Facial palsy after administration of immune checkpoint inhibitors: case report, literature review and clinical care management.

Neurological immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICI) are rare complications of immunotherapy, particularly dreadful for patients and clinical teams. Indeed, neurological irAEs are potentially severe and their diagnosis require prompt recognition and treatment. Additionally, the spectrum of neurological irAEs is broad, affecting either neuromuscular junction, peripheral or central nervous system. Here, we described the case of a 55-year man with metastatic melanoma, facing a brutal right peripheral cerebral palsy after his third ipilimumab/nivolumab infusion. After the case presentation, we reviewed the literature about this rare complication of immunotherapy, and described its diagnosis work-up and clinical management.

Piecemeal Resection for Large Colorectal Adenomas Remains Essential in 2022: A Single-Center Experience in a Tertiary French Center.

BACKGROUND AND AIMS: Colorectal lesions measuring greater than 20 mm are unsuitable for en bloc endoscopic mucosal resection (EMR): piecemeal EMR (PM-EMR) and endoscopic submucosal dissection (ESD) are needed. The European Society of Gastrointestinal Endoscopy (ESGE) recommends ESD only for microinfiltrative lesions, although Japanese teams perform en bloc ESD for all lesions. We report the outcomes obtained in our endoscopy unit for these lesions and assess the hybrid "knife-assisted piecemeal EMR" (KAPM-EMR) technique. The main aim was to assess the short-term outcomes (C1). The secondary objectives were to evaluate the long-term results (C2), adverse event rate and management of recurrence. METHODS: We retrospectively analyzed data from patients treated by PM-EMR, KAPM-EMR and ESD for a colorectal lesion measuring greater than 20 millimeters using prospective inclusion over four years. RESULTS: Data from 167 patients (median age: 70) with a median follow-up of 15.1 months were analyzed after excluding 95 patients. A total of 131 lesions were removed by PM-EMR, 24 by KAPM-EMR and 12 by ESD; 146/167 (87.4%) patients were considered in remission at C1. Recurrence was treated by endoscopy in 20/21 patients (95%); 86/89 (96.6%) were in remission at C2. A total of 16/167 patients developed adverse events, all of whom except one were endoscopically managed. KAPM-EMR was associated with a higher perforation risk (p=0.037). No differences in postoperative bleeding were found among the three groups (p=0.576). CONCLUSIONS: Piecemeal resection remains an effective and safe technique for large colorectal adenomas. KAPM-EMR may be useful but should be applied with caution due to the risk of perforation.

Dysthyroidism during immune checkpoint inhibitors is associated with improved overall survival in adult cancers: data mining of 1385 electronic patient records.

BACKGROUND: Dysthyroidism (DT) is a common toxicity of immune checkpoint inhibitors (ICIs) and prior work suggests that dysthyroidism (DT) might be associated with ICI efficacy. PATIENTS AND METHODS: ConSoRe, a new generation data mining solution, was used in this retrospective study, to extract data from electronic patient records of adult cancer patients treated with ICI at Institut Paoli-Calmettes (Marseille, France). Every DT was verified and only ICI-induced DT was retained. Survival analyses were performed by Kaplan-Meier method (log-rank test) and Cox model. To account for immortal time bias, a conditional landmark analysis was performed (2 months and 6 months), together with a time-varying Cox model. RESULTS: Data extraction identified 1385 patients treated with ICI between 2011 and 2021. DT was associated with improved overall survival (OS) (HR 0.46, (95% CI 0.33 to 0.65), p<0.001), with a median OS of 35.3 months in DT group vs 15.4 months in non-DT group (NDT). Survival impact of DT was consistent using a 6-month landmark analysis with a median OS of 36.7 months (95% CI 29.4 to not reported) in the DT group vs 25.5 months (95% CI 22.8 to 27.8) in the NDT group. In multivariate analysis, DT was independently associated with improved OS (HR 0.49, 95% CI 0.35 to 0.69, p=0.001). After adjustment in time-varying Cox model, this association remained significant (adjusted HR 0.64, 95% CI 0.45 to 0.90, p=0.010). Moreover, patients with DT and additional immune-related adverse event had increased OS compared with patients with isolated DT, with median OS of 38.8 months vs 21.4 months, respectively. CONCLUSION: Data mining identified a large number of patients with ICI-induced DT, which was associated with improved OS accounting for immortal time bias.

