Excisional biopsy of perforated gastric ulcer: mandatory or potentially harmful?

PURPOSE: This study aimed to evaluate the morbidity associated with excisional biopsy in patients with spontaneous gastric perforation. METHODS: A retrospective, single-center, observational study was performed. All consecutive patients with spontaneous gastric perforation who underwent surgical therapy were included. Outcomes were assessed concerning the performance of excisional biopsy. RESULTS: A total of 135 adult patients were enrolled. Of these, 110 (81.5%) patients underwent excisional biopsy, while 17 (12.6%) did not. The remaining eight (5.9%) patients who underwent gastric resection were excluded from the analysis. Patients undergoing excisional biopsy developed significantly higher rates of postoperative complications (p = 0.007) and experienced more severe complications according to the Clavien-Dindo classification, particularly type III and above (p = 0.017). However, no significant differences were observed regarding in-hospital mortality, reoperation, suture dehiscence, or length of hospital stay. CONCLUSION: Excisional biopsy for gastric perforation has been shown to be associated with increased morbidity. Surgical closure followed by early endoscopic biopsy may be a superior approach for gastric perforation management to rule out malignancy.

Chemotherapy and Targeted Therapy Strategies in Patients with Unresectable or Borderline Resectable Metastatic Colorectal Cancer: Evidence for a Lack of Focus on Resection Rates.

BACKGROUND AND AIMS: Chemotherapy (CTx) with targeted therapy (TT) have increased the overall response rate (ORR) and improved survival in unresectable or borderline resectable metastatic colorectal cancer (mCRC). However, the resection rate is an endpoint with often suboptimal expert involvement. The aim was to investigate whether the improvements in ORR have translated to improved resection rates (RR). STUDY DESIGN: A systematic literature search was performed using the PICO process. STATISTICAL ANALYSIS: Odds ratios, and 95% confidence intervals (OR, 95% CI) were analyzed for ORR and RR using dichotomous values with the Mantel-Haenszel method. Progression-free survival (PFS) and overall survival (OS) were analyzed using the inverse-variance method and displayed as hazard ratios and 95% confidence intervals (HR, 95% CI). RESULTS: The literature search returned 469 records. Sixteen articles with 5724 patients were selected for analysis. The qualitative analysis revealed low and moderate risk of bias endpoints. Higher ORR was observed with CTx + TT versus CTx only (OR: 0.62 [95% CI 0.45; 0.82], p = 0.002) and with triplet CTx + TT versus doublet CTx + TT (OR: 0.61 [95% CI 0.46; 0.81], p < 0.001). PFS and OS were improved by use of TT (HR: 0.68-0.84; p < 0.001 to 0.04). The overall RR was low (< 15%) and did not improve in the same way as the other endpoints. CONCLUSION: The ORR and survival rates in unresectable and borderline resectable mCRC were improved by modern CTx and TT that did not translate into higher RR, mostly due to the lack of expert involvement.

Short-term outcome of diverting loop ileostomy reversals performed by residents: a retrospective cohort prognostic factor study.

AIM: The reversal of diverting loop ileostomy (DLI) is one of surgical trainees' first procedures. Complications of DLI reversal can cause life-threatening complications and increase patient morbidity. This study compared DLI reversals performed by surgical trainees with those by attending surgeons. METHOD: This retrospective cohort study was performed at a single primary care center on 300 patients undergoing DLI reversal. The primary outcome was morbidity, according to the Clavien-Dindo classification (CDC), with special attention paid to the surgeon's level of training. The secondary endpoint was postoperative intestinal motility dysfunction. RESULTS: Surgical trainees had significantly longer operation times (p < 0.001) than attending surgeons. Univariate analyses revealed no influence on the level of training for postoperative morbidity. First bowel movement later than 3 days after surgery was a significant risk factor for CDC [Formula: see text] 3 (OR, 4.348; 96% CI, 1670-11.321; p = 0.003). Independent risk factors for surgical site infections (SSIs) were an elevated BMI (OR, 1.162; 95% CI, 1.043-1.1294; p = 0.007) and a delayed bowel movement (OR, 3.973; 95% CI, 1.300-12.138; p = 0.015). For postoperative intestinal motility dysfunction, an independent risk factor was a primary malignant disease (OR, 1.980; 95% CI, 1.120-3.500; p = 0.019), and side-to-side stapled anastomosis was a protective factor (OR, 0.337; 95% CI 0.155-0.733; p = 0.006). CONCLUSION: Even though surgical trainees needed significantly more time to perform the surgery, the level of surgical training was not a risk factor for increased postoperative morbidity. Instead, delayed first bowel movement was predictive of SSI.

