Efficacy of a physiotherapy, yoga and patient education programme for patients with breast cancer and hormone therapy-induced pain: a multicentre randomised study protocol (SKYPE 2).

INTRODUCTION: Osteoarticular pain is experienced by approximately 50% of patients with breast cancer under hormone therapy and can increase the risk of therapy discontinuation. Among complementary therapies, yoga has shown efficacy regarding reduction of fatigue, anxiety, pain due to hormone therapy and inflammation. Personalised patient education programmes increase engagement and motivation, and induce effective behavioural changes. The SKYPE programme, an integrated intervention combining physiotherapy, yoga and patient education, showed promising efficacy on hormone therapy-induced pain in a previous pilot study. In this study, we hypothesised that using theory-based patient education favour learning and practising 15 min of at-home yoga every day to decrease hormone therapy-induced pain. METHODS AND ANALYSIS: This multicentre randomised study will assess the efficacy of the SKYPE programme on pain reduction compared with standard care in patients with breast cancer reporting osteoarticular pain due to hormone therapy. Main secondary objectives will describe pain evolution and characteristics, patient adhesion to yoga sessions and home practice, forward flexibility, quality of life, fatigue, anxiety and compliance to hormone therapy. Patients in the intervention group will participate in 1 weekly educational yoga session of 90 min for 6 weeks, supervised by physiotherapists (period 1). They will also perform daily at-home 15 min yoga sessions for 12 weeks, the total duration of the intervention (periods 1 and 2). Pain will be evaluated during physiotherapy check-ups at baseline (T0), at 6 weeks (T1) and at 12 weeks (T2). ETHICS AND DISSEMINATION: This study was approved by the ethics committee (CPP Ile de France 8 on 22 June 2020). The results will be disseminated to patients and healthcare professionals, and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04457895.

A novel Fc-engineered cathepsin D-targeting antibody enhances ADCC, triggers tumor-infiltrating NK cell recruitment, and improves treatment with paclitaxel and enzalutamide in triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) prognosis is poor. Immunotherapies to enhance the antibody-induced natural killer (NK) cell antitumor activity are emerging for TNBC that is frequently immunogenic. The aspartic protease cathepsin D (cath-D), a tumor cell-associated extracellular protein with protumor activity and a poor prognosis marker in TNBC, is a prime target for antibody-based therapy to induce NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). This study investigated whether Fc-engineered anti-cath-D antibodies trigger ADCC, their impact on antitumor efficacy and tumor-infiltrating NK cells, and their relevance for combinatory therapy in TNBC. METHODS: Cath-D expression and localization in TNBC samples were evaluated by western blotting, immunofluorescence, and immunohistochemistry. The binding of human anti-cath-D F1M1 and Fc-engineered antibody variants, which enhance (F1M1-Fc+) or prevent (F1M1-Fc-) affinity for CD16a, to secreted human and murine cath-D was analyzed by ELISA, and to CD16a by surface plasmon resonance and flow cytometry. NK cell activation was investigated by flow cytometry, and ADCC by lactate dehydrogenase release. The antitumor efficacy of F1M1 Fc-variants was investigated using TNBC cell xenografts in nude mice. NK cell recruitment, activation, and cytotoxic activity were analyzed in MDA-MB-231 cell xenografts by immunophenotyping and RT-qPCR. NK cells were depleted using an anti-asialo GM1 antibody. F1M1-Fc+ antitumor effect was assessed in TNBC patient-derived xenografts (PDXs) and TNBC SUM159 cell xenografts, and in combination with paclitaxel or enzalutamide. RESULTS: Cath-D expression on the TNBC cell surface could be exploited to induce ADCC. F1M1 Fc-variants recognized human and mouse cath-D. F1M1-Fc+ activated NK cells in vitro and induced ADCC against TNBC cells and cancer-associated fibroblasts more efficiently than F1M1. F1M1-Fc- was ineffective. In the MDA-MB-231 cell xenograft model, F1M1-Fc+ displayed higher antitumor activity than F1M1, whereas F1M1-Fc- was less effective, reflecting the importance of Fc-dependent mechanisms in vivo. F1M1-Fc+ triggered tumor-infiltrating NK cell recruitment, activation and cytotoxic activity in MDA-MB-231 cell xenografts. NK cell depletion impaired F1M1-Fc+ antitumor activity, demonstrating their key role. F1M1-Fc+ inhibited growth of SUM159 cell xenografts and two TNBC PDXs. In combination therapy, F1M1-Fc+ improved paclitaxel and enzalutamide therapeutic efficacy without toxicity. CONCLUSIONS: F1M1-Fc+ is a promising immunotherapy for TNBC that could be combined with conventional regimens, including chemotherapy or antiandrogens.

