ROX index performance to predict high-flow nasal oxygen outcome in Covid-19 related hypoxemic acute respiratory failure.

BACKGROUND: Given the pathophysiology of hypoxemia in patients with Covid-19 acute respiratory failure (ARF), it seemed necessary to evaluate whether ROX index (ratio SpO2/FiO2 to respiratory rate) could accurately predict intubation or death in these patients initially treated by high-flow nasal oxygenation (HFNO). We aimed, therefore, to assess the accuracy of ROX index to discriminate between HFNO failure (sensitivity) and HFNO success (specificity). METHODS: We designed a multicentre retrospective cohort study including consecutive patients with Covid-19 ARF. In addition to its accuracy, we assessed the usefulness of ROX index to predict HFNO failure (intubation or death) via logistic regression. RESULTS: Among 218 ARF patients screened, 99 were first treated with HFNO, including 49 HFNO failures (46 intubations, 3 deaths before intubation). At HFNO initiation (H0), ROX index sensitivity was 63% (95%CI 48-77%) and specificity 76% (95%CI 62-87%) using Youden's index. With 4.88 as ROX index cut-off at H12, sensitivity was 29% (95%CI 14-48%) and specificity 90% (95%CI 78-97%). Youden's index yielded 8.73 as ROX index cut-off at H12, with 87% sensitivity (95%CI 70-96%) and 45% specificity (95%CI 31-60%). ROX index at H0 was associated with HFNO failure (p = 0.0005) in univariate analysis. Multivariate analysis showed that SAPS II (p = 0.0003) and radiographic extension of pulmonary injuries (p = 0.0263), rather than ROX index, were predictive of HFNO failure. CONCLUSIONS: ROX index cut-off values seem population-specific and the ROX index appears to have a technically acceptable but clinically low capability to discriminate between HFNO failures and successes in Covid-19 ARF patients. In addition, SAPS II and pulmonary injuries at ICU admission appear more useful than ROX index to predict the risk of intubation.

Impact of low- or moderate-risk gonadotoxic chemotherapy prior to testicular tissue freezing on spermatogonia quantity in human (pre)pubertal testicular tissue.

STUDY QUESTION: What is the impact of low- or moderate-risk gonadotoxic chemotherapy received prior to testicular tissue freezing (TTF), and of the cancer itself, on spermatogonia quantity in testicular tissue from (pre)pubertal boys? SUMMARY ANSWER: Vincristine, when associated with alkylating agents, has an additional adverse effect on spermatogonia quantity, while carboplatin has no individual contribution to spermatogonia quantity, in testicular tissue of (pre)pubertal boys, when compared to patients who have received non-alkylating chemotherapy. WHAT IS KNOWN ALREADY: The improved survival rates after cancer treatment necessitate the inclusion of fertility preservation procedures as part of the comprehensive care for patients, taking into consideration their age. Sperm cryopreservation is an established procedure in post-pubertal males while the TTF proposed for (pre)pubertal boys remains experimental. Several studies exploring testicular tissue of (pre)pubertal boys after TTF have examined the tubular fertility index (TFI, percentage of seminiferous tubule cross-sections containing spermatogonia) and the number of spermatogonia per seminiferous tubule cross-section (S/T). All studies have demonstrated that TFI and S/T always decrease after the introduction of chemotherapeutic agents, especially those which carry high gonadotoxic risks such as alkylating agents. STUDY DESIGN, SIZE, DURATION: Testicular tissue samples from 79 (pre)pubertal boys diagnosed with cancer (from 6 months to 16 years of age) were cryopreserved between May 2009 and June 2014. Their medical diagnoses and previous chemotherapy exposures were recorded. We examined histological sections of (pre)pubertal testicular tissue to elucidate whether the chemotherapy or the primary diagnosis affects mainly TFI and S/T. PARTICIPANTS/MATERIALS, SETTING, METHODS: (Pre)pubertal boys with cancer diagnosis who had been offered TTF prior to conditioning treatment for hematopoietic stem cell transplantation were included in the study. All the patients had previously received chemotherapy with low- or moderate-risk for future fertility. We have selected patients for whom the information on the chemotherapy received was complete. The quantity of spermatogonia and quality of testicular tissue were assessed by both morphological and immunohistochemical analyses. MAIN RESULTS AND THE ROLE OF CHANCE: A significant reduction in the number of spermatogonia was observed in boys treated with alkylating agents. The mean S/T values in boys exposed to alkylating agents were significantly lower compared to boys exposed to non-alkylating agents (P = 0.018). In contrast, no difference was observed for patients treated with carboplatin as the sole administered alkylating agent compared to the group of patients exposed to non-alkylating agents. We observed an increase of S/T with age in the group of patients who did not receive any alkylating agent and a decrease of S/T with age when patients received alkylating agents included in the cyclophosphamide equivalent dose (CED) formula (r = 0.6166, P = 0.0434; r = -0.3759, P = 0.0036, respectively). The TFI and S/T decreased further in the group of patients who received vincristine in combination with alkylating agents (decrease of 22.4%, P = 0.0049 and P < 0.0001, respectively), but in this group the CED was also increased significantly (P < 0.0001). Multivariate analysis, after CED adjustment, showed the persistence of a decrease in TFI correlated with vincristine administration (P = 0.02). LIMITATIONS, REASONS FOR CAUTION: This is a descriptive study of testicular tissues obtained from (pre)pubertal boys who were at risk of infertility. The study population is quite heterogeneous, with a small number of patients in each sub-group. Our results are based on comparisons between patients receiving alkylating agents compared to patients receiving non-alkylating agents rather than chemotherapy-naive patients. The French national guidelines for fertility preservation in cancer patients recommend TTF before highly gonadotoxic treatment. Therefore, all the patients had received low- or moderate-risk gonadotoxic chemotherapy before TTF. Access to testicular tissue samples from chemotherapy-naive patients with comparable histological types of cancer was not possible. The functionality of spermatogonia and somatic cells could not be tested by transplantation or in vitro maturation due to limited sample sizes. WIDER IMPLICATIONS OF THE FINDINGS: This study summarizes the spermatogonial quantity of (pre)pubertal boys prior to TTF. We confirmed a negative correlation between the cumulative exposure to alkylating agents and spermatogonial quantity. In addition, the synergistic use of vincristine in combination with alkylating agents showed a cumulative deleterious effect on the TFI. For patients for whom fertility preservation is indicated, TTF should be proposed for chemotherapy with a predicted CED above 4000 mg/m2. However, the data obtained from vincristine and carboplatin use should be confirmed in a subsequent study including more patients. STUDY FUNDING/COMPETING INTEREST(S): This study had financial support from a French national research grant PHRC No. 2008/071/HP obtained by the French Institute of Cancer and the French Healthcare Organization. The sponsors played no role in the study. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