Opsoclonus-myoclonus syndrome associated with pancreatic neuroendocrine tumor: a case report.

BACKGROUND: Opsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET). CASE PRESENTATION: A 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids. CONCLUSIONS: This case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy.

Complete Pathological Response After Neoadjuvant Short-Course Immunotherapy with Ipilimumab and Nivolumab in Locally Advanced MSI-H/dMMR Rectal Cancer.

BACKGROUND: Patients with colorectal carcinoma and high-grade microsatellite instability (MSI-H) or deficiency in mismatch repair (dMMR) exceptionally respond to immune checkpoint inhibitors (ICIs). ICIs are more active in treatment-naïve patients than in patients with refractory MSI-H/dMMR metastatic colorectal cancer and even more active in patients with locally advanced tumors. MATERIAL AND METHODS: A 33-year-old male patient with Lynch syndrome was diagnosed with a locally advanced rectal cancer and refused standard neoadjuvant chemoradiation because of the potential harm of sexual dysfunction. MMR and microsatellite instability status were analyzed by immunohistochemistry and fragment length polymerase chain reaction followed by capillary electrophoresis. RESULTS: After MSI-H/dMMR was confirmed, the patient was treated with ICIs (1 mg/kg ipilimumab at day 1 and 3 mg/kg nivolumab at day 1 and 15). A complete clinical response was documented at day 21 after start of treatment. The patient underwent a total mesorectal excision at day 30. In the extirpated tissue, a complete pathological response was confirmed. CONCLUSION: In MSI-H/dMMR locally advanced rectal cancer short-course ICI treatment is highly effective and may be discussed in patients with dMMR locally advanced rectal cancer. KEY POINTS: Immune checkpoint inhibitors are more active in treatment-naïve patients than in patients with refractory high-grade microsatellite instability (MSI-H)/deficiency in mismatch repair (dMMR) colorectal cancer. Standard neoadjuvant chemoradiation is less effective in MSI-H/dMMR rectal cancer patients than in patients with proficient mismatch repair. A young patient with Lynch syndrome and MSI-H/dMMR locally advanced rectal cancer refused chemoradiation in order to preserve his fertility. After neoadjuvant treatment with one dose of ipilimumab and two doses of nivolumab a complete clinical and pathological response was documented. Clinical trials are needed to first establish neoadjuvant treatment with immune checkpoint inhibitors in patients with locally advanced MSI-H/dMMR rectal cancer and thereafter to evaluate organ-preservation strategies.

Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives.

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

Patient-reported acute fatigue in elderly breast cancer patients treated with and without regional nodal radiation.

