Safety, quality and efficiency of intra-operative imaging for treatment decisions in patients with suspected choledocholithiasis without pre-operative magnetic resonance cholangiopancreatography.

INTRODUCTION: Cholecystectomy is the accepted treatment for patients with symptomatic gallstones. In this study, we evaluate a simplified strategy for managing suspected synchronous choledocholithiasis by focussing on intra-operative imaging as the primary decision-making tool to target common bile duct (CBD) stone treatment. METHODS: All elective and emergency patients undergoing laparoscopic cholecystectomy (LC) for gallstones with any markers of synchronous choledocholithiasis were included. Patients unfit for surgery or who had pre-operative proof of choledocholithiasis were excluded. Intra-operative imaging was used for evaluation of the CBD. CBD stone treatment was with bile duct exploration (LCBDE) or endoscopic retrograde cholangiopancreatography (LC + ERCP). Outcomes were safety, effectiveness and efficiency. RESULTS: 506 patients were included. 371 (73%) had laparoscopic ultrasound (LUS), 80 (16%) had on-table cholangiography (OTC) and 55 (11%) had both. 164 (32.4%) were found to have CBD stones. There was no increase in length of surgery for LC + LUS compared with average time for LC only in our unit (p = 0.17). 332 patients (65.6%) had clear ducts. Imaging was indeterminate in 10 (2%) patients. Overall morbidity was 10.5%. There was no mortality. 142 (86.6%) patients with stones on intra-operative imaging proceeded to LCBDE. 22 (13.4%) patients had ERCP. Sensitivity and specificity of intra-operative imaging were 93.3 and 99.1%, respectively. Success rate of LCBDE was 95.8%. Effectiveness was 97.8%. CONCLUSIONS: Eliminating pre-operative bile duct imaging in favour of intra-operative imaging is safe and effective. When combined with intra-operative stone treatment, this method becomes a true 'single-stage' approach to managing suspected choledocholithiasis.

Identification of a highly lethal V3+ TP53+ subset in ALK+ lung adenocarcinoma.

Tyrosine kinase inhibitors (TKI) have improved prognosis in metastatic anaplastic lymphoma kinase (ALK)-driven lung adenocarcinoma, but patient outcomes vary widely. We retrospectively analyzed the clinical course of all cases with assessable baseline TP53 status and/or ALK fusion variant treated at our institutions (n = 102). TP53 mutations were present in 17/87 (20%) and the echinoderm microtubule-associated protein-like 4 (EML4)-ALK variant 3 (V3) in 41/92 (45%) patients. The number of metastatic sites at diagnosis was affected more by the presence of V3 than by TP53 mutations, and highest with both factors (mean 5.3, p < 0.001). Under treatment with ALK TKI, progression-free survival (PFS) was shorter with either TP53 mutations or V3, while double positive cases appeared to have an even higher risk (hazard ratio [HR] = 2.9, p = 0.015). The negative effect of V3 on PFS of TKI-treated patients was strong already in the first line (HR = 2.5, p = 0.037) and decreased subsequently, whereas a trend for PFS impairment under first-line TKI by TP53 mutations became stronger and statistically significant only when considering all treatment lines together. Overall survival was impaired more by TP53 mutations (HR = 4.9, p = 0.003) than by V3 (HR = 2.4, p = 0.018), while patients with TP53 mutated V3-driven tumors carried the highest risk of death (HR = 9.1, p = 0.02). Thus, TP53 mutations and V3 are independently associated with enhanced metastatic spread, shorter TKI responses and inferior overall survival in ALK+ lung adenocarcinoma. Both markers could assist selection of cases for more aggressive management and guide development of novel therapeutic strategies. In combination, they define a patient subset with very poor outcome.

Optimizing panel-based tumor mutational burden (TMB) measurement.