Benefits of cardiac coherence combined with medical hypnosis on preoperative anxiety before cancer surgery: the COHEC II study trial protocol.

INTRODUCTION: Preoperative anxiety is a frequent problem that can lead to complications both during anaesthesia and in the postoperative period, especially in oncology. Studies have shown that it can be managed using non-pharmacological approaches, but few works have evaluated psychoeducational programmes. The aim of the COHErence Cardiaque (COHEC) II Study is to evaluate the combination of medical hypnosis (MH) and cardiac coherence (CC) training to manage preoperative anxiety in patients with cancer. METHODS AND ANALYSIS: COHEC II is an ongoing multicentre randomised clinical trial carried out in three French comprehensive cancer centres. In total, 296 patients who will undergo surgery for cancer will be recruited during 18 months and will be randomised in the control arm or the intervention arm. Patients in the intervention arm will follow a daily programme that combines MH and CC, starting 7 days before surgery. The control arm will receive the standard treatment to manage preoperative anxiety. The primary endpoint is the anxiety level on surgery day, measured using a Visual Analogue Scale. Secondary endpoints are patient adherence to the programme, satisfaction and postsurgery recovery quality. ETHICS AND DISSEMINATION: The study protocol was approved by the French Ethics Committee (Comité de Protection des Personnes EST-II) on 24 November 2021 and will be carried out following the good practice guidelines and the Declaration of Helsinki. Results will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT05197972.

Anti-cathepsin D immunotherapy triggers both innate and adaptive anti-tumour immunity in breast cancer.

BACKGROUND AND PURPOSE: Triple-negative breast cancer (TNBC) has poorer outcomes than other breast cancers (BC), including HER2+ BC. Cathepsin D (CathD) is a poor prognosis marker overproduced by BC cells, hypersecreted in the tumour microenvironment with tumour-promoting activity. Here, we characterized the immunomodulatory activity of the anti-CathD antibody F1 and its improved Fab-aglycosylated version (F1M1) in immunocompetent mouse models of TNBC (C57BL/6 mice harbouring E0771 cell grafts) and HER2-amplified BC (BALB/c mice harbouring TUBO cell grafts). EXPERIMENTAL APPROACH: CathD expression was evaluated by western blotting and immunofluorescence, and antibody binding to CathD by ELISA. Antibody anti-tumour efficacy was investigated in mouse models. Immune cell recruitment and activation were assessed by immunohistochemistry, immunophenotyping, and RT-qPCR. KEY RESULTS: F1 and F1M1 antibodies remodelled the tumour immune landscape. Both antibodies promoted innate antitumour immunity by preventing the recruitment of immunosuppressive M2-polarized tumour-associated macrophages (TAMs) and by activating natural killer cells in the tumour microenvironment of both models. This translated into a reduction of T-cell exhaustion markers in the tumour microenvironment that could be locally supported by enhanced activation of anti-tumour antigen-presenting cell (M1-polarized TAMs and cDC1 cells) functions. Both antibodies inhibited tumour growth in the highly-immunogenic E0771 model, but only marginally in the immune-excluded TUBO model, indicating that anti-CathD immunotherapy is more relevant for BC with a high immune cell infiltrate, as often observed in TNBC. CONCLUSION AND IMPLICATION: Anti-CathD antibody-based therapy triggers the anti-tumour innate and adaptive immunity in preclinical models of BC and is a promising immunotherapy for immunogenic TNBC.

Gadolinium-Based Nanoparticles Sensitize Ovarian Peritoneal Carcinomatosis to Targeted Radionuclide Therapy.

Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [177Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. Methods: First, the optimal activity of [177Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2-positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [177Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [177Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs' subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. Results: The optimal [177Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [177Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [177Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to 177Lu increased the Auger electron yield but not the absorbed dose. Conclusion: Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis.