The combination of Ara h 2-sIgE and basophil activation test could be an alternative to oral food challenge in cases of suspected peanut allergy.

BACKGROUND: Most children with peanut sensitisation do not have a clinical peanut allergy (PA). Oral food challenge (OFC) is then necessary to diagnose PA and assess the reactive dose of the allergen. However, OFC is laborious to perform, expensive and stressful. We evaluated whether in vitro tests, such as basophil activation test (BAT), allergen-specific IgE (sIgE) and their combination, could be used to replace OFC for the diagnosis of PA in children. METHODS: Ninety-one patients aged 6 months to 18 years with suspected PA were prospectively recruited. These patients then underwent an OFC to assess PA. Whole peanut-sIgE, Ara h 2-sIgE, Ara h 8-sIgE and %CD63+ basophils (CCR3+ /SCClow ) to peanut measured by BAT were investigated for PA diagnosis. RESULTS: Forty-one patients had a positive peanut OFC, and the remaining 50 were only sensitised. All patients with Ara h 2-sIgE >7 kUA /L were allergic to peanut. A threshold of 6% for activated basophils yielded a sensitivity of 95% and a specificity of 54%. All patients with Ara h 2-sIgE ≤7 kUA /L and BAT ≤6% (n = 22) had a negative OFC except for one who presented an oral syndrome due to PR-10 sensitisation. CONCLUSIONS: We have shown that Ara h 2-sIgE >7 kUA/L is a discriminating threshold for the diagnosis of PA. Furthermore, when Ara h 2-sIgE ≤7 kUA/L and BAT ≤6%, patients do not need to adjust their diet and, thus, do not need an OFC.

Assessment of endobronchial ultrasound-guided bronchoscopy (EBUS) intranodal forceps biopsy added to EBUS 19-gauge transbronchial needle aspiration: A blinded pathology panel analysis.

BACKGROUND: Endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) has significantly improved the diagnostic workup for intrathoracic lymphadenopathies. More recently, EBUS intranodal forceps biopsy (IFB) has been developed in an attempt to maximize diagnostic yield by providing additional tissue. In this study, we aimed to assess the improvement of diagnostic yield with EBUS-TBNA combined with EBUS-IFB, compared to EBUS-TBNA alone. METHODS: Consecutive patients who had 19-G EBUS-TBNA and EBUS-IFB from August 30, 2018, to September 28, 2021, were included. Four senior pathologists retrospectively analyzed, independently and blindly, first, only the EBUS-TBNA samples (cell block), then, at least 1 month later, both samples from EBUS-TBNA and from EBUS-IFB together. RESULTS: Fifty patients were included in the study and 52 lymph nodes were analyzed. Diagnostic yield was 77% (40/52) for EBUS-TBNA alone and 94% (49/52) when combined with EBUS-IFB (p = 0.023). Malignancy was diagnosed with EBUS-TBNA combined with EBUS-IFB in 25/26 cases (96%), versus 22/26 (85%) with EBUS-TBNA alone (p = 0.35); and 4/5 (80%) versus 2/5 (40%) for lymphoma specifically. Kappa interobserver agreement was 0.92 for EBUS-IFB and 0.87 for EBUS-TBNA alone. Nonmalignant condition was diagnosed with EBUS-TBNA combined with EBUS-IFB in 24/26 cases (92%), versus 18/26 (69%) for EBUS-TBNA alone (p = 0.07). CONCLUSION: The use of EBUS-IFB combined with 19-G EBUS-TBNA improves the mediastinal lymph node diagnostic yield However the benefit appears to be mainly restricted to nonmalignant histology.