BACKGROUND: Panel sequencing based estimates of tumor mutational burden (psTMB) are increasingly replacing whole exome sequencing (WES) tumor mutational burden as predictive biomarker of immune checkpoint blockade (ICB). DESIGN: A mathematical law describing psTMB variability was derived using a random mutation model and complemented by the contributions of non-randomly mutated real-world cancer genomes and intratumoral heterogeneity through simulations in publicly available datasets. RESULTS: The coefficient of variation (CV) of psTMB decreased inversely proportional with the square root of the panel size and the square root of the TMB level. In silico simulations of all major commercially available panels in the TCGA pan-cancer cohort confirmed the validity of this mathematical law and demonstrated that the CV was 35% for TMB = 10 muts/Mbp for the largest panels of size 1.1-1.4 Mbp. Accordingly, misclassification rates (gold standard: WES) to separate 'TMBhigh' from 'TMBlow' using a cut-point of 199 mutations were 10%-12% in TCGA-LUAD and 17%-19% in TCGA-LUSC. A novel three-tier psTMB classification scheme which accounts for the likelihood of misclassification is proposed. Simulations in two WES datasets of immunotherapy treated patients revealed that small gene panels were poor predictors of ICB response. Moreover, we noted substantial intratumoral variance of psTMB scores in the TRACERx 100 cohort and identified indel burden as independent marker complementing missense mutation burden. CONCLUSIONS: A universal mathematical law describes accuracy limitations inherent to psTMB, which result in substantial misclassification rates. This scenario can be controlled by two measures: (i) a panel design that is based on the mathematical law described in this article: halving the CV requires a fourfold increase in panel size, (ii) a novel three-tier TMB classification scheme. Moreover, inclusion of indel burden can complement TMB reports. This work has substantial implications for panel design, TMB testing, clinical trials and patient management.

Application of nano-hydroxyapatite/chitosan scaffolds on rat calvarial critical-sized defects: A pilot study.

BACKGROUND: The purpose of this pilot study was to evaluate for the first time the effect of 75/25 w/w nano-Hydroxyapatite/Chitosan (nHAp/CS) scaffolds on Guided Bone Regeneration (GBR) in rat calvarial critical-sized defects (CSDs). MATERIAL AND METHODS: Six adult Sprague Dawley rats, 3 males and 3 females, were used. Two CSDs, full thickness and 5mm in diameter, were trephined in both sides of the parietal bone. The right CSD was filled with nHAp/CS scaffold, while the left CSD remained empty, as the control group. The wound was sutured in layers. Rats were euthanized with diethyl ether inhalation at 2, 4 and 8 weeks after surgical procedure. Histological and histomorphometric analysis was performed within distinct regions of interest (ROI): the lateral area inward of the middle sagittal seam; the lateral area outward of the middle sagittal seam and the central area. RESULTS: The mean surface of newly formed bone (in µm2) in the lateral area inward of the middle sagittal seam of all rats was significantly higher (P=0.039) in the experimental group (91733.00±38855.60) than the control group (46762.17±25507.97). The NOex-c, defined as total number of osteocytes (OST) in newly formed bone surface in experimental group [experimental OST] minus the total number of osteocytes in newly formed bone surface in control group [control OST], was significantly greater (P=0.029) at 4th week post-surgery. Within the experimental group, a statistically significant increase (P=0.042) in the surface of newly formed bone was noticed in rats euthanized in 4th week compared with rats euthanized in 2nd week after surgery in the lateral area inward of the middle sagittal seam. CONCLUSIONS: The results of this study suggest that 75/25 w/w nHAp/CS scaffolds should be considered as a suitable biomaterial for GBR.

Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial.

BACKGROUND: Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC. PATIENTS AND METHODS: In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment. RESULTS: Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%-60%), the disease control rate 74% (CI 59%-85%), the median progression-free survival 4.4 (CI 3.2-6) months and the median overall survival 9.9 (CI 6.9-11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%-88%) according to Kaplan-Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1-2. CONCLUSION: Everolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC. REGISTERED CLINICAL TRIAL NUMBERS: EudraCT number 2010-022273-34, NCT01317615.

Periapical lesions are not always a sequelae of pulpal necrosis: a retrospective study of 1521 biopsies.

