Retinoblastoma: From genes to patient care.

Retinoblastoma is the most common paediatric neoplasm of the retina, and one of the earliest model of cancer genetics since the identification of the master tumour suppressor gene RB1. Tumorigenesis has been shown to be driven by pathogenic variants of the RB1 locus, but also genomic and epigenomic alterations outside the locus. The increasing knowledge on this "mutational landscape" is used in current practice for precise genetic testing and counselling. Novel methods provide access to pre-therapeutic tumour DNA, by isolating cell-free DNA from aqueous humour or plasma. This is expected to facilitate assessment of the constitutional status of RB1, to provide an early risk stratification using molecular prognostic markers, to follow the response to the treatment in longitudinal studies, and to predict the response to targeted therapies. The aim of this review is to show how molecular genetics of retinoblastoma drives diagnosis, treatment, monitoring of the disease and surveillance of the patients and relatives. We first recap the current knowledge on retinoblastoma genetics and its use in every-day practice. We then focus on retinoblastoma subgrouping at the era of molecular biology, and the expected input of cell-free DNA in the field.

Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

Multimodal survival prediction in advanced pancreatic cancer using machine learning.

BACKGROUND: Existing risk scores appear insufficient to assess the individual survival risk of patients with advanced pancreatic ductal adenocarcinoma (PDAC) and do not take advantage of the variety of parameters that are collected during clinical care. METHODS: In this retrospective study, we built a random survival forest model from clinical data of 203 patients with advanced PDAC. The parameters were assessed before initiation of systemic treatment and included age, CA19-9, C-reactive protein, metastatic status, neutrophil-to-lymphocyte ratio and total serum protein level. Separate models including imaging and molecular parameters were built for subgroups. RESULTS: Over the entire cohort, a model based on clinical parameters achieved a c-index of 0.71. Our approach outperformed the American Joint Committee on Cancer (AJCC) staging system and the modified Glasgow Prognostic Score (mGPS) in the identification of high- and low-risk subgroups. Inclusion of the KRAS p.G12D mutational status could further improve the prediction, whereas radiomics data of the primary tumor only showed little benefit. In an external validation cohort of PDAC patients with liver metastases, our model achieved a c-index of 0.67 (mGPS: 0.59). CONCLUSIONS: The combination of multimodal data and machine-learning algorithms holds potential for personalized prognostication in advanced PDAC already at diagnosis.

Psychedelic-assisted psychotherapy to treat psychiatric and existential distress in life-threatening medical illnesses and palliative care.

Psychiatric and existential distress commonly occur in advanced cancer and other serious, life-threatening or end-of-life medical illnesses and are associated with poor medical and psychiatric outcomes. Currently available treatment modalities in this patient population, including medication and psychotherapy, are limited in effectiveness, especially regarding existential distress. The lack of effective psycho-spiritual interventions is a critical shortcoming in palliative care and represents a high unmet need in medicine. In this commentary, we review the rationale of researching and developing psychedelic-assisted psychotherapy as a novel pharmacologic-psychotherapeutic intervention to treat psychiatric and existential distress in life-threatening medical conditions and palliative care. This paper reviews efficacy data from first and second waves of psychedelic research, and future directions for research and implementation science. More rigorous research, especially funded by governments, is needed to assess effectiveness and mechanisms of action of psychedelic therapies to treat psychiatric and existential distress in life-threatening medical illnesses and palliative care. If psychedelic-assisted treatments were made available as approved and prescribable medications in people with serious medical illnesses, it could be a significant development that opens up a pathway for clinical dissemination and public health impact internationally.

[Argentine registry of office blood pressure monitoring. RAMPAC study]. / Registro Argentino de Medición de la Presión Arterial en Consultorio. Estudio RAMPAC.

INTRODUCTION: Hypertension (HTN) is the leading cause of mortality and disability in the world. In Argentina, almost 44% of hypertensives do not know about their condition and this may be due to the low rate of blood pressure (BP) measurements during the office visit. Our hypothesis is that the measurement and electronic recording of BP (BPMR) is not a routine practice in Argentina. OBJECTIVE: To describe the rate of office BP measurement in Argentina. METHODS: This is a retrospective, multicentre, point prevalence study. We analysed all office visits on 9/19/2019 at 9 medical institutions in 6 provinces of Argentina. RESULTS: Two thousand and eighty-two office visits were analysed. The patients' mean age was 52.1 years (18-103), 1790 (59.7%) were female, and 702 (36.1%) were hypertensives. BP was measured in 420 visits (14.1%; 95% CI 12.8-15.4). In a multivariate logistic regression model, history of HTN (OR 1.91, P<.001) and previous cardiovascular event (OR 1.76, P<.001) were associated with more odds of BPMR. The presence of cancer was associated with fewer odds of BPMR (OR .51, P<.01). Cardiology measured BP up to 49.5% (144/291 visits), followed by internal medicine 30% (152/507 visits). CONCLUSION: BPMR during office visits is deficient in Argentina and represents a missed healthcare opportunity. Different strategies are needed to detect hypertensive patients and reduce cardiovascular events.