A prospective registry study of stereotactic magnetic resonance guided radiotherapy (MRgRT) for primary liver tumors.

BACKGROUND AND PURPOSE: Stereotactic body radiation therapy (SBRT) has demonstrated safe and effective results for primary liver tumors. Magnetic Resonance guided Radiotherapy (MRgRT) is an innovative radiotherapy modality for abdominal tumors. The aim of this study is to report on acute and late toxicities and initial oncological results for primary liver tumors treated with MRgRT. MATERIALS AND METHODS: We prospectively included in our cohort all patients treated by MRgRT for a primary liver tumor at the Montpellier Cancer Institute. The primary endpoint was acute and late toxicities assessed according to CTCAE v 5.0. The mean prescribed dose was 50 Gy in 5 fractions. RESULTS: Between October 2019 and April 2022, MRgRT treated 56 patients for 72 primary liver lesions. No acute or late toxicities of CTCAE grade greater than 2 attributable to radiotherapy were noted during follow-up. No cases of radiation-induced liver disease (RILD), either classical or non-classical, occurred. After a median follow-up of 13.2 months (95% CI [8.8; 15.7]), overall survival was 85.1% (95% CI: [70.8; 92.7]) at 1 year and 74.2% at 18 months (95% CI [52.6; 87.0]). Local control was 98.1% (95% CI: [87.4; 99.7]) and 94.7% (95% CI: [79.5; 98.7]) at 12 and 18 months, respectively. Among the HCC subgroup, no local recurrences were observed. CONCLUSION: MRgRT for primary liver tumors is safe without severe adverse events and reach excellent local control. Numerous studies are underway to better assess the value of MRI guidance and adaptive process in these indications.

Bevacizumab in recurrent WHO grades II-III glioma.

Purpose: The management of recurrent WHO grades II-III (rGII-III) glioma is not well established. This study describes the clinical outcomes in patients who received bevacizumab as rescue treatment. Methods: In this retrospective study, the main inclusion criteria were as follows: adult patients with histologicaly proved rGII-III glioma according 2016 WHO classification treated with bevacizumab from 2011 to 2019, T1 contrast enhancement on MRI. Efficacy was assessed using the high-grade glioma 2017 Response Assessment in Neuro-Oncology criteria. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Eighty-one patients were included (M/F ratio: 1.7, median age at diagnosis: 38 years) among whom 46 (56.8%) had an initial diagnosis of grade II glioma. Previous treatments included at least one surgical intervention, radiotherapy (98.8%), and ≥ 2 chemotherapy lines (64.2%). After bevacizumab initiation, partial response, stable disease, and progressive disease were observed in 27.2%, 22.2%, and 50.6% of patients. The median PFS and OS were 4.9 months (95% confidence interval [CI] 3.7-6.1) and 7.6 months (95% CI 5.5-9.9). Bevacizumab severe toxicity occurred in 12.3%. Twenty-four (29.6%) patients discontinued bevacizumab without radiological progression. Oligodendroglioma and age ≥ 38 years at diagnosis were more frequent in this subgroup (odds ratio = 0.24, 95% CI 0.07-0.84, p = 0.023 and 0.36, 95% CI 0.13-0.99, p = 0.042). Ten of these 24 patients were alive at 12 months and two patients at 8 years after bevacizumab initiation, without any subsequent treatment. Conclusion: Bevacizumab can be an option for heavily pretreated patients with rGII-III glioma with contrast enhancement. In our study, bevacizumab displayed prolonged activity in a subgroup of patients.

Design and selection of optimal ErbB-targeting bispecific antibodies in pancreatic cancer.