AIM: To record the incidence of lesions that were not the sequelae of pulpal necrosis (non-SPN) amongst 1521 biopsies of periapical lesions submitted with a clinical diagnosis of a sequelae of pulpal necrosis (SPN). METHODOLOGY: A retrospective study of 1521 biopsy request forms of specimens submitted for histopathological examination with a clinical diagnosis 'periapical inflammation', 'periapical abscess', 'periapical granuloma' or 'periapical cyst' during an arbitrarily selected 14-year period was undertaken. Gender and age of the patient, site and maximum diameter of the lesion, symptoms, inclusion of the final diagnosis in the differential diagnosis and specialty of the clinician submitting the biopsy material were recorded in each case. The final diagnosis for each case was extracted from the pathology report, and two groups were formed, SPN and non-SPN lesions. Differences between the respective features of SPN and non-SPN cases were analysed with Yate's chi-square test and t-test (significance level P < 0.05) RESULTS: In 52 of the 1521 cases examined (3.42%), the histological diagnosis was not consistent with a SPN. In most non-SPN cases, the histopathological diagnosis was not included in the differential diagnosis. The keratocystic odontogenic tumour [odontogenic keratocyst (OKC)] was the most frequent non-SPN lesion (34.62%). Other, yet less frequent, non-SPN lesions included glandular odontogenic cysts, lateral periodontal cysts, central ossifying fibromas as well as malignancies (metastatic carcinomas and Langerhans cell histiocytosis). CONCLUSIONS: Non-SPN lesions appeared in the periapical region mimicking a SPN, although rarely. Most of them were developmental cysts, in particular OKCs, but odontogenic tumours, such as ameloblastoma, or malignant lesions were also diagnosed. Histological examination of tissue harvested from periapical lesions should be performed, in particular when those lesions are large.

Cadherin-11 mRNA transcripts are frequently found in rheumatoid arthritis peripheral blood and correlate with established polyarthritis.

Rheumatoid arthritis (RA) synovial fibroblasts hyperexpress the mesenchymal cadherin-11, which is involved also in tumor invasion/metastasis, whereas anti-cadherin-11 therapeutics prevent and reduce experimental arthritis. To test the hypothesis that cadherin-11 is aberrantly expressed in RA peripheral blood, 100 patients (15 studied serially) and 70 healthy controls were analyzed by real-time reverse transcription-PCR. Cadherin-11 mRNA transcripts were detected in 69.2% of moderately/severely active RA, versus 31.8% of remaining patients (p=0.001), versus 17.1% of controls (p<0.0001). Notably, cadherin-11 positivity correlated significantly and independently only with established (>1year) polyarthritis (>4 swollen tender joints), by multivariate logistic regression analysis including various possible clinical/laboratory factors. Rare cells of undefined nature, detected by flow cytometry following CD45(-) enrichment, strongly expressed surface cadherin-11 (estimated 10-50cells/ml of blood) in 5/6 patients with polyarticular established disease versus 1/6 patients with early RA. Studies on the potential pathogenic role of circulating cells expressing cadherin-11 in RA are warranted.

Fractionated stereotactic radiotherapy of intracranial postoperative cavities after resection of brain metastases - Clinical outcome and prognostic factors.

Background and Purpose: After surgical resection of brain metastases (BM), radiotherapy (RT) is indicated. Postoperative stereotactic radiosurgery (SRS) reduces the risk of local progression and neurocognitive decline compared to whole brain radiotherapy (WBRT). Aside from the optimal dose and fractionation, little is known about the combination of systemic therapy and postoperative fractionated stereotactic radiotherapy (fSRT), especially regarding tumour control and toxicity. Methods: In this study, 105 patients receiving postoperative fSRT with 35 Gy in 7 fractions performed with Cyberknife were retrospectively reviewed. Overall survival (OS), local control (LC) and total intracranial brain control (TIBC) were analysed via Kaplan-Meier method. Cox proportional hazards models were used to identify prognostic factors. Results: Median follow-up was 20.8 months. One-year TIBC was 61.6% and one-year LC was 98.6%. Median OS was 28.7 (95%-CI: 16.9-40.5) months. In total, local progression (median time not reached) occurred in 2.0% and in 20.4% radiation-induced contrast enhancements (RICE) of the cavity (after median of 14.3 months) were diagnosed. Absence of extracranial metastases was identified as an independent prognostic factor for superior OS (p = <0.001) in multivariate analyses, while a higher Karnofsky performance score (KPS) was predictive for longer OS in univariate analysis (p = 0.041). Leptomeningeal disease (LMD) developed in 13% of patients. Conclusion: FSRT after surgical resection of BM is an effective and safe treatment approach with excellent local control and acceptable toxicity. Further prospective randomized trials are needed to establish standardized therapeutic guidelines.

Circulating levels of TNF-like cytokine 1A correlate with the progression of atheromatous lesions in patients with rheumatoid arthritis.