Intestinal permeability and appetite regulating peptides-reactive immunoglobulins in severely malnourished women with anorexia nervosa.

BACKGROUND & AIMS: In the last decades, the role of microbiota-gut-brain axis has emerged in the regulation of eating behavior and in the pathophysiology of anorexia nervosa (AN) that remains poorly understood. Particularly, a gut-derived dysregulation of immune response has been proposed leading to immunoglobulins directed against appetite-regulating peptides. However, intestinal permeability in patients with anorexia nervosa has been poorly documented. METHODS: In the present prospective case-control study, we thus compared intestinal permeability, appetite-regulating peptides and their reactive immunoglobulins measured in severely malnourished women with AN (n = 17; 28 [21-35] y; 14.9 [14.1-15.2] kg/m2) to healthy volunteers (HV, n = 34; 26 [23-35] y; 22.3 [20.6-23.6] kg/m2). RESULTS: Patients with AN exhibited an increased urinary lactulose/mannitol ratio, both in 0-5 h (0.033 [0.013-0.116]) and 5-24 h samples (0.115 [0.029-0.582]), when compared to HV (0.02 [0.008-0.045], p = 0.0074 and 0.083 [0.019-0.290], p = 0.0174, respectively), suggesting an increased intestinal permeability. Urinary excretion of sucralose and plasma zonulin were not different. The levels of plasma total ghrelin and desacyl-ghrelin were increased in patients with AN compared to HV, whereas plasma leptin concentration was decreased. In addition, αMSH remained unchanged compared to HV. Finally, we did not observe any modification of the levels of total or free αMSH, leptin or ghrelin-reactive immunoglobulin G and M, as well as for their affinity properties. Only, a weak decrease of the dissociation constant (kd) for acyl-ghrelin-reactive IgG was observed in patients with AN (p = 0.0411). CONCLUSIONS: In conclusion, severely malnourished patients with AN show a higher intestinal permeability than HV without evidence of an effect on appetite regulating peptides-reactive immunoglobulins.

Long-term Outcomes Following Surgical Management of Rectal Endometriosis: Seven-year Follow-up of Patients Enrolled in a Randomized Trial.

STUDY OBJECTIVE: To compare functional outcomes, recurrence rate, and pregnancy likelihood in patients undergoing conservative or radical surgery for deep rectal endometriosis followed up for 7 years. DESIGN: Prospective study in a cohort of patients enrolled in a 2-arm randomized trial from March 2011 to August 2013. SETTING: A tertiary referral center. PATIENTS: Fifty-five patients with deep endometriosis infiltrating the rectum. INTERVENTIONS: Patients underwent either segmental resection or nodule excision via shaving or disk excision, depending on randomization that was performed preoperatively using sequentially numbered, opaque sealed envelopes. MEASUREMENTS AND MAIN RESULTS: The primary end point was the number of patients experiencing one of the following symptoms: constipation, frequent bowel movements, anal incontinence, or bladder dysfunction 24 months after surgery. The secondary end points were values of gastrointestinal and overall quality of life scores. The 7-year recurrence rates (new deep endometriosis nodules infiltrating the rectum) in the excision vs segmental resection arms were 7.4 % vs 0% (p = .24). One of the symptoms included in the definition of the primary outcomes was recorded in 55.6% vs 60.7% of patients (p = .79). However, 51.9% vs 53.6% of patients considered their bowel movements as normal (p = .99). An intention-to-treat comparison of overall quality of life scores did not find a difference between the 2 groups 7 years after surgery. At the end of the 7-year study period, 31 of 37 patients who tried to conceive were successful (83.8%), including 27 pregnancies (57.4%) resulting from natural conception and 20 pregnancies (42.6%) resulting from assisted reproductive technology procedures. The pregnancy rate was 82.4% vs 85% in the 2 arms (p = .99). A 75.7% live birth rate was recorded. At the end of the follow-up, there were 15 women with 1 child (40.5%) and 13 women with 2 children (35.1%). During the 7-year follow-up, the reoperation rates were 37% and 35.7%, respectively, in each arm (p = .84). Among the 27 reoperation procedures during the follow-up period, 11 (40.7%) were for postoperative complications, 7 (25.9%) were necessary before assisted reproductive technology management, 8 (29.6%) were for recurrent abdominal or pelvic pain, and 1 (3.7%) was for midline ventral hernia after pregnancy. CONCLUSION: Our study did not reveal a considerable difference in terms of digestive functional outcomes, recurrence rate, reoperation risk, and pregnancy likelihood when conservative and radical rectal surgeries for deep endometriosis were compared 7 years after surgery. The postoperative pregnancy rate observed in our series was high.

Assessment of the architecture and integrity of frozen-thawed testicular tissue from (pre)pubertal boys with cancer.