Assessment of biological effect of nab-paclitaxel combined with gemcitabine, using contrast enhanced ultrasonography and elastography, in advanced pancreatic ductal carcinoma: A single-center pilot study.

EUS associated with contrast-enhanced harmonic EUS (CH-EUS) and EUS elastography (EUS-E) are used in clinical practice to assess pancreatic tumor at the diagnosis. In case of pancreatic ductal adenocarcinoma (PDAC) with liver metastasis, nab-paclitaxel combined with gemcitabine is a first-line treatment option. We aimed to assess the modification of PDAC microenvironment induced by the combination of nab-paclitaxel with gemcitabine, by endoscopic ultrasonography techinics. This single center phase III study conducted between February 2015 and June 2016 included patients with pancreatic adenocarcinoma with mesurable liver metastasis and no prior cancer treatment fit for two cycles of nab-paclitaxel combined with gemcitabine. We aimed to perform EUS with CH-EUS and EUS-E of the pancreatic tumor, CT scan and contrast enhanced ultrasonogram (CE-US) of a reference liver metastasis, before and after the two cylces of chemotherapy. Primary end point was modification of vascularizaion of primary tumor and a reference liver metastasis. Secondary end points were modification of stromal content, safety profile of drug combination and tumor response rate. Sixteen patients were analyzed, but only 13 received two cycled of chemotherapy (CT) (toxicity [n = 1] or death [n = 2]). There was no statistical modification induced by CT concering vascularity of primary tumor (time to maximum intensity P = 0.24, value of maximum intensity P = 0.71, hypoechogenic aspect generated by injection of contrast enhancing agent), vascularity of a reference liver metastasis (time to maximum intensity P = 0.99, value of maximum intensity P = 0.71) and tumor elasticity (P = 0.22). Eleven patients had tumor response assessement, 6/11 (54%) had measurable disease response 4/11 (36%) with partial responses and 2/11 (18%) with stable disease. All other patients showed disease progression. No serious side effects occurred, 6/11 patients had a dose adjustment. We did not show significant modification of vascularity and elasticity but these results should be taken with caution because of important limitations.

Management and outcomes of brain metastases from pancreatic adenocarcinoma: a pooled analysis and literature review.

Background: Brain metastases (BM) are rare in pancreatic ductal adenocarcinoma (PDAC) and little data exists concerning these patients and their outcomes. Aim: We aimed to analyze the management, practices, and outcomes of patients presenting BM from PDAC both in our institution and in all cases reported in the literature. Methods: We conducted a retrospective, monocentric analysis using a data mining tool (ConSoRe) to identify all patients diagnosed with PDAC and BM in our comprehensive cancer center (Paoli-Calmettes Institute), from July 1997 to June 2022 (cohort 1). Simultaneously, we reviewed and pooled the case reports and case series of patients with PDAC and BM in the literature (cohort 2). The clinical characteristics of patients in each cohort were described and survival analyses were performed using the Kaplan-Meier method. Results: In cohort 1, 19 patients (0.3%) with PDAC and BM were identified with a median age of 69 years (range: 39-81). Most patients had metastatic disease (74%), including 21% with BM, at diagnosis. Lung metastases were present in 58% of patients. 68% of patients had neurological symptoms and 68% were treated by focal treatment (surgery: 21%, radiotherapy: 42%, Gamma Knife radiosurgery: 5%). In cohort 2, among the 61 PDAC patients with BM described in the literature, 59% had metastatic disease, including 13% with BM at diagnosis. Lung metastases were present in 36% of patient and BM treatments included: surgery (36%), radiotherapy (36%), radiosurgery (3%), or no local treatment (25%). After the pancreatic cancer diagnosis, the median time to develop BM was 7.8 months (range: 0.0-73.9) in cohort 1 and 17.0 months (range: 0.0-64.0) in cohort 2. Median overall survival (OS) in patients of cohort 1 and cohort 2 was 2.9 months (95% CI [1.7,4.0]) and 12.5 months (95% CI [7.5,17.5]), respectively. Conclusion: BM are very uncommon in PDAC and seem to occur more often in younger patients with lung metastases and more indolent disease. BM are associated with poor prognosis and neurosurgery offers the best outcomes and should be considered when feasible.