The ErbB family of receptor tyrosine kinases is a primary target for small molecules and antibodies for pancreatic cancer treatment. Nonetheless, the current treatments for this tumor are not optimal due to lack of efficacy, resistance, or toxicity. Here, using the novel BiXAb™ tetravalent format platform, we generated bispecific antibodies against EGFR, HER2, or HER3 by considering rational epitope combinations. We then screened these bispecific antibodies and compared them with the parental single antibodies and antibody pair combinations. The screen readouts included measuring binding to the cognate receptors (mono and bispecificity), intracellular phosphorylation signaling, cell proliferation, apoptosis and receptor expression, and also immune system engagement assays (antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity). Among the 30 BiXAbs™ tested, we selected 3Patri-1Cetu-Fc, 3Patri-1Matu-Fc and 3Patri-2Trastu-Fc as lead candidates. The in vivo testing of these three highly efficient bispecific antibodies against EGFR and HER2 or HER3 in pre-clinical mouse models of pancreatic cancer showed deep antibody penetration in these dense tumors and robust tumor growth reduction. Application of such semi-rational/semi-empirical approach, which includes various immunological assays to compare pre-selected antibodies and their combinations with bispecific antibodies, represents the first attempt to identify potent bispecific antibodies against ErbB family members in pancreatic cancer.

Improving the response to oxaliplatin by targeting chemotherapy-induced CLDN1 in resistant metastatic colorectal cancer cells.

BACKGROUND: Tumor resistance is a frequent cause of therapy failure and remains a major challenge for the long-term management of colorectal cancer (CRC). The aim of this study was to determine the implication of the tight junctional protein claudin 1 (CLDN1) in the acquired resistance to chemotherapy. METHODS: Immunohistochemistry was used to determine CLDN1 expression in post-chemotherapy liver metastases from 58 CRC patients. The effects of oxaliplatin on membrane CLDN1 expression were evaluated by flow cytometry, immunofluorescence and western blotting experiments in vitro and in vivo. Phosphoproteome analyses, proximity ligation and luciferase reporter assays were used to unravel the mechanism of CLDN1 induction. RNAseq experiments were performed on oxaliplatin-resistant cell lines to investigate the role of CLDN1 in chemoresistance. The "one-two punch" sequential combination of oxaliplatin followed by an anti-CLDN1 antibody-drug conjugate (ADC) was tested in both CRC cell lines and murine models. RESULTS: We found a significant correlation between CLDN1 expression level and histologic response to chemotherapy, CLDN1 expression being the highest in resistant metastatic residual cells of patients showing minor responses. Moreover, in both murine xenograft model and CRC cell lines, CLDN1 expression was upregulated after exposure to conventional chemotherapies used in CRC treatment. CLDN1 overexpression was, at least in part, functionally related to the activation of the MAPKp38/GSK3ß/Wnt/ß-catenin pathway. Overexpression of CLDN1 was also observed in oxaliplatin-resistant CRC cell lines and was associated with resistance to apoptosis, suggesting an anti-apoptotic role for CLDN1. Finally, we demonstrated that the sequential treatment with oxaliplatin followed by an anti-CLDN1 ADC displayed a synergistic effect in vitro and in in vivo. CONCLUSION: Our study identifies CLDN1 as a new biomarker of acquired resistance to chemotherapy in CRC patients and suggests that a "one-two punch" approach targeting chemotherapy-induced CLDN1 expression may represent a therapeutic opportunity to circumvent resistance and to improve the outcome of patients with advanced CRC.

A straightforward method to quantify circulating mRNAs as biomarkers of colorectal cancer.

Optimizing the biomarker combination to be analyzed in liquid biopsies should improve personalized medicine. We developed a method to purify circulating cell-free mRNAs from plasma samples and to quantify them by RT-qPCR. We selected three candidate colorectal cancer biomarkers (B2M, TIMP-1, and CLU). Their mRNA levels were significantly higher in plasma of patients with metastatic colorectal cancer patients (mCRC) (n = 107) than in healthy individuals (HI) (n = 53). To increase the discriminating performance of our method, we analyzed the sum of the three mRNA levels (BTC index). The area under the ROC curve (AUC) to estimate the BTC index capacity to discriminate between mCRC and HI plasma was 0.903. We also determined the optimal BTC index cut-off to distinguish between plasma samples, with 82% of sensitivity and 93% of specificity. By using mRNA as a novel liquid biopsy analytical parameter, our method has the potential to facilitate rapid screening of CRCm.

Trismus Occurrence and Link With Radiotherapy Doses in Head and Neck Cancer Patients Treated With Chemoradiotherapy.

