoms in this aggressive stage III primitive malignant thyroid lymphoma. The prognostic nomogram was calculated by using a seven-item scale, which disclosed a one-year overall survival rate of 52%. The patient underwent three R-CVP chemotherapy courses, then refused further treatment and died within five months. Real-time US-guided CNB approach led to rapid patient's management that was tailored to patient's characteristics. Transformation of Maltoma into diffuse large B cell lymphoma (DLBCL) into two body areas is deemed to be extremely rare.

Mazabraud Syndrome Associated with McCune-Albright Syndrome: A Case Report and Literature Review.

The Mazabraud syndrome is a rare form of bone fibrous dysplasia associated with intramuscular myxomas. The McCune-Albright syndrome is characterized by the association of dysplasia fibrous bone to one or more extra-osseous manifestations, including café-au-lait skin spots and endocrine disturbances. Here, we report on a new case of a 52-year-old man with sacroiliac polyostotic bone fibrous dysplasia associated with intramuscular myxomas of the left buttock and thigh and a café-au-lait skin spot. Biopsy analysis of one muscular lesion on the left thigh analysis revealed a spindle cell tumor with myxoid stroma with GNAS gene mutation, confirming the diagnosis of intramuscular myxoma. Given the absence of radiological sign of malignancy at the bone level and a few pains relieved by simple analgesics, no specific treatment was applied. In March 2022, after 18 months of follow-up, the magnetic resonance imaging and the PET-CT scan showed a stable disease. To our knowledge, this case is the fourth one reporting association of Mazabraud syndrome and McCune-Albright syndrome in a man. The association of intramuscular tumors and bone tumors in the same anatomical region and without any continuity, especially in lower limbs, must evoke the diagnosis of Mazabraud syndrome.

Rationale Efficacy and Safety Evidence of Lenvatinib and Pembrolizumab Association in Anaplastic Thyroid Carcinoma.

Anaplastic thyroid carcinoma (ATC) are highly aggressive malignant tumors with poor overall prognosis despite multimodal therapy. As ATC are extremely rare, no randomized controlled study has been published for metastatic disease. Thyrosine kinase inhibitors, especially lenvatinib and immune checkpoint inhibitors such as pembrolizumab, are emerging drugs for ATC. Few studies have reported the efficacity of pembrolizumab and lenvatinib association, resulting in its frequent off-label use. In this review, we discuss rationale efficacy and safety evidence for the association of lenvatinib and pembrolizumab in ATC. First, we discuss preclinical rationale for pembrolizumab monotherapy, lenvatinib monotherapy and synergistic action of pembrolizumab and lenvatinib in the metastatic setting. We also discuss clinical evidence for immunotherapy and pembrolizumab in ATC through the analysis of studies evaluating immunotherapy, lenvatinib and pembrolizumab lenvatinib association in ATC. In addition, we discuss the safety of this association and potential predictive biomarkers of efficiency.

How to Manage a Patient with Ocular Metastases?

Ocular metastases are the most frequent ocular malignant tumors; their prevalence is estimated around 5-10% and is even higher in patients with breast or lung cancer. They represent various clinical situations, but they share the same hierarchical multidisciplinary therapeutic challenge with respect to the way systemic and local therapies should be selected in combination or sequentially in the personalized medical history of a patient. The challenges include tumor control, eye preservation, and the minimization of iatrogenic damage to sensitive tissues surrounding the tumor in order to preserve vision. These aims should further contribute to maintaining quality of life in patients with metastases. Many patients with choroidal metastases have systemic molecular treatment for their primary tumor. However, secondary resistance to systemic treatment is common and may ultimately be associated with cancer relapse, even after an initial response. Therefore, it makes sense to propose local treatment concomitantly or after systemic therapy to provide a more sustainable response. The aim of this review is to present current therapeutic strategies in ocular metastases and discuss how to tailor the treatment to a specific patient.

Internal Jugular Vein Tumor Thrombus: A Tricky Question for the Thyroid Surgeon.