BACKGROUND: Testicular tissue freezing is proposed for fertility preservation to (pre)pubertal boys with cancer before highly gonadotoxic treatment. Studies accurately comparing human (pre)pubertal testicular tissue quality before freezing and after thawing are exceptional. No study has reported this approach in a systematic manner and routine care. OBJECTIVES: To assess the impact of a control slow freezing protocol on testicular tissue architecture and integrity of (pre)pubertal boys after thawing. MATERIALS AND METHODS: (Pre)pubertal boys (n = 87) with cancer from 8 Reproductive Biology Laboratories of the French CECOS network benefited from testicular tissue freezing before hematopoietic stem cell transplantation. Seminiferous tubule cryodamage was determined histologically by scoring morphological alterations and by quantifying intratubular spermatogonia and the expression of DNA replication and repair marker in frozen-thawed testicular fragments. RESULTS: A significant increase in nuclear and epithelial score alterations was observed after thawing (p < 0.0001). The global lesional score remained lower than 1.5 and comparable to fresh testicular tissue. The number of intratubular spermatogonia and the expression of DNA replication and repair marker in spermatogonia and Sertoli cells did not vary significantly after thawing. These data showed the good preservation of the seminiferous tubule integrity and architecture after thawing, as previously reported in our studies performed in prepubertal mice and rats. DISCUSSION: The current study reports, for the first time, the development of a semi-quantitative analysis of cryodamage in human (pre)pubertal testicular tissue, using a rapid and useful tool that can be proposed in routine care to develop an internal and external quality control for testicular tissue freezing. This tool can also be used when changing one or several parameters of the freezing-thawing procedure. CONCLUSION: Control slow freezing protocol without seeding maintains the seminiferous tubule architecture and integrity, the concentration of spermatogonia and the expression of DNA replication and repair marker in spermatogonia and Sertoli cells after thawing.

High-flow oxygen therapy versus noninvasive ventilation: a randomised physiological crossover study of alveolar recruitment in acute respiratory failure.

High-flow nasal cannula (HFNC) oxygen therapy has recently shown clinical benefits in hypoxaemic acute respiratory failure (ARF) patients, while the value of noninvasive ventilation (NIV) remains debated. The primary end-point was to compare alveolar recruitment using global end-expiratory electrical lung impedance (EELI) between HFNC and NIV. Secondary end-points compared regional EELI, lung volumes (global and regional tidal volume variation (V T)), respiratory parameters, haemodynamic tolerance, dyspnoea and patient comfort between HFNC and NIV, relative to face mask (FM). A prospective randomised crossover physiological study was conducted in patients with hypoxaemic ARF due to pneumonia. They received alternately HFNC, NIV and FM. 16 patients were included. Global EELI was 4083 with NIV and 2921 with HFNC (p=0.4). Compared to FM, NIV and HFNC significantly increased global EELI by 1810.5 (95% CI 857-2646) and 826 (95% CI 399.5-2361), respectively. Global and regional V T increased significantly with NIV compared to HFNC or FM, but not between HFNC and FM. NIV yielded a significantly higher pulse oxygen saturation/inspired oxygen fraction ratio compared to HFNC (p=0.03). No significant difference was observed between HFNC, NIV and FM for dyspnoea. Patient comfort score with FM was not significantly different than with HFNC (p=0.1), but was lower with NIV (p=0.001). This study suggests a potential benefit of HFNC and NIV on alveolar recruitment in patients with hypoxaemic ARF. In contrast with HFNC, NIV increased lung volumes, which may contribute to overdistension and its potentially deleterious effect in these patients.

Single-source dual energy CT to assess myocardial extracellular volume fraction in aortic stenosis before transcatheter aortic valve implantation (TAVI).

PURPOSE: To assess myocardial extracellular volume fraction (ECV) measurement provided by a single-source dual-energy computed tomography (SSDE-CT) acquisition added at the end of a routine CT examination before transcatether aortic valve implantation (TAVI) compared to cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: Twenty-one patients (10 men, 11 women; mean age, 86±4.9 years [SD]; age range: 71-92 years) with severe aortic stenosis underwent standard pre-TAVI CT with additional cardiac SSDE-CT acquisition 7minutes after intravenous administration of iodinated contrast material and myocardial MRI including pre- and post-contrast T1-maps. Myocardial ECV and standard deviation (σECV) were calculated in the 16-segments model. ECV provided by SSDE-CT was compared to ECV provided by MRI, which served as the reference. Analyses were performed on a per-segment basis and on a per-patient involving the mean value of the 16-segments. RESULTS: ECV was slightly overestimated by SSDE-CT (29.9±4.6 [SD] %; range: 20.9%-48.3%) compared to MRI (29.1±3.9 [SD] %; range: 22.0%-50.7%) (P<0.0001) with a bias and limits of agreement of +2.3% (95%CI: -16.1%-+20.6%) and +2.5% (95%CI: -2.1%-+7.1%) for per-segment and per-patient-analyses, respectively. Good (r=0.81 for per-segment-analysis) to excellent (r=0.97 for per-patient-analysis) linear relationships (both P<0.0001) were obtained. The σECV was significantly higher at SSDE-CT (P<0.0001). Additional radiation dose from CT was 1.89±0.38 (SD) mSv (range: 1.48-2.47 mSv). CONCLUSION: A single additional SSDE-CT acquisition added at the end of a standard pre-TAVI CT protocol can provide ECV measurement with good to excellent linear relationship with MRI.

A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP.

The anti-von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.