BACKGROUND: Chemoradiotherapy (CRT) for head and neck cancer (HNC) induces side-effects, including trismus, which impairs quality of life by causing difficulty to eat, speak, and maintain good oral hygiene, and by altering social life. Given the wide variation of reported trismus prevalence and as a first mandatory step for the preventive physiotherapy OPEN program (NCT03979924) this study evaluated trismus occurrence and its link with radiation doses. METHODS: Study population was non-larynx HNC patients with epidermoid carcinoma treated with CRT, with or without surgery. A physiotherapist measured maximal interincisal distance before, during and after CRT, at 10 weeks and 6 months. The proportion of patients with trismus (with a 95% confidence interval) was estimated. Irradiation doses were analyzed between patients with and without trismus using non-parametric Kruskal-Wallis test. RESULTS: We included 45 patients (77.8% male), median age 61 years (range 41-77). The proportion of trismus at baseline was 24.4%, 26.8% at 10 weeks and 37.1% at 6 months. During radiotherapy, it was 27.9% at week 3 and increased to 41.9% at week 6. Trismus occurrence at 10 weeks was higher when the radiation dose to the ipsilateral lateral pterygoid muscle was above the median value, that is, 36.8 grays. CONCLUSION: Trismus occurrence differed according to radiation dose and cancer location. These findings highlight the necessity of early preventive physiotherapy programs to reduce trismus occurrence. The second step, of the interventional multicenter OPEN program, is currently evaluating the impact of preventive physiotherapy and patient education on trismus in a sample of 175 patients.

Hypnosis on patients treated with adjuvant chemotherapy for breast cancer: A feasibility study.

BACKGROUND: Acceptability and tolerance of chemotherapy on patients treated for breast cancer remain challenging. Complementary approaches such as hypnosis may have a favorable impact both at the time of announcing and during chemotherapy, due to the notorious anxiety, distress, and self-perceived dysfunction. The objective of the study was that the patients complied with at least four self-hypnosis sessions out of the six cycles of chemotherapy. METHODS: This open, prospective longitudinal study assessed feasibility of compliance to self-hypnosis during chemotherapy in an outpatients setting. Training sessions were given by a hypnotherapist. Throughout each cycle of chemotherapy, the patient had to use self-hypnosis to better control her anxiety or any difficulties. Nurses could offer help to the patient. Chemotherapy-associated side effects were evaluated through the NCI-Common Toxicity Criteria for Adverse Events v 4.03; moreover, side effects as pain, nausea, vomiting, fatigue, and anxiety were also evaluated during chemotherapy using a visual analogic scale. Health-related quality of life, emotional distress (anxiety and depression), and cancer-related fatigue were assessed (at inclusion, end of chemotherapy and 3 months later) using the EORTC QLQ-C30 and QLQ-BR23, HADS and MFI-20 questionnaires, respectively. The number of patients screened and actually included in the study was reported, as the reasons for refusal. RESULTS: Thirty-five patients were included with a median age of 55 years (35-78). All patients received a hypnosis training session. The overall compliance with self-hypnosis was 68.6% (95% CI: 50.7%-83.2%), meaning that more than two thirds of patients performed at least four sessions of self-hypnosis. According to NCI-CTCAE, Grade 2 nausea and vomiting was observed in 45.7% and 22.9%, respectively, Grade 2 fatigue in 62.9%. Based on the HADS questionnaire, anxiety increased at the end of the chemotherapy and returned to the initial value 3 months later (p = .97) whereas depression significantly decrease 3 months after the end of chemotherapy with respect to the inclusion (p = .003). Role, emotional, and cognitive functioning were slightly affected throughout the treatment, in contrast to dyspnea or physical functioning. CONCLUSION: Our study showed that self-hypnosis was feasible on patients newly diagnosed for breast cancer receiving chemotherapy.

Determination of biomarkers associated with neoadjuvant treatment response focusing on colibactin-producing Escherichia coli in patients with mid or low rectal cancer: a prospective clinical study protocol (MICARE).