Internal jugular vein tumor thrombus is an extremely rare condition in thyroid carcinoma, but it does exist. Correlated with greater aggressiveness with a higher incidence of distant metastases at diagnosis and a higher recurrence rate, this important prognostic element should be systematically investigated by ultrasound operators in all patients presenting with thyroid carcinoma. The patient's follow-up must be careful. This can be a trap that surgeons must look for in their preoperative checklist. We report the case of a 58-year-old woman with an IJV thrombus associated with multiple bone metastases. She underwent successful surgical treatment, and postoperative pathology showed a poorly differentiated follicular carcinoma of the thyroid and a tumor thrombus in the internal jugular vein.

CISH Expression Is Associated with Metastasis-Free Interval in Triple-Negative Breast Cancer and Refines the Prognostic Value of PDL1 Expression.

Strategies are being explored to increase the efficiency of immune checkpoint inhibitors (ICIs) targeting PD1/PDL1 in triple-negative breast cancer (TNBC), including combination with therapies inhibiting intracellular immune checkpoints such as CISH (Cytokine-induced SH2 protein). Correlation between CISH expression and TNBC features is unknown. We retrospectively analyzed CISH expression in 1936 clinical TNBC samples and searched for correlations with clinical variables, including metastasis-free interval (MFI). Among TNBCs, 44% were identified as "CISH-up" and 56% "CISH-down". High expression was associated with pathological axillary lymph node involvement, more adjuvant chemotherapy, and Lehmann's immunomodulatory and luminal AR subtypes. The "CISH-up" class showed longer 5-year MFI (72%) than the "CISH-down" class (60%; p = 2.8 × 10-2). CISH upregulation was associated with activation of IFNα and IFNγ pathways, antitumor cytotoxic immune response, and signatures predictive for ICI response. When CISH and PDL1 were upregulated together, the 5-year MFI was 81% versus 52% when not upregulated (p = 6.21 × 10-6). The two-gene model provided more prognostic information than each gene alone and maintained its prognostic value in multivariate analysis. CISH expression is associated with longer MFI in TNBC and refines the prognostic value of PDL1 expression. Such observation might reinforce the therapeutic relevance of combining CISH inhibition with an anti-PD1/PDL1 ICI.

Identification of Atypical Circulating Tumor Cells with Prognostic Value in Metastatic Breast Cancer Patients.

Circulating tumor cells have a strong potential as a quasi-non-invasive tool for setting up a precision medicine strategy for cancer patients. Using a second-generation "filtration-based" technology to isolate CTCs, the Screencell™ technology (Sarcelles, France), we performed a large and simultaneous analysis of all atypical circulating tumor cells (aCTCs) isolated from the blood of metastatic breast cancer (mBC) patients. We correlated their presence with clinicopathological and survival data. We included 91 mBC patients from the PERMED-01 study. The median number of aCTCs was 8.3 per mL of blood. Three subsets of aCTCs, absent from controls, were observed in patients: single (s-aCTCs), circulating tumor micro-emboli (CTM), and giant-aCTCs (g-aCTCs). The presence of g-aCTCs was associated with shorter progression free survival and overall survival. This study highlights the heterogeneity of aCTCs in mBC patients both at the cytomorphological and molecular levels. In addition, it suggests the usefulness of the g-aCTC subset as a prognostic factor and a potential stratification tool to treat late-stage mBC patients and improve their chances of benefiting from early clinical trials.

Immune landscape of inflammatory breast cancer suggests vulnerability to immune checkpoint inhibitors.