Impact of fiducial markers placement on the delineation of target volumes in radiation therapy for oesophageal cancer: FIDUCOR study.

Purpose: This prospective monocentric phase II study (FIDUCOR-study, NCT02526134) aimed to assess the impact of fiducial markers (FMs) implantation on conformal chemo-radiation therapy (CRT) planning in oesophageal carcinoma (EC) patients. Methods/materials: Fifteen EC patients were enrolled in the study. Each patient underwent two simulation CT-scans before (CT1) and after (CT2) FMs implantation, in the same position. FMs (3 mm length gold markers, preloaded in a 22G needle) were implanted after sedation, under endoscopic ultrasound (EUS) and X-Ray guidance, and were placed at the tumor's extremities, and in the visible lymph nodes. Target delineation and treatment plan were both performed first on CT1 with the assistance of diagnosis CT, gastroscopy and EUS details, and second on CT2 using FMs and CT-data. The value of FMs implantation was assessed by the difference of growth-tumor-volume (GTV) and clinical-target-volume (CTV) between CT1-based and CT2-based delineation. A significant difference was defined as a ≥5 mm-difference on axial(x) or coronal(y) slices, a ≥10mm-difference on sagittal slices, or a ≥20%-difference in GTV. The impact on dose distribution in organs at risk (OAR) (lung, heart, liver) was also studied. Results: Between 09/2014 and 12/2015, 15 patients could achieve fiducial procedures, without any complication. One FM migration occurred. We observed a significant modification of the GTV-dimension in 100% of the cases (15/15, 95%CI: [78.2;100.0]), mainly due to a difference in sagittal dimension with a mean variation of 11.2 mm and a difference> 10 mm for 8/15 patients (53.3%). One patient had a significant isocenter displacement as high as 20 mm. The oesophagus tumor was not seen on the CT-scan in one patient due to its small size. One patient had a distant lymph node metastasis not visible on CT-scan. We observed no significant impact on OAR distribution. Conclusion: In our study, FMs-implantation under EUS had a positive impact on accurate volume definition in EC-patients (modification of GTV in 15/15 patients). Close cooperation between gastroenterologist and radiation oncologist has the potential to improve local treatment of oesophageal carcinoma.