Prognosis and tumor biology of pancreatic cancer patients with isolated lung metastases: translational results from the German multicenter AIO-YMO-PAK-0515 study.

BACKGROUND: Pulmonary metastasis (M1-PUL) as first site of dissemination in pancreatic ductal adenocarcinoma (PDAC) is a rare event and may define a distinct biological subgroup. PATIENTS AND METHODS: Arbeitsgemeinschaft Internistische Onkologie-Young Medical Oncologists-Pankreas-0515 study (AIO-YMO-PAK-0515) was a retrospective German multicenter study investigating clinical and molecular characteristics of M1-PUL PDAC patients; 115 M1-PUL PDAC patients from 7 participating centers were included. Clinical characteristics and potential prognostic factors were defined within the M1-PUL cohort. Archival tumor samples were analyzed for Her2/neu, HNF1A and KRT81 expression. Additionally, messenger RNA (mRNA) expression analysis (using a 770-gene immune profiling panel) was carried out in the M1-PUL and in a control cohort (M1-ANY). RESULTS: Median overall survival in the entire M1-PUL cohort was 20 months; the most favorable prognosis (median survival: 28 months) was observed in the subgroup of 66 PDAC patients with metachronous lung metastases after previous curative-intent surgery. The number of metastatic lesions, uni- or bilateral lung involvement as well as metastasectomy were identified as potential prognostic factors. Her2/neu expression and PDAC subtyping (by HNF1A and KRT81) did not differ between the M1-PUL and the M1-ANY cohort. mRNA expression analysis revealed significant differentially expressed genes between both cohorts: CD63 and LAMP1 were among the top 20 differentially expressed genes and were identified as potential mediators of organotropism and favorable survival outcome of M1-PUL patients. CONCLUSION: M1-PUL represents a clinically favorable cohort in PDAC patients. Site of relapse might already be predetermined at the time of surgery and could potentially be predicted by gene expression profiling.

Does circumferential casting prevent fracture redisplacement in reduced distal radius fractures? A retrospective multicentre study.

BACKGROUND: This study evaluates whether a circumferential cast compared to a plaster splint leads to less fracture redisplacement in reduced extra-articular distal radius fractures (DRFs). METHODS: This retrospective multicentre study was performed in four hospitals (two teaching hospitals and two academic hospitals). Adult patients with a displaced extra-articular DRF, treated with closed reduction, were included. Patients were included from a 5-year period (January 2012-January 2017). According to the hospital protocol, fractures were immobilized with a below elbow circumferential cast (CC) or a plaster splint (PS). The primary outcome concerned the difference in the occurrence of fracture redisplacement at one-week follow-up. RESULTS: A total of 500 patients were included in this study (PS n = 184, CC n = 316). At one-week follow-up, fracture redisplacement occurred in 52 patients (17%) treated with a CC compared to 53 patients (29%) treated with a PS. This difference was statistically significant (p = 0.001). CONCLUSION: This study suggests that treatment of reduced DRFs with a circumferential cast might cause less fracture redisplacement at 1-week follow-up compared to treatment with a plaster splint. Level of Evidence Level III, Retrospective study.

Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: a randomized, open-label, phase 2 trial.

Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB-IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58-0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30-0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8+ density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB-IVM1a melanoma.

[Plastic surgery and fighting: Our experience during Nagorno-Karabakh war in 2020]. / Chirurgie plastique et conflit armé : notre expérience lors du conflit au Haut-Karabakh en 2020.

