Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIM: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. APPROACH AND RESULTS: This bi-institutional study of patients with confirmed iCCA (n = 412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain-containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1-associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08-3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95-5.94; P < 0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P < 0.001]; regional lymph node metastases [P < 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97-2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high-risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8-73.5) or high-risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. CONCLUSIONS: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.

Genetic And Morphological Evaluation (GAME) score for patients with colorectal liver metastases.

BACKGROUND: This study sought to develop a clinical risk score for resectable colorectal liver metastasis (CRLM) by combining clinicopathological and clinically available biological indicators, including KRAS. METHODS: A cohort of patients who underwent resection for CRLM at the Johns Hopkins Hospital (JHH) was analysed to identify independent predictors of overall survival (OS) that can be assessed before operation; these factors were combined into the Genetic And Morphological Evaluation (GAME) score. The score was compared with the current standard (Fong score) and validated in an external cohort of patients from the Memorial Sloan Kettering Cancer Center (MSKCC). RESULTS: Six preoperative predictors of worse OS were identified on multivariable Cox regression analysis in the JHH cohort (502 patients). The GAME score was calculated by allocating points to each patient according to the presence of these predictive factors: KRAS-mutated tumours (1 point); carcinoembryonic antigen level 20 ng/ml or more (1 point), primary tumour lymph node metastasis (1 point); Tumour Burden Score between 3 and 8 (1 point) or 9 and over (2 points); and extrahepatic disease (2 points). The high-risk group in the JHH cohort (GAME score at least 4 points) had a 5-year OS rate of 11 per cent, compared with 73·4 per cent for those in the low-risk group (score 0-1 point). Importantly, in cohorts from both the JHH and MSKCC (747 patients), the discriminatory capacity of the GAME score was superior to that of the Fong score, as demonstrated by the C-index and the Akaike information criterion. CONCLUSION: The GAME score is a preoperative prognostic tool that can be used to inform treatment selection.

Prostate cancer detection among readers with different degree of experience using ultra-high b-value diffusion-weighted Imaging: Is a non-contrast protocol sufficient to detect significant cancer?

AIM: To evaluate the accuracy of a T2-weighted (T2w) - and a parallel transmit zoomed b = 2000 s/mm2 (b2000) - diffusion-weighted imaging sequence among three readers with different degrees of experience for prostate cancer (Pca) detection. METHODS: Ninety-three patients with suspected Pca were enrolled. For b2000 a two-dimensional spatially-selective RF pulse using an echo-planar transmit trajectory was applied, and the field of view (FOV) was reduced to one-third. All three readers (Reader A: 7, B 4 and C <1 years of experience in prostate MRI) independently evaluated b2000 with regard to the presence of suspicious lesions that displayed increased signal. The results were compared to histopathology obtained by real-time MR/ultrasound fusion and systematic biopsy. RESULTS: In 62 patients Pca was confirmed. One significant Pca (Gleason score (GS) 7b) was missed by Reader C. Overall, sensitivity/specificity/positive predictive value/negative predictive value were 90/71/86/79% for Reader A, 87/84/92/76% for Reader B and 85/74/87/72% for Reader C, respectively. Detection rates for significant Pca (GS >7a) were 100/100/94% for Readers A/B/C, respectively. Inter-reader agreement was generally good (Kappa A/B: 0.8; A/C: 0.82; B/C: 0.74). CONCLUSION: B2000 in combination with a T2w could be useful to detect clinically significant Pca. KEY POINTS: • Significant prostate cancer using zoomed ultra-high b-value DWI was detected. • Diagnostic performance among readers with different degrees of experience was good. • mp- MRI of the prostate using a comprehensive non-contrast protocol is clinically feasible.

Impact of early postoperative platelet count on volumetric liver gain and perioperative outcomes after major liver resection.