Mass Cytometry Reveals Classical Monocytes, NK Cells, and ICOS+ CD4+ T Cells Associated with Pembrolizumab Efficacy in Patients with Lung Cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non-small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. EXPERIMENTAL DESIGN: We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis). RESULTS: We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12-0.51; P < 0.0001). CONCLUSIONS: As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Case-Matched Comparison of Functional and Quality of Life Outcomes of Local Excision and Total Mesorectal Excision Following Chemoradiotherapy for Rectal Cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by radical surgery is the standard curative treatment for mid- to low-rectal cancer. However, the combination of these treatments may affect patients' GI and genitourinary functions and their quality of life. In the cases of good clinical response to neoadjuvant treatment, local excision is a rectal sparing strategy that would limit these side effects. OBJECTIVE: The aim of this study is to compare the effects of local excision or conventional laparoscopic total mesorectal excision after chemoradiotherapy in patients with rectal cancer. DESIGN: The design is a retrospective study. SETTING: The setting used is a single tertiary center. PATIENTS: Patients with mid- to low-rectal cancer treated with chemoradiotherapy and accessible via conservative surgery at our hospital between January 2010 and December 2018 were included. Patients undergoing local excision were matched 1 to 1 with the patients undergoing total mesorectal excision by age, sex, body mass index, tumor height, and year of surgery. MAIN OUTCOME MEASURES: Quality of life and digestive and genitourinary functions were measured using validated questionnaires. The socioeconomic impact was also assessed. RESULTS: Forty-four patients undergoing local excision agreed to participate and were matched with 44 patients undergoing total mesorectal excision. Patients who underwent local excision reported a more favorable global health status ( p < 0.01), emotional function ( p = 0.035), social function ( p = 0.04), and body image ( p = 0.04). The low anterior resection syndrome score (rate of major syndrome, 23.8% vs 54.5%; p < 0.01) and the specific fecal incontinence subscale score ( p < 0.01) were more favorable in the local excision group. Sexual and urinary outcomes were comparable between the 2 groups. Local excision had a lower impact on the professional status (35.7% vs 76.5%; p = 0.03). LIMITATIONS: The study limitations include its retrospective design and small sample size. CONCLUSIONS: When indicated, local excision improves the bowel function and quality of life of patients undergoing surgery for rectal cancer after chemoradiotherapy compared with total mesorectal excision. See Video Abstract at http://links.lww.com/DCR/B997 . COMPARACIN DE CASOS EMPAREJADOS DE LOS RESULTADOS FUNCIONALES Y DE CALIDAD DE VIDA DE LA ESCISIN LOCAL Y LA ESCISIN TOTAL DE MESORECTO DESPUS DE QUIMIORRADIOTERAPIA EN CNCER DE RECTO: ANTECEDENTES:La quimiorradioterapia neoadyuvante seguida de cirugía radical es el tratamiento curativo estándar para el cáncer de recto medio-bajo. Sin embargo, la combinación de estos tratamientos puede afectar las funciones gastrointestinales y genitourinarias de los pacientes y su calidad de vida. En casos de buena respuesta clínica al tratamiento neoadyuvante, la escisión local es una estrategia conservadora del recto que limitaría estos efectos secundarios.OBJETIVO:Este estudio comparó los efectos de la escisión local o escisión total de mesorecto laparoscópica convencional después de quimiorradioterapia en pacientes con cáncer de recto.DISEÑO:Estudio retrospectivo.ENTORNO CLINICO:Centro terciario único.PACIENTES:Se incluyeron pacientes con cáncer de recto medio-bajo tratados con quimiorradioterapia y accesibles mediante cirugía conservadora en nuestro hospital entre enero del 2010 y diciembre del 2018. Los pacientes sometidos a escisión local se emparejaron uno a uno con los sometidos a escisión total de mesorecto por edad, sexo, índice de masa corporal, altura del tumor y año de cirugía.PRINCIPALES MEDIDAS DE RESULTADO:La calidad de vida, las funciones digestivas y genitourinarias se midieron mediante cuestionarios validados. También se evaluó el impacto socioeconómico.RESULTADOS:Cuarenta y cuatro pacientes sometidos a escisión local aceptaron participar y fueron emparejados con 44 pacientes sometidos a escisión mesorrectal total. Los pacientes que se sometieron a escisión local informaron un estado de salud global más favorable ( p <0,01), función emocional ( p = 0,035), función social ( p = 0,04) e imagen corporal ( p = 0,04). La puntuación baja del síndrome de resección anterior (tasa de síndrome mayor: 23,8 % frente a 54,5 %; p <0,01) y la puntuación de la subescala de incontinencia fecal específica ( p <0,01) fueron más favorables en el grupo de escisión local. Los resultados sexuales y urinarios fueron comparables entre los dos grupos. La escisión local tuvo un menor impacto en el estatus profesional (35,7% vs 76,5%; p = 0,03).LIMITACIONES:Diseño retrospectivo, tamaño de muestra pequeño.CONCLUSIONES:Cuando está indicada, la escisión local mejora la función intestinal y la calidad de vida de los pacientes sometidos a cirugía por cáncer de recto después de quimiorradioterapia en comparación con escisión total de mesorecto. Consulte Video Resumen en http://links.lww.com/DCR/B997 . (Traducción-Dr. Francisco M. Abarca-Rendon ).

Pasireotide for Refractory Hypoglycemia in Malignant Insulinoma- Case Report and Review of the Literature.