Background. Anti-PD1/PDL1 immune checkpoint inhibitors (ICIs) showed promising results in breast cancer, and exploration of additional actionable immune checkpoints is ongoing. Inflammatory breast cancer (IBC) is an aggressive form of disease, the immune tumor microenvironment (TME) of which is poorly known. We aimed at providing the first comprehensive immune portrait of IBCs. Methods. From the gene expression profiles of 137 IBC and 252 non-IBC clinical samples, we measured the fractions of 22 immune cell types, expression of signatures associated with tertiary lymphoid structures (TLS) and with the response to ICIs (T cell-inflamed signature: TIS) and of 18 genes coding for major actionable immune checkpoints. The IBC/non-IBC comparison was adjusted upon the clinicopathological variables. Results. The immune profiles of IBCs were heterogeneous. CIBERSORT analysis showed profiles rich in macrophages, CD8+ and CD4 + T-cells, with remarkable similarity with melanoma TME. The comparison with non-IBCs showed significant enrichment in M1 macrophages, γδ T-cells, and memory B-cells. IBCs showed higher expression of TLS and TIS signatures. The TIS signature displayed values in IBCs close to those observed in other cancers sensitive to ICIs. Two-thirds of actionable immune genes (HAVCR2/TIM3, CD27, CD70, CTLA4, ICOS, IDO1, LAG3, PDCD1, TNFRSF9, PVRIG, CD274/PDL1, and TIGIT) were overexpressed in IBCs as compared to normal breast and two-thirds were overexpressed in IBCs versus non-IBCs, with very frequent co-overexpression. For most of them, the overexpression was associated with better pathological response to chemotherapy. Conclusion. Our results suggest the potential higher vulnerability of IBC to ICIs. Clinical trials.

Role of Cancer Surgery in the Improvement of the Operative Skills of Military Surgeons During Deployment: A Single-Center Study.

INTRODUCTION: The maintenance of military surgeons' operative skills is challenging. Different and specific training strategies have been implemented in this context; however, little has been evaluated with regard to their effectiveness. Cancer surgery is a part of military surgeons' activities in their home hospitals. This study aimed to assess the role of oncological surgery in the improvement of military surgeons' operative skills. METHODS: Between January and June 2019, the surgical activities of the departments of visceral, ear, nose, and throat, urological, and thoracic surgery were retrospectively reviewed and assessed in terms of the operative time (OT). All surgeons working at the Sainte Anne Military Teaching Hospital were sent a survey to rate on a 5-point scale the current surgical practices on their usefulness in improving surgical skills required for treating war injuries during deployment (primary endpoint) and to compare on a 10-point visual analog scale the influence of cancer surgery and specific training on surgical fluency (secondary endpoint). RESULTS: Over the study period, 2,571 hours of OT was analyzed. Oncological surgery represented 52.5% of the surgical activity and almost 1,350 hours of cumulative OT. Considering the primary endpoint, the mean rating allocated to cancer surgery was 4.53 ± 0.84, which was not statistically different than that allocated to trauma surgery (4.42 ± 1.02, P = 0.98) but higher than other surgery (2.47 ± 1.00, P < 0.001). Considering the secondary endpoint, cancer surgery was rated higher than specific training by all surgeons, without statistically significant difference (positive mean score of + 2.00; 95% IC: 0.85-3.14). CONCLUSION: This study demonstrates the usefulness of cancer surgery in improving the operative skills of military surgeons.

How did we take care of our older cancer patients during the first COVID-19 wave? The French experience.

BACKGROUND: The management of older cancer patients has been highly challenging for clinicians in a health-care system operating at maximum capacity during the COVID-19 pandemic. PATIENTS AND METHODS: We analyzed data from 9 different institutions. The primary endpoint was to assess the prevalence of adapted patient care during the pandemic for elderly cancer patients. The secondary endpoint was to assess the incidence of hospitalization and mortality due to COVID-19. All patients were older than 65years of age. RESULTS: We analyzed data from 332 outpatients' case files between 9th of March and 30th of April 2020. The median age was 75years (range: 65-101) and 53% were male. Because of the COVID-19 pandemic, more than half of the outpatients received modified patient care, defined as postponement or cancellation of surgery, irradiation scheme adapted, systemic treatment or the use of telemedicine. Among patients with localized cancer, 60% had a change in management strategy due to the pandemic. Changes in management strategy were made for 53% of patients at the metastatic stage. GCSF was used , in 83% of patients, increasing considerably in the context of the pandemic. Sixty-nine percent of physicians used telemedicine. In the final analysis, only one patient was hospitalized for COVID-19 infection. No deaths due to COVID-19 were reported in elderly cancer patients during this time period. CONCLUSION: Our study is the first to assess modification of patient care in elderly cancer outpatients during an epidemic. With this unprecedented crisis, our objective is to protect our patients from infection via protective barrier measures and social distancing, but also to guarantee the continuity of cancer care without overexposing this fragile population. Physicians were able to adapt their practice and used new forms of management, like telemedicine.