BACKGROUND: Although perioperative platelet count has been associated with postoperative morbidity and mortality, its impact on liver regeneration has not been examined directly. This study sought to determine the impact of platelet count on liver regeneration after major liver resection using cross-sectional imaging volumetric assessment. METHODS: Patients who underwent major liver resection between 2004 and 2015 and had available data on immediate postoperative platelet count, as well as preoperative and postoperative CT images, were identified retrospectively. Resected liver volume was subtracted from total liver volume (TLV) to define postoperative remnant liver volume (RLVp ). The liver regeneration index was defined as the relative increase in liver volume within 2 months ((RLV2m - RLVp )/RLVp , where RLV2m is the remnant liver volume around 2 months after surgery). The association between platelet count, liver regeneration and outcomes was assessed. RESULTS: A total of 99 patients met the inclusion criteria. Overall, 25 patients (25 per cent) had a low platelet count (less than 150 × 10(9) /l), whereas 74 had a normal-high platelet count (at least 150 × 10(9) /l). Despite having comparable clinicopathological characteristics and RLVp /TLV at surgery (P = 0·903), the relative increase in liver volume within 2 months was considerably lower in the low-platelet group (3·9 versus 16·5 per cent; P = 0·043). Patients with a low platelet count had an increased risk of postoperative complications (72 versus 38 per cent; P = 0·003), longer hospital stay (8 versus 6 days; P = 0·004) and worse median overall survival (24·5 versus 67·3 months; P = 0·005) than those with a normal or high platelet count. CONCLUSION: After major liver resection, a low postoperative platelet count was associated with inhibited liver regeneration, as well as worse short- and long-term outcomes. Immediate postoperative platelet count may be an early indicator to identify patients at increased risk of worse outcomes.

A preoperative prediction model for anastomotic leakage after rectal cancer resection based on 13.175 patients.

INTRODUCTION: This study aims to develop a robust preoperative prediction model for anastomotic leakage (AL) after surgical resection for rectal cancer, based on established risk factors and with the power of a large prospective nation-wide population-based study cohort. MATERIALS AND METHODS: A development cohort was formed by using the DCRA (Dutch ColoRectal Audit), a mandatory population-based repository of all patients who undergo colorectal cancer resection in the Netherlands. Patients aged 18 years or older were included who underwent surgical resection for rectal cancer with primary anastomosis (with or without deviating ileostomy) between 2011 and 2019. Anastomotic leakage was defined as clinically relevant leakage requiring reintervention. Multivariable logistic regression was used to build a prediction model and cross-validation was used to validate the model. RESULTS: A total of 13.175 patients were included for analysis. AL was diagnosed in 1319 patients (10%). A deviating stoma was constructed in 6853 patients (52%). The following variables were identified as significant risk factors and included in the prediction model: gender, age, BMI, ASA classification, neo-adjuvant (chemo)radiotherapy, cT stage, distance of the tumor from anal verge, and deviating ileostomy. The model had a concordance-index of 0.664, which remained 0.658 after cross-validation. In addition, a nomogram was developed. CONCLUSION: The present study generated a discriminative prediction model based on preoperatively available variables. The proposed score can be used for patient counselling and risk-stratification before undergoing rectal resection for cancer.

Risk attribution of Campylobacter infection by age group using exposure modelling.

Knowledge on the relative importance of alternative sources of human campylobacteriosis is important in order to implement effective disease prevention measures. The objective of this study was to assess the relative importance of three key exposure pathways (travelling abroad, poultry meat, pet contact) for different patient age groups in Switzerland. With a stochastic exposure model data on Campylobacter incidence for the years 2002-2007 were linked with data for the three exposure pathways and the results of a case-control study. Mean values for the population attributable fractions (PAF) over all age groups and years were 27% (95% CI 17-39) for poultry consumption, 27% (95% CI 22-32) for travelling abroad, 8% (95% CI 6-9) for pet contact and 39% (95% CI 25-50) for other risk factors. This model provided robust results when using data available for Switzerland, but the uncertainties remained high. The output of the model could be improved if more accurate input data are available to estimate the infection rate per exposure. In particular, the relatively high proportion of cases attributed to 'other risk factors' requires further attention.

Low Socioeconomic Status Is Associated with Worse Outcomes After Curative Surgery for Colorectal Cancer: Results from a Large, Multicenter Study.