Malignant insulinomas are functional neuroendocrine tumors of the pancreas and the primary cause of tumor-related hypoglycemia. Malignant insulinoma is rare and has a poor prognosis. We report a case of metastatic malignant insulinoma in a 64-year-old female patient with severe and refractory hypoglycemia. After several ineffective locoregional and systemic therapeutic lines for the secretory disease, the introduction of pasireotide, a second-generation somatostatin analog, provided an improved clinical and secretory evolution both quickly and sustainably, with an excellent safety profile. Pasireotide is an effective and well-tolerated therapy in the treatment of refractory hypoglycemia in metastatic insulinoma.

Genomic analysis of paired IDHwt glioblastomas reveals recurrent alterations of MPDZ at relapse after radiotherapy and chemotherapy.

PURPOSE: We aimed to identify genomic drivers of glioblastoma inevitable recurrence. METHODS: Ten pairs of initial and recurrent frozen IDHwt glioblastoma samples were screened by CGH Array. Next Generation Sequencing (NGS) was then performed on an enriched cohort of 19 pairs. MPDZ alterations were analyzed using TCGA dataset. RESULTS: Nineteen IDHwt glioblastoma patients were included. Median age was 54.5 y/o (37.2-72.8). Using CGH array, unsupervised analysis aggregated the cohort by paired initial and recurrent tumors. Only 44% of CGH Array alterations were conserved at recurrence (amplifications: 55%; deletions: 30%). Two regions (including FPR1, 2 and 3) were lost at relapse: 19q13.33 and 19q13.41. MPDZ and 25 other genes were altered in ≥20% of recurrent tumors. NGS analysis of 29 candidate genes revealed 4 genes with pathogenic mutations: (FPR2, REL, TYRP1 and MPDZ). MPDZ (Multiple PDZ Domain Crumbs Cell Polarity Complex Component) was altered by two pathogenic mutations occurring at relapse. Using TCGA dataset we observed that a lower MPDZ mRNA expression was associated with IDHwt (p < 0.001) and grade IV (p < 0.001) gliomas. Finally, a low mRNA MPDZ expression was significantly correlated to poor overall survival in both IDHwt and IDH mutated gliomas, reinforcing the potential pejorative impact of MPDZ loss. CONCLUSION: Our results suggest that MPDZ is more frequently altered at relapse after radio-chemotherapy in glioblastoma IDHwt patients, suggesting that MPDZ impairment could contribute to the systematic resistance of these tumors opening new therapeutic perspectives.

Endoscopic Ultrasound-Guided Radiofrequency Ablation as an Future Alternative to Pancreatectomy for Pancreatic Metastases from Renal Cell Carcinoma: A Prospective Study.

BACKGROUND: Pancreatic metastases (PM) from renal cell carcinoma (RCC) are rare, are associated with favorable outcomes and are usually handled by surgery or VEGFR inhibitors, which both have side effects. Endoscopic Ultrasound (EUS)-guided radiofrequency ablation (RFA) is an innovative approach to treat focally deep metastases and could be a relevant technique to control PM from RCC. METHODS: This monocentric, prospective study aimed to evaluate the safety and efficacy of EUS-RFA to treat PM. We included patients with confirmed and progressive PM from RCC. PM was ablated under general anesthesia with a linear EUS scope and a EUS-RFA 19-gauge needle electrode placed into the tumor. RESULTS: Twelve patients from Paoli-Calmettes Institute were recruited between May 2017 and December 2019. Median age was 70.5 years (range 61-75), 50% were female, 100% were ECOG 0-1. At inclusion, mean PM size was 17 mm (range 3-35 mm); and all were progressive before EUS-RFA. Seven patients had EUS-RFA as the only treatment for RCC. We performed 26 EUS-RFA procedures and 21 PM was ablated. Median follow up was 27.7 months (range 6.4-57.1). For evaluable PM, the 6- and 12-month focal control rates were 84% and 73% respectively. One patient treated with TKI developed a paraduodenal abscess 2 months after EUS-RFA and another patient with biliary stent developed hepatic abscesses few days after EUS-RFA. No other severe side effects were experienced. CONCLUSIONS: in this series, which is the largest ever reported, we showed that EUS-RFA is feasible and yields an excellent local control rate for PM from mRCC. With manageable complications, it could be a valuable alternative to pancreatic surgery in well-selected patients.