PURPOSE: Although regional nodal irradiation (RNI) improves outcomes in breast cancer (BC) patients, it is associated with increased toxicity. Therefore, controversy still exists surrounding its indications. The purpose of this study was to evaluate and compare patient-reported acute fatigue in elderly BC patients with and without regional nodal radiation (RNI). METHODS: Elderly breast cancer patients (≥ 65 years) treated with adjuvant radiotherapy (RT) between 2012 and 2017 were identified from a prospective database. The validated Edmonton Symptom Assessment System-revised (ESAS-r) questionnaire, which assesses fatigue, was completed prior to (baseline), during, at end of RT and first follow-up (3-6 months). Symptoms were rated on a 10-point Likert scale, with higher scores indicating higher fatigue. Patient's treatment characteristics were also recorded prospectively. This was a retrospective study which identified elderly breast cancer patients who had received adjuvant radiation, completed ESAS-r prospectively and provided research consent for using ESAS-r. Patients were divided into two cohorts: those who received RNI (cohort 1) and those who did not (cohort 2). A minimal clinically important difference (MID) was defined using an anchor of ≥ 1-point compared to baseline. The proportion of patients reporting a change in fatigue at the end of RT was evaluated. To test the robustness of the results, dynamic changes of fatigue scores over time were further compared between the cohorts using a general linear mixed model (GLMM) after assuming individual patient with random effect. Univariate and multivariable logistic regression were conducted to assess the association between RNI and MID after adjusting for potential confounders. In addition to longitudinal analysis, a multivariable mixed effect model was developed to determine the association of RNI with fatigue after adjusting for potential confounders. A two-tailed p value ≤ 0.05 was considered statistically significant. RESULTS: Of the 1198 patients, 859 had provided research consent and completed the ESAS-r at baseline and any other time-point and were included in the longitudinal analysis (cohort 1 = 159, cohort 2 = 700), while 637 (cohort 1 = 135, cohort 2 = 502) patients completed the ESAS-r at baseline and end of radiotherapy and were included in the anchor-based analysis. Mean age at diagnosis was similar between the groups: cohort 1; 71.5 ± 5.7 vs. cohort; 2 72 ± 5.4 years (total 71.8 ± 5.5). Overall, cohort 1 had higher stage (Stage 3: 32.7% vs 3.6%, p < 0.001) and reception of chemotherapy (68.6% vs. 16.1%, p < 0.001). Mean baseline fatigue was higher for cohort 1 vs. 2 (2.7 ± 2.5 vs. 2.1 ± 2.3, p = 0.006). On univariate and multivariable analyses, RNI was not associated with an increased odd of MID for fatigue at the end of RT (44% vs. 47%; OR 0.89, 95% CI 0.61-1.30, p = 0.56). After adjusting for confounders (age, duration of RT, endocrine therapy), treatment with RNI was not associated with increased odds of worse fatigue at the end of RT (OR 1.33, 95% CI 0.85-2.10, p = 0.22). Higher baseline fatigue (OR 0.86, 95% CI 0.79-0.92, p < 0.001) and receipt of chemotherapy had decreased odds (OR 0.50, 95% CI 0.32-0.86, p = 0.001) and were the only factors associated with decreased odds of MID. Dynamic changes showed a significant worsening of fatigue scores over time (p < 0.001) towards the end of RT and recovery at first follow-up (p < 0.001) with no difference between the cohorts (p = 0.38); both experienced parallel worsening of fatigue levels over time (cohort*time p = 0.71 and cohort*time2p = 0.78). On multivariable analysis earlier stage, the absence of chemotherapy and higher baseline depression were independent predictors of worse fatigue scores over time (p = 0.01, p = 0.003, and p = 0.02, respectively). CONCLUSION: The addition of RNI in elderly BC patients is not associated with a significant worsening of patient-reported fatigue. Predictors of acute fatigue will enable shared decision making between patients and clinicians.

Poor Prognosis of Advanced Cholangiocarcinoma: Real-World Data from a Tertiary Referral Center.

BACKGROUND: Incidence of cholangiocarcinoma (CCA) in western countries is rising. In the palliative setting, chemotherapy is the only established treatment. The evidence for other treatments including locoregional therapy is low. However, such individual treatments are offered in a real-world setting. The aim of this study is to document the offered treatments and to analyze the survival of patients with unresectable CCA treated at a tertiary referral center. PATIENTS AND METHODS: Data from 220 consecutive patients with CCA treated at a German university cancer center from January 1, 2008, until December 31, 2012. Of those, 105 patients were unresectable. Survival curves were calculated according to the Kaplan-Meier method; log-rank test was applied for survival analysis. RESULTS: Any palliative treatment was beneficial for patients with unresectable CCA when compared to best supportive care (BSC) alone; median OS with BSC was 10 weeks (BSC vs. transarterial chemoembolization [TACE] p = 0.017, HR 0.36; BSC vs. TACE/chemotherapy p < 0.001, HR 0.24; BSC vs. chemotherapy p < 0.001, HR 0.31). Combination of TACE and chemotherapy prolonged overall survival as compared to TACE alone (105 vs. 43 weeks, p = 0.045). CONCLUSION: Prognosis in advanced stage CCA is still very poor. However, multimodal treatment in palliative patients significantly prolong survival.