BACKGROUND: Socioeconomic status (SES) has been associated with early mortality in cancer patients. However, the association between SES and outcome in colorectal cancer patients is largely unknown. The aim of this study was to investigate whether SES is associated with short- and long-term outcome in patients undergoing curative surgery for colorectal cancer. METHODS: Patients who underwent curative surgery in the region of Rotterdam for stage I-III colorectal cancer between January 2007 and July 2014 were included. Gross household income and survival status were obtained from a national registry provided by Statistics Netherlands Centraal Bureau voor de Statistiek. Patients were assigned percentiles according to the national income distribution. Logistic regression and Cox proportional hazard regression were performed to assess the association of SES with 30-day postoperative complications, overall survival and cancer-specific survival, adjusted for known prognosticators. RESULTS: For 965 of the 975 eligible patients (99%), gross household income could be retrieved. Patients with a lower SES more often had diabetes, more often underwent an open surgical procedure, and had more comorbidities. In addition, patients with a lower SES were less likely to receive (neo) adjuvant treatment. Lower SES was independently associated with an increased risk of postoperative complications (Odds ratio per percent increase 0.99, 95%CI 0.99-0.998, p = 0.004) and lower cancer-specific mortality (Hazard ratio per percent increase 0.99, 95%CI 0.98-0.99, p = 0.009). CONCLUSION: This study shows that lower SES is associated with increased risk of postoperative complications, and poor cancer-specific survival in patients undergoing surgery for stage I-III colorectal cancer after correcting for known prognosticators.

The effect of intravenous iron therapy on long-term survival in anaemic colorectal cancer patients: Results from a matched cohort study.

INTRODUCTION: Intravenous iron therapy has been shown to be advantageous in treating anaemia and reducing the need for blood transfusions. Iron treatment, however, may also be hazardous by supporting cancer growth. Present clinical study explores, for the first time, the effect of preoperative intravenous iron therapy on tumour prognosis in anaemic colorectal cancer patients. METHODS: A retrospective cohort study was performed on consecutive patients who underwent surgery for colorectal cancer between 2010 and 2016 in a single teaching hospital. The primary outcomes were 5-year overall survival (OS) and disease-free survival (DFS). Survival estimates were calculated using the Kaplan-Meier method and patients were matched based on propensity score. RESULTS: 320 (41.0%) of all eligible patients were anaemic, of whom 102 patients received preoperative intravenous iron treatment (31.9%). After propensity score matching 83 patients were included in both intravenous and non-intravenous iron group. The estimated 1-, 3-, and 5-year OS (91.6%, 73.1%, 64.3%, respectively) and DFS (94.5%, 86.7%, 83.4%, respectively) in the intravenous iron group were comparable with the non-intravenous iron group (p = 0.456 and p = 0.240, respectively). In comparing patients with an event (death or recurrence) and no event in the intravenous iron group, a distinct trend was found for decreased transferrin in the event group (median 2.53  g/L vs 2.83  g/L, p = 0.052). CONCLUSION: The present study illustrates that a dose of 1000-2000 mg preoperative intravenous iron therapy does not have a profound effect on long-term overall and disease-free survival in anaemic colorectal cancer patients. Future randomised trials with sufficient power are required to draw definite conclusions on the safety of intravenous iron therapy.

Non-classical light emission from a single electrically driven quantum dot.

Easy to handle light sources with non-classical emission features are strongly demanded in the growing field of quantum communication. We report on single-photon emission from an electrically pumped quantum dot with unmatched spectral purity, making spatial or spectral filtering dispensable.

Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease.

NKX2-5 is a pivotal transcription factor in heart development. Previous studies on lymphocytic DNA provided evidence of familial NKX2-5 gene mutations in cardiac malformations. Common mutations are rare in unrelated families. We analysed, by direct sequencing, the gene encoding NKX2-5 in the diseased heart tissues of 68 patients with complex congenital heart disease, focussing particularly on atrial, ventricular, and atrioventricular septal defects. We identified 35 non-synonymous NKX2-5 mutations in the diseased heart tissues of patients. These mutations were mainly absent in normal, for example, unaffected, heart tissue of the same patient, indicating the somatic nature and mosaicism of mutations. We also observed multiple mutations and multiple haplotypes, as well as mutations in Down's syndrome patients with cardiac malformations. Taken collectively, the above results suggest the somatic nature of NKX2-5 mutations associated with complex cardiac malformations. Somatic mutations in transcription factor genes of cardiac progenitor cells provide a novel mechanism of disease.

Loss of apoptosis-inducing factor critically affects MIA40 function.