Soluble BTN2A1 Is a Potential Prognosis Biomarker in Pre-Treated Advanced Renal Cell Carcinoma.

The development of immune checkpoint inhibitors (ICI) has dramatically changed the landscape of therapies for metastatic renal cell carcinoma. However, many patients do not benefit from such therapy and prognostic or predictive validated biomarker validated for ICI are still needed to better select and treat patient. Plasmatic soluble immune checkpoints have been described as potential immune biomarkers in hematological malignancies and solids tumors, then, we would like to explore the prognostic value of different soluble immune checkpoints in patients with mRCC treated with nivolumab after TKI. We prospectively collected plasma samples before nivolumab infusion from 38 patients previously treated for mRCC with TKI at Paoli-Calmettes Institute, from the NIVOREN GETUG-AFU 26 study (NCT03013335). Enzyme-linked immunosorbent assays (ELISA) were performed for soluble forms of PD-1, PD-L1, global BTN3, BTLA, BTN3A1 and BTN2A1. Among the different soluble checkpoints analyzed, only high baseline plasmatic level of BTN2A1 was significantly associated with shorter PFS: median PFS was 3.95 months for sBTN2A1high vs 14.30 months for sBTN2A1low (sBTN2A1 cut-off: 6.7ng/mL; HR = 2.26, 95%CI [0.68 - 4.60], p = 0.0307). There was no statistical difference in OS between sBTN2A1high and sBTN2A1low. Our results suggest that the baseline level of plasmatic BTN2A1 could be an independent prognosis factor of PFS after nivolumab for pre-treated patient with mRCC. However, these results need to be validated in a larger prospective cohort and the biological role of BTN subfamily and γδ T cell immunity in mRCC must be elucidated.

EB1 Restricts Breast Cancer Cell Invadopodia Formation and Matrix Proteolysis via FAK.

Regulation of microtubule dynamics by plus-end tracking proteins (+TIPs) plays an essential role in cancer cell migration. However, the role of +TIPs in cancer cell invasion has been poorly addressed. Invadopodia, actin-rich protrusions specialized in extracellular matrix degradation, are essential for cancer cell invasion and metastasis, the leading cause of death in breast cancer. We, therefore, investigated the role of the End Binding protein, EB1, a major hub of the +TIP network, in invadopodia functions. EB1 silencing increased matrix degradation by breast cancer cells. This was recapitulated by depletion of two additional +TIPs and EB1 partners, APC and ACF7, but not by the knockdown of other +TIPs, such as CLASP1/2 or CLIP170. The knockdown of Focal Adhesion Kinase (FAK) was previously proposed to similarly promote invadopodia formation as a consequence of a switch of the Src kinase from focal adhesions to invadopodia. Interestingly, EB1-, APC-, or ACF7-depleted cells had decreased expression/activation of FAK. Remarkably, overexpression of wild type FAK, but not of FAK mutated to prevent Src recruitment, prevented the increased degradative activity induced by EB1 depletion. Overall, we propose that EB1 restricts invadopodia formation through the control of FAK and, consequently, the spatial regulation of Src activity.

Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials.

The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials.

Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report.

Immune checkpoint inhibitors (ICI) reinvigorate the immune system to recognize and destroy tumor cells. Because of this biological mechanism, patients might develop autoimmune toxicities, notably in the digestive tract (most frequently, hepatitis or colitis). A 70-year-old man with relapsed mesothelioma was treated with nivolumab in 3rd line. He was hospitalized for watery and foul-smelling diarrhea. He underwent gastrointestinal endoscopy, showing duodenitis and villous atrophy and measurement of serum IgA antibodies to tissue transglutaminase (tTG-IgA+), leading to the diagnosis of ICI-induced celiac disease. He was treated with steroids, proton pump inhibitors, and a gluten-free diet. If ICI-induced celiac disease is rare in the literature, increasing reports suggest that celiac disease might represent an underestimated ICI toxicity. This case highlights the necessity of complementary investigation (including tTG-IgA and endoscopic biopsies) in patients with atypical digestive symptoms during immunotherapy.