INTRODUCTION: The management of mid and low rectal cancer is based on neoadjuvant chemoradiotherapy (CRT) followed by standardised surgery. There is no biomarker in rectal cancer to aid clinicians in foreseeing treatment response. The determination of factors associated with treatment response might allow the identification of patients who require tailored strategies (eg, therapeutic de-escalation or intensification). Colibactin-producing Escherichia coli (CoPEC) has been associated with aggressive colorectal cancer and could be a poor prognostic factor. Currently, no study has evaluated the potential association between intestinal microbiota composition and tumour response to CRT in mid and low rectal cancer. The aim of this study is to assess the association between response to neoadjuvant CRT and faecal intestinal microbiota composition and/or CoPEC prevalence in patients with mid or low rectal cancer. METHODS AND ANALYSIS: This is a non-randomised bicentric prospective clinical study with a recruitment capacity of 200 patients. Three stool samples will be collected from participants with histological-proven adenocarcinome of mid or low rectum who meet eligibility criteria of the study protocol: one before neoadjuvant treatment start, one in the period between CRT end and surgery and one the day before surgery. In each sample, CoPEC will be detected by culture in special media and molecular (PCR) approaches. The global microbiota composition will be also assessed by the bacterial 16S rRNA gene sequencing. Neoadjuvant CRT response and tumour regression grade will be described using the Dworak system at pathological examination. Clinical data and survival outcomes will also be collected and investigated. ETHICS AND DISSEMINATION: MICARE was approved by the local ethics committee (Comité de Protection des Personnes Sud-Est II, 18 December 2019. Reference number 2019-A02493-54 and the institutional review board. Patients will be required to provide written informed consent. Results will be published in a peer reviewed journal. TRIAL REGISTRATION NUMBER: NCT04103567.

Targeting the splicing isoforms of spleen tyrosine kinase affects the viability of colorectal cancer cells.

Spleen tyrosine kinase (Syk) expression have been both positively and negatively associated with tumorigenesis. Our goal was to evaluate the contribution of Syk and its two splice variants, full length Syk (L) and short isoform Syk (S), in the tumor biology of colorectal cancer cells (CRC). The analysis of Syk expression in primary human colorectal tumors, as well as the analysis of TCGA database, revealed a high Syk mRNA expression score in colorectal cancer tumors, suggesting a tumor promotor role of Syk in CRC. Our analysis showed that Syk (L) isoform is highly expressed in the majority of the tumor tissues and that it remains expressed in tumors in which global Syk expression is downregulated, suggesting the dependence of tumors to Syk (L) isoform. We also identified a small cluster of tumor tissues, which express a high proportion of Syk (S) isoform. This specific cluster is associated with overexpressed genes related to translation and mitochondria, and down regulated genes implicated in the progression of mitosis. For our functional studies, we used short hairpin RNA tools to target the expression of Syk in CRC cells bearing the activating K-Ras (G13D) mutation. Our results showed that while global Syk knock down increases cell proliferation and cell motility, Syk (L) expression silencing affects the viability and induces the apoptosis of the cells, confirming the dependence of cells on Syk (L) isoform for their survival. Finally, we report the promising potential of compound C-13, an original non-enzymatic inhibitor of Syk isolated in our group. In vitro studies showed that C-13 exerts cytotoxic effects on Syk-positive CRC cells by inhibiting their proliferation and their motility, and by inducing their apoptosis, while Syk-negative cell lines viability was not affected. Moreover, the oral and intraperitoneal administration of C-13 reduced the tumor growth of CRC DLD-1 cells xenografts in Nude mice in vivo.

The desmoplastic growth pattern is associated with second-stage completion and longer survival in 2-stage hepatectomy for colorectal cancer liver metastases.