Evaluation of medical practices in oncology in the context of the COVID-19 pandemic in France: Physicians' point of view: the PRATICOVID study.

The cancer population seems to be more susceptible to COVID-19 infection and have worse outcomes. We had to adapt our medical practice to protect our patients without compromising their cancer prognosis. The national PRATICOVID study aims to describe the adaptation of cancer patient care for this population. We analyzed data from nine different institutions. The primary endpoint was to assess the prevalence of adapted patient care during the pandemic. The secondary endpoints were to describe the point of view of clinicians and patients during and after the pandemic. We analyzed 435 medical procedures between 9th of March and 30th of April. Because of the COVID-19 pandemic, 47.6% of the outpatients received modified patient care. Twenty-four percent of scheduled surgeries were postponed, or were performed without perioperative chemotherapy, 18.4% followed a hypofractioned schedule, and 57% had an adaptive systemic protocol (stopped, oral protocol, and spacing between treatments). Seventy percent of physicians used telemedicine. During this period, 67% of the physicians did not feel distressed taking care of their patients. However, 70% of physicians are worried about the aftermath of the lockdown, as regards future patient care. The PRATICOVID study is the first to assess modification of patient care in cancer outpatients during an epidemic. With this unprecedented crisis, physicians were able to adapt their practice in order to protect their patients against the virus while ensuring continuity of patient care. But physicians are worried about the aftereffects of the lockdown specifically in regard to care pathway issues.

[Impact of Her2 and BRCA1/2 status in high-dose chemotherapy and autologous stem cells transplantation in the treatment of breast cancer: The Institut Paoli Calmettes' experience]. / Expérience de l'institut Paoli-Calmettes concernant la chimiothérapie à haute dose et autogreffe de cellules souches hématopoïétiques pour la prise en charge des cancers mammaires : impact du statut Her2 et BRCA1/2.

INTRODUCTION: Studies evaluating chemotherapy high dose chemotherapy with autologous haematopoietic stem cell transplantation (HDC-ACSH) in the treatment of metastatic (MBC), locally advanced (LABC) and inflammatory (IBC) breast cancer have in common lack of biomarker information, in particular the HER2 status. PATIENTS AND METHODS: All consecutive female patients treated for breast cancer with HDC and AHSCT at Institut Paoli Calmettes between 2003 and 2012 were included. Patients were categorized in three subtypes based on hormonal receptor (HR) and HER2 status of the primary tumor: luminal, (HR+/HER2-), HER2 (HER2+, any HR) and triple negative (TN) (HER2- and HR-). The main objective was the analysis of overall survival (OS) according to the IHC subtypes. RESULTS: Three hundred and seventy-seven patients were included. For MBC, the TN subtype appeared to have the worst prognosis with a median OS of 19.68 months (95 % CI 11.76-44.4) compared to 44.64 months (95 % CI 40.32-67.56) for the luminal subtype and a median OS not reached for the HER2 subtype (P<0.01). For IBC, HER2 subgroup appeared to have the best prognosis with a 5-year OS of 89 % (95 % CI 64-97) compared to 57 % (95 % CI 33-76) for the TN subgroup (HR 5.38, 95 % CI 1.14-25.44; P=0.034). For CSLA, luminal subgroup appeared to have the best prognosis with a 5-year OS of 92 % (95 % CI 71-98) against 75 % (95 % CI 46-90) for HER 2 subtype and 70 % (95 %CI 97-88) for TN subtype (P=0.301). CONCLUSION: The HDC-ACSH does not change the prognosis value of IHC subtype in breast cancer patients.