Medical Treatment of Lung Cancer: Can Immune Cells Predict the Response? A Systematic Review.

The landscape for medical treatment of lung cancer has irreversibly changed since the development of immuno-oncology (IO). Yet, while immune checkpoint blockade (ICB) revealed that T lymphocytes play a major role in lung cancer, the precise dynamic of innate and adaptive immune cells induced by anticancer treatments including chemotherapy, targeted therapy, and/or ICB is poorly understood. In lung cancer, studies evaluating specific immune cell populations as predictors of response to medical treatment are scarce, and knowledge is fragmented. Here, we review the different techniques allowing the detection of immune cells in the tumor and blood (multiplex immunohistochemistry and immunofluorescence, RNA-seq, DNA methylation pattern, mass cytometry, functional tests). In addition, we present data that consider different baseline immune cell populations as predictors of response to medical treatments of lung cancer. We also review the potential for assessing dynamic changes in cell populations during treatment as a biomarker. As powerful tools for immune cell detection and data analysis are available, clinicians and researchers could increase understanding of mechanisms of efficacy and resistance in addition to identifying new targets for IO by developing translational studies that decipher the role of different immune cell populations during lung cancer treatments.

Place of anti-EGFR therapy in older patients with metastatic colorectal cancer in 2020.

Almost half of the new cases of colorectal cancer concern patients aged ≥70 years. However, very few clinical trials have specifically included older patients. As a consequence, the treatment of these patients is controversial because the balance between clinical benefits and toxicities remains uncertain. In patients without comorbidities and with an ECOG performance score of 0-1, treatment indications are similar to those of younger patients. For frail patients, chemotherapy is possible, but a comprehensive geriatric assessment is recommended. Anti-EGFR (epidermal growth factor receptor) therapy is indicated either in combination with chemotherapy in the first-line or second-line setting or as monotherapy in the third-line setting (i.e., after failure of chemotherapy). For fit older patients, clinical trials that compared chemotherapy alone with doublet chemotherapy plus anti-EGFR in either first-line or second-line setting suggested that age is not an absolute contraindication for the use of this regimen. In frail patients, anti-EGFR monotherapy in the first-line, second-line or third-line setting has shown feasibility and antitumor activity and had mainly cutaneous toxicities that were easily managed. In any case, administration of treatment must be very cautious in older patients and the treatment dose needs to be adapted according to comorbidities.

A proximity-labeling proteomic approach to investigate invadopodia molecular landscape in breast cancer cells.

Metastatic progression is the leading cause of mortality in breast cancer. Invasive tumor cells develop invadopodia to travel through basement membranes and the interstitial matrix. Substantial efforts have been made to characterize invadopodia molecular composition. However, their full molecular identity is still missing due to the difficulty in isolating them. To fill this gap, we developed a non-hypothesis driven proteomic approach based on the BioID proximity biotinylation technology, using the invadopodia-specific protein Tks5α fused to the promiscuous biotin ligase BirA* as bait. In invasive breast cancer cells, Tks5α fusion concentrated to invadopodia and selectively biotinylated invadopodia components, in contrast to a fusion which lacked the membrane-targeting PX domain (Tks5ß). Biotinylated proteins were isolated by affinity capture and identified by mass spectrometry. We identified known invadopodia components, revealing the pertinence of our strategy. Furthermore, we observed that Tks5 newly identified close neighbors belonged to a biologically relevant network centered on actin cytoskeleton organization. Analysis of Tks5ß interactome demonstrated that some partners bound Tks5 before its recruitment to invadopodia. Thus, the present strategy allowed us to identify novel Tks5 partners that were not identified by traditional approaches and could help get a more comprehensive picture of invadopodia molecular landscape.