Interactions between TNF-like Cytokine 1A (TL1A) and its receptors, death receptor-3 (DR3) and decoy receptor-3 (DcR3) may be important in atherogenesis. We hypothesized that dysregulation of this system predicts formation of new atheromatic plaques in rheumatoid arthritis (RA). Forty-five patients were prospectively followed up for 40.5 ± 3.6 months. Serum concentrations of TL1A and DcR3 were measured at baseline and carotid and femoral arteries examined by ultrasound at baseline and at the end of follow-up. Individual serum levels of TL1A correlated with the progression of carotid atheromatic plaque height (Spearman rho = 0.550, p = 0.003). Patients with low TL1A and undetectable DcR3 serum levels at baseline showed significantly fewer newly formed carotid plaques during the next 3.5 years than the remaining patients (P = 0.016). Univariate analysis showed that a "low TL1A/DcR3" immunophenotype predicted a preserved atherosclerosis profile in carotid (P = 0.026), or carotid and/or femoral arteries (P = 0.022). Dysregulated TL1A-induced signaling may be associated with risk for accelerated atherosclerosis in RA.

Validation of the ALK-Brain Prognostic Index for patients with ALK-rearranged lung cancer and brain metastases.

BACKGROUND: Brain metastases (BMs) are a key challenge in the management of anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC), but prognostic scores are complicated or rely on data before the era of tyrosine kinase inhibitors (TKIs). This study aimed to validate the novel ALK-Brain Prognostic Index (ALK-BPI), which was originally proposed based on 44 TKI-treated ALK+ NSCLC patients from Karolinska University Hospital, using an external clinical cohort. PATIENTS AND METHODS: TKI-treated ALK+ NSCLC patients with BM from Heidelberg (n = 82, cohort 1) were retrospectively analyzed alone and together with the original Karolinska cohort (n = 126, cohort 2). Cox regression models were used to determine the association of clinical variables and scores with overall survival (OS) after BM diagnosis (BM-related OS). RESULTS: Both cohorts showed a similar median age (58 years), roughly balanced sex distributions (52%-56% females), and Eastern Cooperative Oncology Group performance status (PS) 0-2 for most patients (87%-92%) at the time of BM development, which were present already at initial diagnosis in 36%-38% of the patients. Most patients had received next-generation ALK inhibitors (54%-63%), while 55%-56% of patients did not receive any radiotherapy. The ALK-BPI identified poor-risk patients (i.e. featuring ≥ 2/3 risk factors: PS > 2, male sex, development of BM after initial diagnosis) with a significantly shorter BM-related OS than other patients in both cohorts: 32/82 in cohort 1 with 21.3 versus 62.2 months in median [hazard ratio (HR) = 2.5, P < 0.001]; 59/126 in cohort 2 with 23.1 versus 67.2 months in median (HR = 2.6, P < 0.001). The five-parameter Lung-molGPA score did not achieve statistical significance and/or clear prognostic separation in all four groups, while the Disease-Specific Graded Prognostic Assessment score did not show consistent results. CONCLUSIONS: The ALK-BPI is a reliable tool for easy prognostic dichotomization of TKI-treated ALK+ NSCLC patients with BM in daily clinical practice, without the complexity of previous models.

Sexual delusion in a case of vaginal aplasia after surgical operation for neovagina.

The Mayer-Rokitansky-Kuster-Hauser (MRKH) is a syndrome of unknown etiology characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in women showing normal development of secondary sexual characteristics. We report the case of a patient with vaginal aplasia and schizophrenia presenting with sexual delusion. To the authors' knowledge this is the first case to provide evidence of coexistence between MRKH and sexual delusion in a schizophrenic patient. The core of the patient's delirium was that she was having sexual intercourse with an eminent person through the big toe of her right foot. We approached this case using a neurological and a psychodynamic hypothesis. The neurological hypothesis suggests that the "deactivation" of the patient's genitalia led to an expansion of the adjacent big toe cortical area. The psychodynamic hypothesis supports that the sexual function and pleasure was partially expelled from the body image and was stored in a non sexual part of the body (i.e., big toe). Clinicians should be aware of this association and offer patients with MRKH psychological or/and psychiatric evaluation.

Obstetric hysterectomy: a review of cases over 16 years.