INTRODUCTION: This work relates the experience of three French surgical missions in the care of the war wounded during the armed conflict in Nagorno Karabakh which took place from September 27 to November 10, 2020. MATERIALS AND METHODS: Three surgical missions were carried out in Armenia between October 2020 and January 2021. Surgeons intervened in different hospitals, at different times of the conflict and on various war wounds. RESULTS: The presence of a plastic surgeon proved to be essential in the care of war wounded, especially in delayed emergency and secondary care. The ortho-plastic treatment offered during these missions has proven to be effective in the reconstruction of limbs. These missions made it possible to introduce the induced membrane technique of Masquelet AC in Armenia. During our visit to the Yerevan burn center, we mentioned the very probable use of white phosphorus as an etiology in several of the cases analyzed. CONCLUSION: We relate the particular experience of civilian surgeons in the context of a modern armed conflict. The presence of a plastic surgeon proved to be indispensable in the care of war wounded and especially in their secondary reconstructions.

Cervical Cordotomy for Intractable Pain: Do Postoperative Imaging Features Correlate with Pain Outcomes and Mirror Pain?

BACKGROUND AND PURPOSE: Percutaneous cervical cordotomy offers relief of unilateral intractable oncologic pain. We aimed to find anatomic and postoperative imaging features that may correlate with clinical outcomes, including pain relief and postoperative contralateral pain. MATERIALS AND METHODS: We prospectively followed 15 patients with cancer who underwent cervical cordotomy for intractable pain during 2018 and 2019 and underwent preoperative and up to 1-month postoperative cervical MR imaging. Lesion volume and diameter were measured on T2-weighted imaging and diffusion tensor imaging (DTI). Lesion mean diffusivity and fractional anisotropy values were extracted. Pain improvement up to 1 month after surgery was assessed by the Numeric Rating Scale and Brief Pain Inventory. RESULTS: All patients reported pain relief from 8 (7-10) to 0 (0-4) immediately after surgery (P = .001), and 5 patients (33%) developed contralateral pain. The minimal percentages of the cord lesion volume required for pain relief were 10.0% on T2-weighted imaging and 6.2% on DTI. Smaller lesions on DWI correlated with pain improvement on the Brief Pain Inventory scale (r = 0.705, P = .023). Mean diffusivity and fractional anisotropy were significantly lower in the ablated tissue than contralateral nonlesioned tissue (P = .003 and P = .001, respectively), compatible with acute-phase tissue changes after injury. Minimal postoperative mean diffusivity values correlated with an improvement of Brief Pain Inventory severity scores (r = -0.821, P = .004). The average lesion mean diffusivity was lower among patients with postoperative contralateral pain (P = .037). CONCLUSIONS: Although a minimal ablation size is required during cordotomy, larger lesions do not indicate better outcomes. DWI metrics changes represent tissue damage after ablation and may correlate with pain outcomes.

Surgical management of infected abdominal wall mesh: an analysis using the American Hernia Society Quality Collaborative.

INTRODUCTION: Several management strategies exist for the treatment of infected abdominal mesh. Using the American Hernia Society Quality Collaborative, we examined management patterns and 30-day outcomes of infected mesh removal with concomitant incisional hernia repair. METHODS: All patients undergoing incisional hernia repair with removal of infected mesh were identified. A complete repair (CR) was defined as fascial closure with mesh; a partial repair (PR) was defined as fascial closure without mesh or no fascial closure with mesh. A two-tailed p value less than or equal to 0.05 was considered statistically significant. RESULTS: A total of 282 patients were identified: 136 patients in CR group and 146 patients in PR group. Patients had similar comorbidities but differed in wound class (class IV: 55% CR vs 83% SR, p < 0.001) and incidence of associated concomitant colorectal procedures (5% CR vs 18% SR, p = 0.015). Sublay placement was used primarily in CR (94%) compared to PR (52% inlay, 48% sublay). When comparing CR to PR, length of stay (median 6, p = 0.69), complications (40% vs 44%, p = 0.44), surgical site infections (16% vs 21%, p = 0.27), surgical site occurrence (30% vs 35%, p = 0.45), and readmission within 30 days (9% vs. 13%) were not statistically different. CONCLUSIONS: Analysis of data from a multicenter hernia registry comparing CR and PR during infected mesh removal and concurrent incisional hernia repair has not identified higher rates of short-term complications between groups in the presence of infection.

Comparison of behavioral patterns of dairy cows with natural estrus and induced ovulation detected by an ear-tag based accelerometer.