Early Postoperative Renal Dysfunction Predicts Long-Term Renal Function Degradation after Type IV Thoracoabdominal Aortic Aneurysm Surgical Repair.

BACKGROUND: Type IV thoracoabdominal aortic aneurysm surgical repair is often complicated by postoperative acute kidney injury. The aim was to evaluate early renal injury influence on long-term renal function. METHODS: All type IV thoracoabdominal surgical repair performed between January 2000 and January 2014 in our tertiary hospital were included in this retrospective observational study. All procedures were performed through a retroperitoneal approach with at least suprarenal aortic cross-clamping. Cold Ringer Lactate was used to perfuse the kidneys. Serum creatinine (Scr.) and glomerular filtration rate (GFR) were recorded preoperatively, daily until discharge and at least annually during follow-up. Postoperative renal dysfunction was classified using the RIFLE score. Predictors of long-term renal decline were identified by logistic regression and a Cox model. RESULTS: Of total, 80 patients were included. Aortic clamping level was suprarenal (10%), supramesenteric (37%) or supracoeliac (53%). Ischemic durations were 29 ± 9 min for the gastrointestinal tract and the right kidney, 54 ± 28 min for the left kidney. Three patients died postoperatively. At discharge, 31 (38.8%) patients did not have a postoperative renal impairment (RIFLE-), compared with 49 (61.2%) who had a renal dysfunction (RIFLE+). GFR was 89 ± 29 ml/min vs 68 ± 37 ml/min, respectively (P < 0.01). In the RIFLE + group, Scr. was increased by x1.5 (Risk) for 22 patients, x2 (Injury) for 19 patients, and ×3 (Failure) for 8 patients. Mean follow-up was 59 months. Eighteen patients died, and 2 patients started permanent dialysis at 46 and 118 months during follow-up. The only predictive factor of long-term GFR degradation was a postoperative GFR below 45 ml/min (OR: 16.5; 95%; P < 0.001). CONCLUSIONS: Postoperative renal dysfunction was a frequent complication, associated with long-term renal function degradation.

Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer.

BACKGROUND: Endocrine therapy is recommended as a first-line treatment for hormone receptor-positive metastatic breast cancer (HR+MBC) patients. No biomarker has been validated to predict tumor progression in that setting. We aimed to prospectively compare the risk of early progression according to circulating ESR1 mutations, CA-15.3, and circulating cell-free DNA in MBC patients treated with a first-line aromatase inhibitor (AI). METHODS: Patients with MBC treated with a first-line AI were prospectively included. Circulating biomarker assessment was performed every 3 months. The primary objective was to determine the risk of progression or death at the next follow-up visit (after 3 months) in case of circulating ESR1 mutation detection among patients treated with a first-line AI for HR+MBC. RESULTS: Overall, 103 patients were included, and 70 (68%) had progressive disease (PD). Circulating ESR1 mutations were detected in 22/70 patients with PD and in 0/33 patients without progression (p < 0.001). Among the ESR1-mutated patients, 18/22 had a detectable mutation prior to progression, with a median delay of 110 days from first detection to PD. The detection of circulating ESR1 mutations was associated with a 4.9-fold (95% CI 3.0-8.0) increase in the risk of PD at 3 months. Using a threshold value of 25% or 100%, a CA-15.3 increase was also correlated with progression (p < 0.001 and p = 0.003, respectively). In contrast to ESR1, the CA-15.3 increase occurred concomitantly with PD in most cases, in 27/47 (57%) with a 25% threshold and in 21/25 (84%) with a 100% threshold. Using a threshold value of either 25% or 100%, cfDNA increase was not correlated with progression. CONCLUSION: The emergence of circulating ESR1 mutations is associated with a 4.9-fold increase in the risk of early PD during AI treatment in HR+MBC. Our results also highlighted that tracking circulating ESR1 mutations is more relevant than tracking CA-15.3 or cfDNA increase to predict progression in this setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02473120. Registered 16 June 2015-retrospectively registered after one inclusion (first inclusion 1 June 2015).

Peritoneal Carcinomatosis Risk and Long-Term Survival Following Hepatectomy for Spontaneous Hepatocellular Carcinoma Rupture: Results of a Multicenter French Study (FRENCH-AFC).

BACKGROUND: Spontaneous rupture of hepatocellular carcinoma (HCC) remains a life-threatening complication, with a reported mortality rate of between 16 and 30% and an incidence rate of approximately 3% in Europe. Survival data and risk factors after ruptured HCC are lacking, especially for peritoneal metastasis (PM). OBJECTIVES: The aims of this study were to evaluate the pattern of recurrence and mortality after hepatectomy for ruptured HCC, and to focus on PM. METHODS: We retrospectively reviewed the files of patients admitted to 14 French surgical centers for spontaneous rupture of HCC between May 2000 and May 2012. RESULTS: Overall, 135 patients were included in this study. The median disease-free survival and overall survival (OS) rates were 16.1 (11.0-21.1) and 28.7 (26.0-31.5) months, respectively, and the median follow-up period was 29 months. At last follow-up, recurrences were observed in 65.1% of patients (n = 88). The overall rate of PM following ruptured HCC was 12% (n = 16). Surgical management of PM was performed for six patients, with a median OS of 36.6 months. An α-fetoprotein level > 30 ng/mL (p = 0.0009), tumor size at rupture > 70 mm (p = 0.0009), and vascular involvement (p < 0.0001) were found to be independently associated with an increased likelihood of recurrence. No risk factor for PM was observed. CONCLUSION: This large-cohort French study confirmed that 12% of patients had PM after ruptured HCC. A curative approach may be an option for highly selected patients with exclusive PD because of the survival benefit it could provide.