Anti-EGF Receptor-Based Conversion Chemotherapy in RAS Wild-Type Colorectal Cancer Patients: Impact on Survival and Resection Rates.

BACKGROUND: Initially unresectable colorectal liver metastases can become resectable after chemotherapy. Combination chemotherapy with epidermal growth factor receptor (EGFR) antibodies has shown consistent high response rates in patients with all rat sarcoma (RAS) wild-type tumors. METHODS: Out of a cohort of 424 patients with metastatic colorectal cancer, we identified 30 patients with initially unresectable Kirsten RAS (KRAS) exon 2 wild-type colorectal liver metastases who received neoadjuvant chemotherapy with anti-EGFR agents between January 2008 and February 2014. In all patients, extended RAS analysis (KRAS and NRAS exon 3 codon 59/61 and exon 4 codon 117/146) was carried out retrospectively. RESULTS: RAS mutation analysis identified further KRAS mutations in 4/30 patients (13.3%). In none of these 4 patients a R0 resection was achieved. In contrast, 15/26 (57.7%) RAS wild-type patients were R0 resected. Median overall survival was > 63.3 months in R0-resected patients versus 30.0 months in those with a R1 or R2 resection (HR 0.23; [95% CI 0.10-0.75; p = 0.008). CONCLUSION: Our data suggest that a RAS wild-type and a R0 resection are the strongest predictors for overall survival.

Redefining the projectional and clinical anatomy of the duodenojejunal flexure in children.

The duodenojejunal flexure (DJF) is an important surgical landmark that enables the pediatric surgeon to establish whether normal intestinal rotation has occurred. The degree of variation in the position of the DJF has not been studied in the pediatric population, and there have been only limited studies on adults. The aim of the present study was to determine the position and relationships of the DJF in infants and children utilizing cross-sectional imaging. Computer tomography scans of 120 children were divided into three age groups and systematically analyzed. The DJF position was measured in relation to the vertebral body level, midline, anterior-posterior distance from the vertebral body, transpyloric plane, and mesenteric vessels. The position of the third part of the duodenum and the length of the mesenteric root were also determined. There was considerable variation in the DJF position with respect to the above landmarks in all three age groups. The vertebral body level of the DJF was centered on L1, but ranged between T11 and L3. In 3% of children with normal rotation the SMA/SMV relationship was abnormal. The third part of the duodenum was consistently found to be retromesenteric. The length of the mesenteric root ranged from 7 to 22 cm, and generally lengthened with increasing age. Owing to its variable position in infants and children, the DJF on its own may not be a reliable landmark for establishing normal intestinal rotation. Assessing for normal rotation is multifaceted and further comparative studies are required to characterize the anatomical features of normal and abnormal rotation.

Established and Potential Predictive Biomarkers in Gastrointestinal Cancer--c-Kit, Her2, Ras and Beyond.

BACKGROUND: Gastrointestinal cancers are among the leading causes of cancer-related deaths worldwide. In different tumor types, personalized systemic treatment strategies based upon biomarker-selection were established over the last years. Although there is a flood of targeted agents in clinical development, only a few targeted agents with a predictive biomarker could be established for the treatment of patients with gastrointestinal cancer patients so far. SUMMARY: Currently, predictive biomarkers for gastrointestinal cancers include Her2 overexpression or amplification (gastroesophageal adenocarcinoma), c-Kit overexpression (gastrointestinal stromal tumors) and RAS wild-type (colorectal cancer). Selection of patients based on these biomarkers allows the efficient use of targeted agents. The presence of a BRAF mutation and/or high microsatellite instability is prognostic and rather a predictive marker in CRC. Promising candidate markers in advanced clinical development are MET amplification in gastroesophageal adenocarcinoma, Met overexpression and high AFP serum levels in hepatocellular carcinoma. KEY MESSAGE: Biomarker-guided systemic treatment is established in a subset of patients with gastrointestinal cancer. Ongoing clinical trials and further advances in high-throughput technologies will hopefully result in more personalized systemic treatment strategies for these patients in the near future.