Dairy farms face many challenges and changes. With increasing herd sizes and fewer farmers or employees per cow, new strategies to maintain or improve reproductive management are required. One of the major challenges is to detect cows in estrus and to estimate the perfect time for artificial insemination (AI). Several estrus and ovulation synchronization programs with timed AI as well as estrus detection aids, e.g., tail-paint, pedometer, accelerometer, and others are available. A combination of ovulation synchronization programs and technical solutions, however, has rarely been tested. This study was designed to gain insights into behavioral patterns of cows subjected to an Ovsynch program and to test if behavioral data could be used to optimize the timing of insemination within an Ovsynch program. In this study, we used an ear-tag based 3D-accelerometer system (SMARTBOW, Smartbow GmbH, Weibern, Austria) to generate data of behavioral patterns, i.e., rumination and activity. In Part 1 of this study, behavioral patterns during the peri-estrus period were compared between cows with physiological estrus and cows subjected to an Ovsynch protocol. On the day before estrus and on the day of estrus/AI, cows with natural estrus showed a clear drop in rumination and "inactivity" and an increase in "high activity", based on an algorithm of the accelerometer system, whereas, cows in the Ovsynch protocol showed only minor changes in behavioral patterns. In Part 2, we analyzed behavioral patterns between synchronized cows that became pregnant after AI and synchronized cows that remained open. As a result, no differences were detected between these two Ovsynch groups before AI. Thus, in this study we found no evidence that behavioral patterns can be used to improve conception rates within an Ovsynch protocol.

Glycemic variability in patients with gastrointestinal cancer: An integrative review.

PURPOSE: Glycemic variability is associated with risks for adverse events in patients with cancer. Several studies have evaluated the presence and impact of hyperglycemia and/or hypoglycemia in patients with cancer; however, few studies have evaluated glycemic variability. The purpose of this integrative review of studies in patients with gastrointestinal cancers was to investigate the presence and methods of reporting glycemic variability during and following treatments. METHODS: A comprehensive review of the literature was conducted. PubMed, CINAHL, EMBASE, and Cochrane databases were searched for publications between 1/1/1969 and 7/24/2019. Studies of patients with gastrointestinal cancer following surgery, during treatment, and <5 years following treatment were included and evaluated by cancer type and method of glucose and glycemic variability measurement. RESULTS: Among 1526 patients with gastrointestinal cancer across 19 studies, gastric and pancreatic cancers were most prevalent. Timing of glucose testing and methods of analyzing glycemic variability varied. Most analyses used the standard deviation or interquartile range. Glycemic variability was more prevalent among patients with Type 2 Diabetes and among those with pancreatic cancer. In some patients glycemic variability remained notable > one year following surgery despite improvements in glycemic control. CONCLUSION: Patients with gastrointestinal cancer experience glycemic variability during and up to one year following treatment. There was heterogeneity in methods related to timing of testing and reporting glycemic variability among the 19 studies in this review. Future investigations need to identify the presence and define the methods of measuring glycemic variability in patients with gastrointestinal cancer.

Prophylactic salpingectomy for prevention of ovarian cancer at the time of elective laparoscopic cholecystectomy.

BACKGROUND: Most serous ovarian cancers are now understood to originate in the fallopian tubes. Removing the tubes (salpingectomy) likely reduces the risk of developing high-grade serous ovarian cancer. Numerous gynaecological societies now recommend prophylactic (or opportunistic) salpingectomy at the time of gynaecological surgery in appropriate women, and this is widely done. Salpingectomy at the time of non-gynaecological surgery has not been explored and may present an opportunity for primary prevention of ovarian cancer. METHODS: This study investigated whether prophylactic salpingectomy with the intention of reducing the risk of developing ovarian cancer would be accepted and could be accomplished at the time of elective laparoscopic cholecystectomy. Women aged at least 45 years scheduled for elective laparoscopic cholecystectomy were recruited. They were counselled and offered prophylactic bilateral salpingectomy at the time of cholecystectomy. Outcome measures were rate of accomplishment of salpingectomy, time and procedural steps needed for salpingectomy, and complications. RESULTS: A total of 105 patients were included in the study. The rate of acceptance of salpingectomy was approximately 60 per cent. Salpingectomy was performed in 98 of 105 laparoscopic cholecystectomies (93·3 per cent) and not accomplished because of poor visibility or adhesions in seven (6·7 per cent). Median additional operating time was 13 (range 4-45) min. There were no complications attributable to salpingectomy. One patient presented with ovarian cancer 28 months after prophylactic salpingectomy; histological re-evaluation of the tubes showed a previously undetected, focal serous tubal intraepithelial carcinoma. CONCLUSION: Prophylactic salpingectomy can be done during elective laparoscopic cholecystectomy.