Randomised phase II trial evaluating the safety of peripherally inserted catheters versus implanted port catheters during adjuvant chemotherapy in patients with early breast cancer.

BACKGROUND: Both peripherally inserted central catheters (PICCs) and implanted port catheters (PORTs) are used for adjuvant chemotherapy (ACT) administration in patients with early breast cancer (EBC). We aimed to compare the safety between PICCs and PORTs in this setting. PATIENTS AND METHODS: This monocentric phase II randomised trial (NCT02095743) included patients with EBC who were eligible for ACT. Patients with curative anticoagulation therapy were excluded. The primary objective was to identify which device has a lower probability of catheter-related significant adverse events (CR-SAEs) within the 35 weeks after device implantation. The secondary objective was to evaluate quality of life (QoL) and patient satisfaction. RESULTS: From February 2014 to May 2018, 256 patients were included, and 253 (99%) were analysed. Overall, 31 patients (12.2%) experienced CR-SAEs, which mainly included thromboembolic events. In an intention-to-treat analysis, the probability that a CR-SAE would occur was 7.8% (10 events) with PORTs versus 16.6% (21 events) with PICCs (hazard ratio [HR] = 2.2 [1.03-4.62], P = 0.036). In a per-protocol analysis, PICCs were also associated with a higher risk of CR-SAEs than PORTs (HR = 2.82 [1.26-6.25], P = 0.007). Regarding the secondary objectives, if there was no difference in QoL between the arms, then significantly more discomfort was reported among patients with PICCs than among patients with PORTs (P = 0.002 after implantation and P < 0.001 at mid-treatment or at the end of treatment). CONCLUSIONS: CR-SAEs in patients with EBC are frequent but rarely impact the ACT process. Compared with PORTs, PICCs are associated with a significantly higher risk of CR-SAEs and more discomfort. PORTs should be preferred for ACT administration in patients with EBC.

Excision versus colorectal resection in deep endometriosis infiltrating the rectum: 5-year follow-up of patients enrolled in a randomized controlled trial.

STUDY QUESTION: Is there a difference in functional outcomes and recurrence rate between conservative versus radical rectal surgery in patients with large deep endometriosis infiltrating the rectum 5 years postoperatively? SUMMARY ANSWER: No evidence was found that long-term outcomes differed when nodule excision was compared to rectal resection for deeply invasive endometriosis involving the bowel. WHAT IS KNOWN ALREADY: Functional outcomes of nodule excision and rectal resection for deeply invasive endometriosis involving the bowel are comparable 2 years after surgery. Despite numerous previously reported case series enrolling patients managed for colorectal endometriosis, long-term data remain scarce in the literature. STUDY DESIGN, SIZE, DURATION: From March 2011 to August 2013, we performed a two-arm randomized trial, enrolling 60 patients with deep endometriosis infiltrating the rectum up to 15 cm from the anus, measuring >20 mm in length, involving at least the muscular layer in depth, and up to 50% of rectal circumference. Among them, 55 women were enrolled at one tertial referral centre in endometriosis, using a randomization list drawn up separately for this centre. Institute review board approval was obtained to continue follow-up to 10 years postoperatively. One patient requested to stop the follow-up 2 years after surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients underwent either nodule excision by shaving or disc excision, or segmental resection. Randomization was performed preoperatively using sequentially numbered, opaque, sealed envelopes, and patients were informed of randomization results. The primary endpoint was the proportion of patients experiencing one of the following symptoms: constipation (1 stool/>5 consecutive days), frequent bowel movements (≥3 stools/day), anal incontinence, dysuria or bladder atony requiring self-catheterization 24 months postoperatively. Secondary endpoints were values taken from the Knowles-Eccersley-Scott-symptom questionnaire (KESS), the gastrointestinal quality of life index (GIQLI), the Wexner scale, the urinary symptom profile (USP) and the Short Form 36 Health Survey (SF36). MAIN RESULTS AND THE ROLE OF CHANCE: Fifty-five patients were enrolled. Among the 27 patients in the excision arm, two were converted to segmental resection (7.4%). One patient managed by segmental resection withdrew from the study 2 years postoperatively, presuming that associated pain of other aetiologies may have jeopardized the outcomes. The 5 year-recurrence rate for excision and resection was 3.7% versus 0% (P = 1), respectively. For excision and resection, the primary endpoint was present in 44.4% versus 60.7% of patients (P = 0.29), respectively, while 55.6% versus 53.6% of patients subjectively reported normal bowel movements (P = 1). An intention-to-treat comparison of overall KESS, GIQLI, Wexner, USP and SF36 scores did not reveal significant differences between the two arms 5 years postoperatively. Statistically significant improvement was observed shortly after surgery with no further improvement or impairment recorded 1-5 years postoperatively. During the 5-year follow-up, additional surgical procedures were performed in 25.9% versus 28.6% of patients who had undergone excision or resection (P = 0.80), respectively. LIMITATIONS, REASONS FOR CAUTION: The presumption of a 40% difference concerning postoperative functional outcomes in favour of nodule excision resulted in a lack of power for demonstration of the primary endpoint difference. WIDER IMPLICATIONS OF THE FINDINGS: Five-year follow-up data do not show statistically significant differences between conservative and radical rectal surgery for long-term functional digestive and urinary outcomes in this specific population of women with large involvement of the rectum. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was received. Patient enrolment and follow-up until 2 years postoperatively was supported by a grant from the clinical research programme for hospitals in France. The authors declare no competing interests related to this study. TRIAL REGISTRATION NUMBER: This randomized study is registered with ClinicalTrials.gov, number NCT01291576. TRIAL REGISTRATION DATE: 31 January 2011. DATE OF FIRST PATIENT'S ENROLMENT: 7 March 2011.