Emergency peripartum hysterectomy (EPH), is performed when life-threatening obstetric conditions occur. The authors attempt to assess the incidence of EPH as well as to investigate risk factors and patients' characteristics. A retrospective study of all cases of EPH performed at the 2nd Department of Obstetrics and Gynecology, Medical School of Athens University, from 1994 to 2009 has been conducted. Data were abstracted from individual medical charts and laboratory records. Among 16,182 deliveries, 15 EPH were performed (0.92 per 1,000 deliveries). Indication was uncontrollable haemorrhage due to placenta accreta (73.3%) or uterine atony (26.6%). Incidence of 1.54 EPHs per 1,000 caesarean sections and 0.51 per 1,000 vaginal deliveries, were noted. Morbidity rate was 46.6%. One (6.6%) mother died because of pulmonary embolism. In conclusion, peripartum hysterectomy is a severe but life-saving procedure. Caesarean section increases the risk of EPH. Obstetricians should always be prepared to confront this emergency situation.

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer.

BACKGROUND: The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This study included all epidermal growth factor receptor-mutated (EGFR+, n = 108) and anaplastic lymphoma kinase-rearranged (ALK+, n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed (n = 34; 24%) or no LT (n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases. RESULTS: Median overall survival (OS) was 49.1 months for ALK+ and 19.5 months for EGFR+ patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and 'short' EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR+ and ALK+ subsets. CONCLUSIONS: Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR+/ALK+ NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR/ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management.

The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma.

BACKGROUND: Targeted therapies have improved survival and quality of life for patients with non-small-cell lung cancer with actionable driver mutations. However, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 gene (HER2, also known as ERBB2) exon 20 insertions (Ex20mut) are characterized by a poor response to currently approved tyrosine kinase inhibitors and immunotherapies. The underlying immune biology is not well understood. MATERIALS AND METHODS: We carried out messenger RNA expression profiling of lung adenocarcinomas (ADCs) with ERBB2 (n = 19) and EGFR exon 20-insertion mutations (n = 13) and compared these to tumors with classical EGFR mutations (n = 40, affecting EGFR exons 18, 19 or 21) and EGFR/ERBB2 mutation-negative lung ADC (EGFR/ERBB2wt, n = 26) focusing on immunologically relevant transcripts. Tumor-infiltrating immune cells were estimated from gene expression profiles. RESULTS: Cytotoxic cells were significantly lower in EGFR-mutated tumors regardless of the affected exon, while Th1 cells were significantly lower in EGFR-Ex20mut compared to EGFR/ERBB2wt tumors. We assessed the differentially expressed genes of ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. Of these, the genes GUSB, HDAC11, IFNGR2, PUM1, RASGRF1 and RBL2 were up-regulated, while a lower expression of CBLC, GBP1, GBP2, GBP4 and MYC was observed in all three comparison groups. The omnibus test revealed 185 significantly (FDR = 5%) differentially expressed genes and we found these four most significant gene expression changes in the study cohort: VHL and JAK1 were overexpressed in ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to both EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. RIPK1 and STK11IP showed the highest expression in ERBB2-Ex20mut tumors. CONCLUSIONS: Targeted gene expression profiling is a promising tool to read out the characteristics of the tumor microenvironment from routine diagnostic lung cancer biopsies. Significant immune reactivity and specific immunosuppressive characteristics in ERBB2-Ex20mut and EGFR-Ex20mut lung ADC with at least some degree of immune infiltration support further clinical evaluation of immune-modulators as partners of immune checkpoint inhibitors in such tumors.

Association of the advanced lung cancer inflammation index (ALI) with immune checkpoint inhibitor efficacy in patients with advanced non-small-cell lung cancer.

BACKGROUND: The advanced lung cancer inflammation index [ALI: body mass index × serum albumin/neutrophil-to-lymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: This retrospective study included 672 stage IV NSCLC patients treated with programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index. RESULTS: High ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) = 0.402, P < 0.0001, n = 460], but not chemo-immunotherapy (HR = 0.624, P = 0.111, n = 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P = 0.008) and time-on-treatment (HR = 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR = 0.694, P = 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor proportion score ≥50% receiving first-line ICI monotherapy, a high ALI score >18 identified a subset with longer OS and time-on-treatment (median 35 and 16 months, respectively), similar to these under chemo-immunotherapy. CONCLUSIONS: The ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-L1 inhibitors alone, but not in combination with chemotherapy. Its association with outcomes appears to be stronger than that of other widely used parameters. For PD-L1-high patients, an ALI score >18 could assist the selection of cases that do not need addition of chemotherapy.

Risk stratification of EGFR+ lung cancer diagnosed with panel-based next-generation sequencing.