Systemic Drugs for Hepatocellular Carcinoma: What Do Recent Clinical Trials Reveal About Sequencing and the Emerging Complexities of Clinical Decisions?

Liver cancer was the fourth leading cause of cancer death in 2015 with increasing incidence between 1990 and 2015. Orthotopic liver transplantation, surgical resection and ablation comprise the only curative therapy options. However, due to the late manifestation of clinical symptoms, many patients present with intermediate or advanced disease, resulting in no curative treatment option being available. Whereas intermediate-stage hepatocellular carcinoma (HCC) is usually still addressable by transarterial chemoembolization (TACE), advanced-stage HCC is amenable only to pharmacological treatments. Conventional cytotoxic agents failed demonstrating relevant effect on survival also because their use was severely limited by the mostly underlying insufficient liver function. For a decade, tyrosine kinase inhibitor (TKI) sorafenib was the only systemic therapy that proved to have a clinically relevant effect in the treatment of advanced HCC. In recent years, the number of substances for systemic treatment of advanced HCC has increased enormously. In addition to tyrosine kinase inhibitors, immune checkpoint inhibitors (ICI) and antiangiogenic drugs are increasingly being applied. The combination of anti-programmed death ligand 1 (PD-L1) antibody atezolizumab and anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has become the new standard of care for advanced HCC due to its remarkable response rates. This requires more and more complex clinical decisions regarding tumor therapy. This review aims at summarizing recent developments in systemic therapy, considering data on first- and second-line treatment, use in the neoadjuvant and adjuvant setting and combination with locoregional procedures.

Diagnostic performance of non-invasive liver fibrosis scores in patients with early-intermediate hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) arises in individuals with underlying liver disease. Diagnosing the degree of hepatic fibrosis helps to determine the severity of the underlying liver disease and may influence therapeutic decisions in HCC patients. Non-invasive fibrosis scores can be used to estimate the degree of fibrosis in liver disease patients, but most of these scores were developed in patients with viral hepatitis and without HCC. This study explored the ability of the Fibrosis-4 Index (FIB-4), the AST/Platelet Ratio Index (APRI), and the AST/ALT ratio to diagnose or exclude advanced fibrosis (METAVIR F3/4 versus F0-2) in patients with early-intermediate, potentially resectable HCC. METHODS: We retrospectively reviewed 119 patients who underwent hepatic resection for HCC at a tertiary centre (2007-2019), 75 of whom had advanced fibrosis (prevalence 63%). Histological assessment of the surgical liver specimen was used as a reference standard for the degree of fibrosis. RESULTS: Overall diagnostic performance was highest for the FIB-4 Index, with an area under the receiver operating characteristic curve (AUROC) of 0.82, compared with 0.78 for APRI, and 0.56 for the AST/ALT ratio. Using established cut-off values, FIB-4 achieved a 90% positive predictive value at the higher cut-off (3.25) and a 90% negative predictive value at the lower cut-off (1.45). CONCLUSION: The FIB-4 Index could reliably diagnose or exclude advanced fibrosis in patients with early-intermediate HCC, and may thus have a role in guiding therapeutic decisions in these patients.

Prognostic value of paraaortic lymph node metastases in patients with ductal adenocarcinoma of the pancreatic head.