Baseline severe constipation negatively impacts functional outcomes of surgery for deep endometriosis infiltrating the rectum: Results of the ENDORE randomized trial.

BACKGROUND: Predictive factors of functional outcomes after the surgery of rectal endometriosis are not well identified. Our recent randomized trial did not find significant differences between functional outcomes in patients managed by radical or conservative rectal surgery. OBJECTIVE: To identify preoperative factors which determine functional outcomes of surgery in patients with rectal endometriosis. STUDY DESIGN: We performed a cohort study on the population of a 2-arm randomised trial, from March 2011 to August 2013. Patients were enrolled in three French university hospitals and had either conservative surgery by shaving or disc excision, or radical rectal surgery by segmental resection. The primary endpoint was the proportion of patients experiencing one of the following symptoms: constipation, frequent bowel movements, anal incontinence, dysuria or bladder atony requiring self-catheterisation 24 months postoperatively. Secondary endpoints were the values of the Knowles-Eccersley-Scott-Symptom Questionnaire (KESS), the Gastrointestinal Quality of Life Index (GIQLI), the Wexner scale, the Urinary Symptom Profile (USP) and the Short Form 36 Health Survey (SF36). A logistic regression model based on backward selection was used to screen for baseline factors that could impact the primary endpoint. A generalized estimating equations model for repeated measures was used to assess whether a trend could be observed over the follow-up period as regards gastrointestinal and quality of life scores. RESULTS: 60 patients with deep endometriosis infiltrating the rectum were managed by conservative surgery (27 cases) and segmental colorectal resection (33 cases). The primary endpoint was recorded in 26 patients (48.1% for conservative surgery vs. 39.4% for radical surgery, OR = 0.70, 95% CI 0.22-2.21). There was a significant improvement in values of all gastrointestinal, quality of life and urinary scores after surgery. Comparing patients with KESS scores < 10 (reference) to those with scores between 10 and 17 (OR = 2.1, 95%CI 0.4-12.2), as well as those with scores >17 (OR = 11.1, 95%CI 2.2-20.5), revealed that the odds to record the primary endpoint are significantly higher in the latter group. Trend analyses suggest that the odds of an elevated KESS score are significantly higher at baseline than at 6 months, but significantly lower after 12 months. CONCLUSIONS: Patients with severe preoperative constipation are less likely to achieve normal bowel movements after surgery for rectal endometriosis, using either radical or conservative rectal procedures.

Impact of prehabilitation on morbidity and mortality after pulmonary lobectomy by minimally invasive surgery: a cohort study.

BACKGROUND: Thoracic surgery is currently the optimal treatment for non-small cell lung cancer (NSCLC). However, it may be responsible for numerous postoperative complications and is often used in patients with multi co morbidities. In recent years, the optimization of a patient's physical capacity before surgery has been the subject of several studies. The objective of this study was to determine whether participation in a prehabilitation program would improve outcomes after surgery and lower morbidity according to the Clavien-Dindo classification. METHODS: This retrospective cohort study was performed between 1st January 2014 and 31st January 2016 at Rouen University Hospital. All adult patients with NSCLC (IIIa or <) who had pulmonary lobectomy by minimally invasive surgery and cardiopulmonary exercise testing [CPET (VO2max ≤20 mL/min/kg)] were included. RESULTS: The cohort included 38 patients. Two groups were formed: one group with prehabilitation (n=19) and one group without prehabilitation (n=19). Four patients were not included leaving 34 patients for the final analysis. Most patients with a Clavien-Dindo grade of ≤2 had received prehabilitation compared to patients who had not received prehabilitation, respectively 17/19 vs. 8/15; P=0.0252. Patients who had received prehabilitation had fewer postoperative complications than patients who had not received prehabilitation, respectively 8/19 vs. 12/15; P=0.0382. CONCLUSIONS: We have shown that prehabilitation has a positive impact on the occurrence and severity of postoperative complications after pulmonary lobectomy by minimally invasive surgery. Further studies conducted in larger populations are warranted to confirm these results.

Conservative surgery versus colorectal resection in deep endometriosis infiltrating the rectum: a randomized trial.