BACKGROUND: Two-stage hepatectomy for bilobar colorectal cancer liver metastases is potentially curative for selected patients. Histological growth patterns of colorectal liver metastases (desmoplastic, replacement, and pushing) have prognostic value. Our aim was to evaluate their association with pathologic response to preoperative treatment, second-stage hepatectomy completion, and survival in patients treated with a curative-intent 2-stage hepatectomy. METHODS: In 67 patients planned for 2-stage hepatectomy, colorectal liver metastases resected from the first-stage hepatectomy were retrospectively evaluated for growth patterns and pathologic response according to Tumor Regression Grading, modified Tumor Regression Grading, and Blazer grading. Tumor Regression Grading 1 to 3, modified Tumor Regression Grading 1 to 3, and Blazer 0 and 1 defined good responders. RESULTS: Desmoplastic growth patterns (GP) were more frequent among good responders (P < .001). Second-stage hepatectomy completion was associated with desmoplastic growth patterns and pathologic response on univariate analysis and multivariable analyses (P = .017 and P = .041, respectively). Median follow-up was 84 months (95% confidence interval: 53.4 [not reached]). Nondesmoplastic GP patients and nonresponders had a poorer overall survival (hazard ratio = 3.86, 95% confidence interval: 2.11-7.07, P < .001 and hazard ratio = 2.14, 95% confidence interval: 1.19-3.83, P = .009, respectively) on univariate analysis. Nondesmoplastic growth pattern was the only factor associated with a poorer overall survival on multivariable analysis (hazard ratio = 4.17, 95% confidence interval: 1.79-9.74, P < .001). Nondesmoplastic GP was also associated with a poorer recurrence-free survival (hazard ratio = 2.05, 95% confidence interval: 1.13-3.70, P = .017). CONCLUSION: Desmoplastic GP could represent a useful morphological marker for early identification of patients who might benefit from 2-stage hepatectomy completion.

Hypnosis and cognitive behavioral therapy with online sessions to reduce fatigue in patients undergoing chemotherapy for a metastatic colorectal cancer: Rational and study protocol for a feasibility study.

Background: In metastatic colorectal cancer (CRCm), fatigue is pervasive, reduces quality of life, and is negatively associated with survival. Its course is explained in part by psychosocial variables such as emotional distress, coping strategies, or perceived control. Thus, to reduce fatigue, psychosocial interventions appear to be relevant. In some cancers, Cognitive Behavioral Therapies (CBT) reduce fatigue. Hypnosis is also used as a complementary therapy to reduce the side effects of cancer. While CBT requires specific training often reserved for psychologists, hypnosis has the advantage of being increasingly practiced by caregivers and is therefore less expensive (Montgomery et al., 2007). On the other hand, CBT and hypnosis remain understudied in the CRC, do not focus on the symptom of fatigue and in Europe such programs have never been evaluated. Objectives: Implementing an intervention in a healthcare setting is complex (e.g., economic and practical aspects) and recruiting participants can be challenging. The primary objective will therefore be to study the feasibility of two standardized interventions (hypnosis and CBT) that aim to reduce fatigue in patients with CRCm treated in a French cancer center. Methods and design: A prospective, single-center, randomized interventional feasibility study, using mixed methods (both quantitative and qualitative). A total of 60 patients will be allocated to each intervention group [Hypnosis (n = 30) and CBT (n = 30)]. Participants will be randomized into two parallel groups (ratio 1:1). Both programs will consist of 6 weekly sessions focusing on the CRF management over a period of 6 weeks. Trained therapists will conduct the program combining 3 face-to-face sessions and 3 online sessions. The feasibility and experience of interventions will be evaluated by the outcome variables, including the adhesion rate, the reasons for acceptability, relevance or non-adherence, the satisfaction, the fatigue evolution (with ecological momentary assessments), and the quality of life. All questionnaires will be self-assessment using an online application from the cancer center. Discussion: Results will highlight the barriers/facilitators to the implementation of the program and the relevance of the program to the patients, and will be used to generate hypotheses for a randomized control trial. Clinical trial registration: ClinicalTrials.gov Identifier: NCT04999306; https://clinicaltrials.gov/ct2/show/NCT04999306.

Tailored Management with Highly-Selective Diversion for Low Colorectal Anastomosis: Biochemical Postoperative Follow-Up and Long-Term Results from a Single-Institution Cohort.