ANTECEDENTES: La mayoría de carcinomas serosos de ovario se originan en las trompas de Falopio. La exéresis de las trompas (salpingectomía) probablemente reduce el riesgo de desarrollar un carcinoma seroso ovárico de alto grado. Numerosas sociedades ginecológicas recomiendan efectuar una salpingectomía profiláctica (u oportunista) en el momento de una cirugía ginecológica en determinadas mujeres, y esta conducta está ampliamente difundida. Sin embargo, no se ha analizado la realización de la salpingectomía durante cirugías no ginecológicas como forma de prevención primaria del carcinoma ovárico. MÉTODOS: Determinar si la salpingectomía profiláctica con intención de reducir el riesgo de desarrollar cáncer de ovario sería aceptada y podría llevarse a cabo durante una colecistectomía laparoscópica electiva. Se reclutaron mujeres ≥ 45 años de edad programadas para colecistectomía laparoscópica electiva. A todas ellas se les aconsejó y ofreció la realización de una salpingectomía bilateral profiláctica en el momento de su colecistectomía. Las variables analizadas fueron la tasa de realización de la salpingectomía, la duración y las etapas quirúrgicos para efectuar este procedimiento, y las complicaciones. RESULTADOS: La aceptación de la salpingectomía fue aproximadamente del 60%. La salpingectomía se realizó en 98 de 105 colecistectomías laparoscópicas (93%) y no se pudo realizar en 7 pacientes (7%) por escasa visibilidad o adherencias. La mediana del tiempo quirúrgico adicional fue de 13 (rango 4-45) minutos. No hubo complicaciones atribuibles a la salpingectomía. Una paciente presentó cáncer de ovario 28 meses después de la salpingectomía profiláctica; la reevaluación histológica de las trompas mostró un carcinoma intraepitelial seroso focal tubárico (serous tubal intraepithelial carcinoma, STIC) no detectado previamente. CONCLUSIÓN: La salpingectomía profiláctica se puede realizar durante la colecistectomía laparoscópica electiva.

Small bowel polyp resection using device-assisted enteroscopy in Peutz-Jeghers Syndrome: Results of a specialised tertiary care centre.

INTRODUCTION: Enteroscopy resection of small bowel polyps in Peutz-Jeghers syndrome has only been described in small case series. Herein, we aimed to assess the efficacy of enteroscopy resection of small bowel polyps within a specialised tertiary care centre and the impact on intraoperative enteroscopy. METHODS: This was an observational single-centre study. All adult Peutz-Jeghers syndrome patients followed in the Predisposition Digestive Ile-de-France network who underwent an endoscopic resection of at least one small bowel polyp ≥ 1 cm by enteroscopy between 2002-2015 were included. Small bowel polyps were detected under a dedicated screening programme by previous capsule endoscopy and/or magnetic resonance enterography, performed every 2-3 years. Complete treatment was defined as the absence of polyps ≥ 1 cm after conventional endoscopic resection. Intraoperative enteroscopy or surgical resection were indicated in incomplete treatments. The overall complete treatment rate including conventional enteroscopy and intraoperative enteroscopy was also considered. RESULTS: Endoscopic resection of 216 small bowel polyps (median: 8.6 per patient, size: 6-60 mm) was performed by 50 enteroscopies in 25 patients (mean age: 36 years, range: 18-71, 56% male) with small bowel polyp ≥ 1 cm. Twenty-three patients (92%) underwent 42 screening capsule endoscopies and 14 (57%) had 23 magnetic resonance enterographies during a median follow-up of 60 months. Complete treatment was achieved in 76%. Intraoperative enteroscopy and surgical resection were performed in four (16%) and two (8%) patients. Intraoperative enteroscopy improved by 16% the complete treatment rate and the overall rate was 92%. The complication rate was 6%. CONCLUSION: This long-term study confirmed the efficacy and safety of endoscopic resection of small bowel polyps in Peutz-Jeghers syndrome. Intraoperative enteroscopy can be a complementary approach in selected cases.

Nal-IRI with 5-fluorouracil (5-FU) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial (AIO-YMO HEP-0315) an open label, non-comparative, randomized, multicenter phase II study.