STUDY QUESTION: Is there a difference in functional outcome between conservative versus radical rectal surgery in patients with large deep endometriosis infiltrating the rectum 2 years postoperatively? SUMMARY ANSWER: No evidence was found that functional outcomes differed when conservative surgery was compared to radical rectal surgery for deeply invasive endometriosis involving the bowel. WHAT IS KNOWN ALREADY: Adopting a conservative approach to the surgical management of deep endometriosis infiltrating the rectum, by employing shaving or disc excision, appears to yield improved digestive functional outcomes. However, previous comparative studies were not randomized, introducing a possible bias regarding the presumed superiority of conservative techniques due to the inclusion of patients with more severe deep endometriosis who underwent colorectal resection. STUDY DESIGN SIZE, DURATION: From March 2011 to August 2013, we performed a 2-arm randomized trial, enroling 60 patients with deep endometriosis infiltrating the rectum up to 15 cm from the anus, measuring more than 20 mm in length, involving at least the muscular layer in depth and up to 50% of rectal circumference. No women were lost to follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were enroled in three French university hospitals and had either conservative surgery, by shaving or disc excision, or radical rectal surgery, by segmental resection. Randomization was performed preoperatively using sequentially numbered, opaque, sealed envelopes, and patients were informed of the results of randomization. The primary endpoint was the proportion of patients experiencing one of the following symptoms: constipation (1 stool/>5 consecutive days), frequent bowel movements (≥3 stools/day), defecation pain, anal incontinence, dysuria or bladder atony requiring self-catheterization 24 months postoperatively. Secondary endpoints were the values of the Visual Analog Scale (VAS), Knowles-Eccersley-Scott-Symptom Questionnaire (KESS), the Gastrointestinal Quality of Life Index (GIQLI), the Wexner scale, the Urinary Symptom Profile (USP) and the Short Form 36 Health Survey (SF36). MAIN RESULTS AND THE ROLE OF CHANCE: A total of 60 patients were enroled. Among the 27 patients in the conservative surgery arm, two were converted to segmental resection (7.4%). In each group, 13 presented with at least one functional problem at 24 months after surgery (48.1 versus 39.4%, OR = 0.70, 95% CI 0.22-2.21). The intention-to-treat comparison of the overall scores on KESS, GIQLI, Wexner, USP and SF36 did not reveal significant differences between the two arms. Segmental resection was associated with a significant risk of bowel stenosis. LIMITATIONS REASONS FOR CAUTION: The inclusion of only large infiltrations of the rectum does not allow the extrapolation of conclusions to small nodules of <20 mm in length. The presumption of a 40% difference favourable to conservative surgery in terms of postoperative functional outcomes resulted in a lack of power to demonstrate a difference for the primary endpoint. WIDER IMPLICATIONS OF THE FINDINGS: Conservative surgery is feasible in patients managed for large deep rectal endometriosis. The trial does not show a statistically significant superiority of conservative surgery for mid-term functional digestive and urinary outcomes in this specific population of women with large involvement of the rectum. There is a higher risk of rectal stenosis after segmental resection, requiring additional endoscopic or surgical procedures. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a grant from the clinical research programme for hospitals (PHRC) in France. The authors declare no competing interests related to this study. TRIAL REGISTRATION NUMBER: This study is registered with ClinicalTrials.gov, number NCT 01291576. TRIAL REGISTRATION DATE: 31 January 2011. DATE OF FIRST PATIENT'S ENROLMENT: 7 March 2011.

Bleeding Recurrence and Mortality Following Interventional Management of Spontaneous HCC Rupture: Results of a Multicenter European Study.

BACKGROUND: The incidence of spontaneous rupture of hepatocellular carcinoma (HCC) is low in Europe, at less than 3%. HCC rupture remains a life-threatening complication, with mortality reported between 16 and 30%. The risk of bleeding recurrence has never been clearly evaluated in such clinical situation. The objectives of this study were to evaluate the current risk of mortality related to HCC rupture and to focus on the risk of bleeding recurrence following interventional management. METHODS: All patients admitted to 14 French-Italian surgical centers for spontaneous rupture of HCC between May 2000 and May 2012 were retrospectively included. Clinical data, imaging features, relevant laboratory data, treatment strategies, and prognoses were analyzed. RESULTS: Overall, 58 of the 138 included patients (42%) had cirrhosis. Thirty-five patients (25%) presented with hemorrhagic shock, and 19% with organ(s) dysfunction. Bleeding control was obtained by interventional hemostasis, emergency liver resection, and conservative medical management in 86 (62%), 24 (18%), and 21 (15%) patients, respectively. Best supportive care was chosen for 7 (5%) patients. The mortality rate following rupture was 24%. The bleeding recurrence rate was 22% with related mortality of 52%. In multivariate analysis, a bilirubin level >17 micromol/L (HR 3.768; p = 0.006), bleeding recurrence (HR 5.400; p < 0.0001), and ICU admission after initial management (HR 8.199; p < 0.0001) were associated with in-hospital mortality. CONCLUSION: This European, multicenter, large-cohort study confirmed that the prognosis of ruptured HCC is poor with an overall mortality rate of 24%, despite important advances in endovascular techniques. Overall, the rate of bleeding recurrence was more than 20%, with a related high risk of mortality.