INTRODUCTION: The role of paraaortic lymphadenectomy for cancer of the pancreatic head is controversial. The aim of this study is to analyze the prognostic role of paraaortic lymph node (PALN) metastases after resection for ductal adenocarcinoma of the pancreatic head. MATERIALS AND METHODS: A retrospective analysis of all patients, who underwent upfront resection for ductal adenocarcinoma of the pancreatic head at the Frankfurt University Hospital from 2011 to 2020 was performed. The primary endpoint was survival, according to the presence of PALN metastases. RESULTS: Out of 468 patients with pancreatic resection, 148 had an upfront resection for ductal adenocarcinoma. Of those, in 125 (85%) a paraaortic lymphadenectomy was performed. In 19 (15.2%) PALN metastases were detected. The estimated overall median survival after resection was 21.7 months (95% CI 18.8 to 26.4), the disease free survival 16 months (95% CI 12 to 18). Among the patients with lymph node metastases, PALN metastases had no significant influence on overall (18.9 versus 19 months, HR = 1.3, 95% CI 0.7 to 2.6, p = 0.392) or disease free survival (14 versus 10.7 months, HR = 1.7, 95% CI 0.9 to 3.2, p = 0.076). After adjusting for T-stage, N-stage, grade, resection margin, PALN metastases, and adjuvant therapy, only adjuvant therapy had a prognostic significance for overall survival (HR = 0.47, 95% CI 0.26 to 0.85, p = 0.013). CONCLUSION: Patients with ductal adenocarcinoma of the pancreatic head and PALN metastases do not have inferior outcomes than those with regional lymph node metastases. Thus, positive PALN should not be considered a contraindication for resection.

Impact of IDH1 mutation on clinical course of patients with intrahepatic cholangiocarcinoma: a retrospective analysis from a German tertiary center.

PURPOSE: IDH1 mutation is a known biomarker for targeted therapy of intrahepatic cholangiocarcinoma (iCCA), while its prognostic relevance for current palliative chemotherapy is still unclear. Aim of this study was to analyze clinicopathological characteristics of patients with IDH1 mutations and to outline a potential impact on the outcome after state-of-the-art palliative chemotherapy regimens. METHODS: All patients with iCCA receiving large panel molecular profiling and follow-up treatment at Frankfurt University Hospital until 04/2022 were retrospectively analyzed. Clinicopathological characteristics were assessed for IDH1 mutated (mut) and IDH1 wild type (wt) patients, and progression-free survival (PFS) and overall survival (OS) were determined. RESULTS: In total, 75 patients with iCCA received molecular profiling. Of the patients with available DNA data, pathogenic mutations in IDH1 were found in 14.5% (n = 10). IDH1 mut status was associated with lower serum CA-19/9 (p = 0.023), lower serum lactate dehydrogenase (p = 0.006), and a higher proportion of primary resectability (p = 0.028) as well as response to chemotherapy after recurrence (p = 0.009). Median PFS was 5.9 months (95% CI 4.4-7.3 months) for IDH1 wt in comparison to 9.8 months (95% CI 7.7-12 months) for patients with IDH1 mut (p = 0.031). IDH1 wt was a significant risk factor for shortened PFS in univariate (p = 0.043), but not in multivariate analysis (p = 0.061). There was no difference in OS between both groups. CONCLUSION: Patients with IDH1 mutated iCCA seem to have a favorable tumor biology including a longer PFS for palliative chemotherapy regimens compared to IDH1 wild type.

NTRK fusion events and targeted treatment of advanced radioiodine refractory thyroid cancer.

PURPOSE: Pathogenic fusion events involving neurotrophic receptor tyrosine kinase (NTRK) have been described in ~ 2% of differentiated thyroid cancer (DTC). The selective tropomyosin receptor kinase (TRK) inhibitors entrectinib and larotrectinib have been approved in a tumor agnostic manner based on phase 1/2 clinical trials. In a real-world setting at five referral centers, we aimed to describe the prevalence of NTRK gene fusions and the efficacy and safety of TRK inhibitor treatment for non-medullary, advanced thyroid cancer (TC). METHODS: A total of 184 TC patients with testing for NTRK gene fusions were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method in six patients with NTRK fusion-positive TC who underwent TRK inhibitor therapy. RESULTS: 8/184 (4%) patients harbored NTRK gene fusions. Six patients with radioiodine (RAI)-refractory TC harboring NTRK1 (n = 4) and NTRK3 (n = 2) gene fusions were treated with larotrectinib. Five patients (83%) had received ≥ 1 prior systemic therapy and one patient did not receive prior systemic therapy. All patients had morphologically progressive disease before treatment initiation. Objective response rate was 83%, including two complete remissions. Median PFS from start of TRK inhibitor treatment was 23 months (95% confidence interval [CI], 0-57.4) and median OS was not reached (NR) (95% CI, NR). Adverse events were of grade 1-3. CONCLUSION: The prevalence of NTRK gene fusions in our cohort of RAI-refractory TC is slightly higher than reported for all TC patients. Larotrectinib is an effective treatment option in the majority of NTRK gene fusion-positive advanced TC patients after prior systemic treatment and has a favorable safety profile.