Mitochondrial apoptosis-inducing factor (AIF) influences the oxidative phosphorylation (OXPHOS) system and can be recruited as a mediator of cell death. Pathogenic mutations in the AIFM1 gene cause severe human diseases. Clinical manifestations include inherited peripheral neuropathies, prenatal cerebral abnormalities and progressive mitochondrial encephalomyopathies. In humans, rodents and invertebrates, AIF deficiency results in loss of respiratory complexes and, therefore, impaired OXPHOS. The molecular mechanisms underlying AIF-induced mitochondrial dysfunction remain elusive. Here we show that AIF physically interacts with the oxidoreductase CHCHD4/MIA40. In patient-derived fibroblasts as well as in tissues and glia cells from Harlequin (Hq) mutant mice, AIF deficiency correlates with decreased MIA40 protein levels, without affecting mRNA transcription. Importantly, MIA40 overexpression counteracts loss of respiratory subunits in Hq cells. Together, our findings suggest that MIA40 reduction contributes to the effects of AIF deficiency on OXPHOS, as it may impact on the correct assembly and maintenance of the respiratory subunits. This may be relevant for the development of new therapeutic approaches for AIF-related mitochondrial disorders.

Lessons from the trenches in physician integration.

Beyond the theoretical basis for integration, three core considerations stand out as the primary reasons for pursuing integration from a physician's perspective. In the authors' experience, the ability to make a case for physician integration stands or falls based on the ability of the integrated delivery system to address these considerations: Gain greater access to capital; develop human resources with talents in managed care and the full spectrum of care services; and sustain an information infrastructure. This article explores the lessons learned in pursuing physician integration.

Asialoglycoprotein receptor function in benign liver disease: evaluation with MR imaging.

An arabinogalactan-coated ultrasmall superparamagnetic iron oxide (AG-USPIO) preparation specific for asialoglycoprotein (ASG) receptors on hepatocytes was used as a magnetic resonance (MR) imaging contrast agent in the evaluation of a spectrum of benign liver diseases in animal models. The activity of hepatocyte ASG receptors, which directly reflects liver function, was directly assessed by measuring liver relaxation times in vitro and MR signal intensity in vivo. The following measurements allowed three-dimensional assessment of liver function: (a) liver relaxation time, (b) native MR signal intensities of liver, (c) response of liver to the AG-USPIO probe (percentage decrease of liver signal intensity after intravenous administration of 10 mumol/kg of AG-USPIO: normal liver 55%, fatty liver 57%, acute hepatitis 36%, chronic hepatitis 29%, and cirrhosis 46%), and (d) redistribution of hepatocyte-specific AG-USPIO to the spleen (present in hepatitis and cirrhosis but not in normal liver and fatty liver). The results of this study indicate that cellular hepatic abnormalities can be detected and quantitated with MR receptor imaging.

Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8466 patients.

In a prospective cohort study 8466 women attending routine cervical cancer screening were recruited. Colposcopy was performed on women with any degree of atypia on cytology and/or a positive high-risk human papillomavirus (HPV)-DNA test (HC2; Hybrid Capture 2((c))), and for a randomly selected sample of 3.4% women with negative findings on both. Quality control included reviews of cytology, histology, colposcopy images and retesting of samples with polymerase chain reaction. Test diagnostic performances were based on 7908 women who had complete baseline and follow-up results. Routine histology identified 86 women with high-grade cervical intraepithelial neoplasia (CIN2+), which was confirmed by review histology in only 46 cases. Sensitivity of routine cytology for the detection of CIN2+ was 43.5%, with a specificity, positive predictive value (PPV), negative predictive value (NPV) of 98.0, 11.4 and 99.7%, respectively. Sensitivity of the HC2 test for the detection of CIN2+ was 97.8%, with a specificity, PPV and NPV, of 95.3, 10.9 and 100%, respectively. No high-grade neoplasia was detected in the randomly selected control group. A negative HPV-test result, even in combination with a positive Papanicolaou (Pap) result, virtually excluded any risk of underlying high-grade disease, but this was not the case for a negative Pap result. These data show that HPV testing is of value for the detection or exclusion of prevalent CIN in a routine cervical cancer-screening setting and could be used for further risk classification of women for follow-up management.