BACKGROUND: Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. METHODS: NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m2, 46 h infusion)/5-FU (2400 mg/m2, 46 h infusion)/leucovorin (400 mg/m2, 0.5 h infusion) d1 on 14 day-cycles; Arm B (standard of care) cisplatin (25 mg/m2, 1 h infusion)/gemcitabine (1000 mg/m2, 0.5 h infusion) d1 and d8 on 21 day-cycles. The randomization (1:1) is stratified for tumor site (intrahepatic vs. extrahepatic biliary tract), disease stage (advanced vs. metastatic), age (≤70 vs. > 70 years), sex (male vs. female) and WHO performance score (ECOG 0 vs. ECOG 1). Primary endpoint of the study is the progression free survival (PFS) rate at 4 months after randomization by an intention-to-treat analysis in each of the groups. Secondary endpoints are the overall PFS rate, the 3-year overall survival rate, the disease control rate after 2 months, safety and patient related outcome with quality of life. The initial assessment of tumor resectability for locally advanced BTCs is planned to be reviewed retrospectively by a central surgical board. Exploratory objectives aim at establishing novel biomarkers and molecular signatures to predict response. The study was initiated January 2018 in Germany. DISCUSSION: The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. TRIAL REGISTRATION: Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.

Genotyping of circulating tumor DNA in cholangiocarcinoma reveals diagnostic and prognostic information.

Diagnosis of Cholangiocarcinoma (CCA) is difficult, thus a noninvasive approach towards (i) assessing and (ii) monitoring the tumor-specific mutational profile is desirable to improve diagnosis and tailor treatment. Tumor tissue and corresponding ctDNA samples were collected from patients with CCA prior to and during chemotherapy and were subjected to deep sequencing of 15 genes frequently mutated in CCA. A set of ctDNA samples was also submitted for 710 gene oncopanel sequencing to identify progression signatures. The blood/tissue concordance was 74% overall and 92% for intrahepatic tumors only. Variant allele frequency (VAF) in ctDNA correlated with tumor load and in the group of intrahepatic CCA with PFS. 63% of therapy naive patients had their mutational profile changed during chemotherapy. A set of 76 potential progression driver genes was identified among 710 candidates. The molecular landscape of CCA is accessible via ctDNA. This could be helpful to facilitate diagnosis and personalize and adapt therapeutic strategies.

Neurophysiological evidence of impaired attention and working memory in untreated hematologic cancer patients.

OBJECTIVE: Neuroimaging studies of hematologic cancer patients report altered activity in dorsal attention and central executive networks. To determine the consequences of these altered brain networks, we evaluated neurophysiological correlates of attention and working memory in hematologic cancer patients prior to initiating treatment. METHODS: Hematologic cancer patients (19-80 years) were excluded for premorbid cognitive impairment, prior non-hematologic cancer diagnosis, and prior chemotherapy. Attention was manipulated by presenting an irrelevant spatial cue prior to visual search displays. Working memory was manipulated by presenting irrelevant distractors within memory displays. Electroencephalogram was recorded during task performance. RESULTS: Patients (n = 28) and controls (n = 15) were balanced on age, gender, and education. Spatial cues evoked larger N2pc amplitudes, a correlate of spatial attention, in patients than controls (p < .05; Cohen's d > 0.7). Memory distractors evoked larger contralateral delay activity amplitudes, a correlate of working memory load, in patients (p = .028; Cohen's d = 1.1) but not controls (p = .64). CONCLUSIONS: Prior to initiating treatment, hematologic cancer patients demonstrated poor control over spatial attention and working memory, consistent with altered dorsal attention and central executive network activity. SIGNIFICANCE: Hematologic cancer patients may be at a higher risk for selecting, processing, and storing distracting information that would compete with more immediate goal-related behaviors.

Low mortality and short-term morbidity in very preterm infants in Austria 2011-2016.

AIM: The current study determined survival, short-term neonatal morbidity and predictors for death or adverse outcome of very preterm infants in Austria. METHODS: This population-based cohort study included 5197 very preterm infants (53.3% boys) born between 2011 and 2016 recruited from the Austrian Preterm Outcome Registry. Main outcome measures were gestational age-related mortality and major short-term morbidities. RESULTS: Overall, survival rate of all live-born infants included was 91.6% and ranged from 47.1% and 73.4% among those born at 23 and 24 weeks of gestation to 84.9% and 88.2% among infants born at 25 and 26 weeks to more than 90.0% among those with a gestational age of 27 weeks or more. The overall prevalence of chronic lung disease, necrotising enterocolitis requiring surgery, intraventricular haemorrhage Grades 3-4, and retinopathy of prematurity Grades 3-5 was 10.0%, 2.1%, 5.5%, and 3.6%, respectively. Low gestational age, low birth weight, missing or incomplete course of antenatal steroids, male sex, and multiple births were significant risk predictors for death or adverse short-term outcome. CONCLUSION: In this national cohort study, overall survival rates were high and short-term morbidity rate was low.