Decomposition of Organic Perovskite Precursors on MoO3: Role of Halogen and Surface Defects.

Despite the rapid progress in perovskite solar cells, their commercialization is still hindered by issues regarding long-term stability, which can be strongly affected by metal oxide-based charge extraction layers next to the perovskite material. With MoO3 being one of the most successful hole transport layers in organic photovoltaics, the disastrous results of its combination with perovskite films came as a surprise but was soon attributed to severe chemical instability at the MoO3/perovskite interface. To discover the atomistic origin of this instability, we combine density functional theory (DFT) calculations and X-ray photoelectron spectroscopy (XPS) measurements to investigate the interaction of MoO3 with the perovskite precursors MAI, MABr, FAI, and FABr. From DFT calculations we suggest a scenario that is based upon oxygen vacancies playing a key role in interface degradation reactions. Not only do these vacancies promote decomposition reactions of perovskite precursors, but they also constitute the reaction centers for redox reactions leading to oxidation of the halides and reduction of Mo. Specifically iodides are proposed to be reactive, while bromides do not significantly affect the oxide. XPS measurements reveal a severe reduction of Mo and a loss of the halide species when the oxide is interfaced with I-containing precursors, which is consistent with the proposed scenario. In line with the latter, experimentally observed effects are much less pronounced in case of Br-containing precursors. We further find that the reactivity of the MoO3 substrate can be moderated by reducing the number of oxygen vacancies through a UV/ozone treatment, though it cannot be fully eliminated.

Survival According to Therapy Regimen for Small Intestinal Neuroendocrine Tumors.

INTRODUCTION: Scarce data exist for therapy regimens other than somatostatin analogues (SSA) and peptide receptor radiotherapy (PRRT) for siNET. We analyzed real world data for differences in survival according to therapy. PATIENTS AND METHODS: Analysis of 145 patients, diagnosed between 1993 and 2018 at a single institution, divided in treatment groups. Group (gr.) 0: no treatment (n = 10), gr 1: TACE and/or PRRT (n = 26), gr. 2: SSA (n = 32), gr. 3: SSA/PRRT (n = 8), gr. 4: chemotherapy (n = 8), gr. 5: not metastasized (at diagnosis), surgery only (n = 53), gr. 6 = metastasized (at diagnosis), surgery only (n = 10). RESULTS: 45.5% female, median age 60 years (range, 27-84). A total of 125/145 patients with a resection of the primary tumor. For all patients, 1-year OS (%) was 93.8 (95%-CI: 90-98), 3-year OS = 84.3 (CI: 78-90) and 5-year OS = 77.5 (CI: 70-85). For analysis of survival according to therapy, only stage IV patients (baseline) that received treatment were included. Compared with reference gr. 2 (SSA only), HR for OS was 1.49 (p = 0.47) for gr. 1, 0.72 (p = 0.69) for gr. 3, 2.34 (p = 0.19) for gr. 4. The 5 y OS rate of patients whose primary tumor was resected (n = 125) was 73.1%, and without PTR was 33.3% (HR: 4.31; p = 0.003). Individual patients are represented in swimmer plots. CONCLUSIONS: For stage IV patients in this analysis (limited by low patient numbers in co. 3/4), multimodal treatment did not significantly improve survival over SSA treatment alone. A resection of primary tumor significantly improves survival.