BACKGROUND: Defunctioning stoma (DS) can decrease the rate of symptomatic anastomotic leakage (AL). Since 2010, we have used tailored, highly selective DS management for low colorectal anastomosis (LCRA). METHODS: In total, 433 rectal cancer patients underwent the same standardized procedure. Non-stoma (NS) management was used in patients with no surgical difficulties as well as good colonic preparation and quality of anastomoses. In all other cases, DS was used. C-reactive protein was measured during postoperative follow-up. Imbalance in the initial population was adjusted using propensity-score matching according to sex, age, body mass index, tumor location, and American Society of Anesthesiologists score. Rate of AL within 30 days, 5-year overall survival, local relapse-free survival, and disease-free survival were recorded. RESULTS: Anastomosis was mostly ultra-low and was performed equally by laparoscopy or robotic surgery. The overall rate of AL was 13.4%, with no significant differences between groups (DS, 12.2%; NS, 14.6%; p = 0.575). Operative time, blood loss, and hospital stay were significantly lower for NS patients. The rate of secondary stoma was 11.4% overall. Pathological results were similar, with a 98% R0 resection rate. With a median follow-up of 5.5 years for the NS and DS groups, the overall survival was 84.9% and 73.4%, respectively (p = 0.064), disease-free survival was 67.0% and 55.8%, respectively (p = 0.095), and local relapse-free survival was 95.2% and 88.7%, respectively (p = 0.084). The long-term, stoma-free rate was 89.1% overall. CONCLUSIONS: Tailoring DS for LCRA seems safe and could provide potential benefits in postoperative morbidity with the same long-term oncological results in NS patients. Prospective, multicentric studies should validate this approach.

Sexual quality of life assessment in young women with breast cancer during adjuvant endocrine therapy and patient-reported supportive measures.

PURPOSE: Sexual quality of life (QoL) is affected during and after breast cancer (BC) treatment. The purpose was to investigate sexual and global QoL and patient-reported measures to address this issue in young women (< 51 years) with BC after the acute treatment phase, during adjuvant endocrine therapy. METHODS: Three EORTC questionnaires and an additional specific questionnaire, developed for the study, were used to assess sexual and global QoL and patient-reported supportive measures in BC patients who had received their endocrine therapy for at least 24 months. Among the 54 eligible patients, 45 (83%) agreed to participate in the study. RESULTS: We showed a deterioration in sexual QoL and poor communication with healthcare professionals. Most patients (88.9%) declared that it was important that sexuality should be discussed with caregivers and that the partner should also be involved. Most patients (60%) had taken at least one action to overcome their sexual problems. Most of these interventions (63%) originated from the patient herself. CONCLUSIONS: Sexual QoL is a major issue in young BC patients and is poorly addressed by healthcare professionals. Most of the supportive methods used by the patients to overcome these side effects were on their own initiative. Communication and counseling on sexuality by healthcare professionals need to be improved during BC treatment. Patients suggested supportive measures they would find useful and appropriate to develop in the clinic. The final goal is to improve the sexual QoL of BC patients with the appropriate intervention and support.

Importance of Patient Education for At-home Yoga Practice in Women With Hormonal Therapy-induced Pain During Adjuvant Breast Cancer Treatment: A Feasibility Study.

BACKGROUND: Osteo-articular pain (OAP) is experienced by approximately 50% of women under hormonal therapy (HT) for breast cancer (BC), which increases the risk for therapy discontinuation. This study was aimed to assess benefits of yoga practice combined with patient education (PE) for at-home practice by evaluating feasibility among BC patients under HT and measuring OAP, flexibility and satisfaction. METHODS: Feasibility was evaluated by patient adherence as accomplishment of at least 4 out of 6 supervised yoga-PE sessions along with 70% or more at-home yoga sessions. Intervention (12 weeks) included two 6-weeks periods: P1 comprising one 90-minutes supervised yoga-PE session/week and 15-minutes daily at-home yoga and P2, daily autonomous at-home yoga sessions. Evaluations (at inclusion and by the end of each period) consisted in assessment of OAP on Visual Analog Scale (VAS), forward flexibility (cm) and patient satisfaction on Likert (0-10 points) scale. RESULTS: Between September 2018 and May 2019 we included 24 patients of median 53 years (range 36-72). Feasibility was validated by 83% successful adherence rate. Pain was significantly reduced from median VAS of 6 [range 4-10] to 4 [range 0-7] at the end of both P1 and P2 (p < 0.01), albeit with no difference between P1 and P2. Forward flexibility improved by a median gain of 8 cm (end of P2) and median satisfaction score of 10/10 [range 8-10]. CONCLUSION: Combined physiotherapy-yoga-PE intervention is a feasible strategy to increase at-home yoga practice with potential benefit on pain, flexibility, and satisfaction, thus prompting further evaluations in larger randomized multicenter trials. CLINICALTRIALS.GOV: NCT04001751.