OBJECTIVE: Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters. MATERIALS AND METHODS: To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFR+ NSCLC patients with validation of results in an independent cohort (n = 130). RESULTS: EGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1-2.3) and overall survival (OS HR 1.7-2.2), in combination defining patient subgroups with distinct outcome (EGFR+NSCLC risk Score, "ENS", p < 0.001). Co-mutations beyond TP53 were rarely detected by our multigene panel (<5%) and not associated with clinical endpoints. Smoking did not affect outcome independently, but was associated with non-del19 EGFR mutations (p < 0.05) and comorbidities (p < 0.001). Laboratory parameters, like the blood lymphocyte-to-neutrophil ratio and serum LDH, correlated with the metastatic pattern (p < 0.01), but had no independent prognostic value. Reduced ECOG performance status (PS) was associated with comorbidities (p < 0.05) and shorter OS (p < 0.05), but preserved TKI efficacy. Non-adenocarcinoma histology was also associated with shorter OS (p < 0.05), but rare (2-3 %). The ECOG PS and non-adenocarcinoma histology could not be validated in our independent cohort, and did not increase the range of prognostication alongside the ENS. CONCLUSIONS: EGFR variant, TP53 status and brain metastases predict TKI efficacy and survival in EGFR+ NSCLC irrespective of other currently available parameters ("ENS"). Together, they constitute a practical and reproducible approach for risk stratification of newly diagnosed metastatic EGFR+ NSCLC.

T-cell large granular lymphocyte leukemia presenting as end-stage renal disease: the diagnostic role of flow-cytometric and clonality analysis of the urine sediment.

A 65-year-old white female patient with normal baseline renal function was referred to our hospital with nonoliguric renal failure requiring hemodialysis after progressive deterioration over the previous 6 months. Her past medical history was remarkable for easy fatigability, weight loss, low-grade fever, hypogammaglobulinemia and mild hepatosplenomegaly manifested over the past 6 years. Several liver and bone marrow biopsies during that period had shown a nonspecific polyclonal T-cell infiltration, and she was administered low-dose steroids for symptomatic relief. Physical examination, laboratory workup and imaging studies at presentation showed pancytopenia, hepatosplenomegaly, large symmetric kidneys with normal cortices and no evidence of obstructive uropathy, aseptic pyuria with neutrophils and lymphocytes and mild proteinuria. On biopsy the renal interstitium was infiltrated by large, granular CD3+CD8+CD56-CD57+ lymphocytes, clonal by molecular analysis, which established the diagnosis of T-cell large granular lymphocyte leukemia. Most urinary and peripheral blood lymphocytes bore the same T-LGL surface markers and were also clonal, as shown by flow-cytometry and PCR amplification of the T-cell receptor g-chain genes. A subsequent bone marrow biopsy revealed infiltration by lymphoma cells and excluded a myelodysplastic or hemophagocytic syndrome. After exclusion of an underlying EBV, CMV, HBV, HCV or HIV infection with negative serology and blood PCR the patient received one cycle of chemotherapy with cyclophosphamide, vincristine and prednisone. No improvement of renal function was achieved, while complication with a prolonged pulmonary infection and severe sepsis precluded further treatment. Our report indicates that the T-LGL leukemia should be considered in the differential diagnosis of renal failure with large-sized kidneys, especially when hepatosplenomegaly, pancytopenia and aseptic pyuria are also present. In the latter case, flow-cytometric and clonality analysis of the urine sediment can aid in establishing a diagnosis. Since renal function may deteriorate rapidly, chemotherapy should not be delayed.

Noncanalized horns of uterus didelphys with prolapse: a unique case in a young woman.

The authors report the unique case of a 20-year-old patient with prolapsed uterus didelphys with noncanalized horns, who complained of primary amenorrhea. Clinical examination revealed a rudimentary noncanalized cervix with a third degree prolapse and no palpable uterus. A small prolapsing remnant of a uterus didelphys with 2 noncanalized uterine horns was excised by laparotomy. Ultrastructural examination of subepithelial cervical connective tissue revealed collagen of normal structure, but of low concentration. The etiologies of both the Mullerian ducts anomalies and the genital prolapse are probably multifactorial. Low collagen concentration indicates a constitutional tissue weakness contributing to the development of genital prolapse.

Human papilloma virus molecular profile and mechanisms of cancerogenesis: a review.

Human papilloma virus (HPV) is frequently present in the genital tract. It causes various lesions at the mucosa of both sexes. It is considered as a causative factor of cervical cancer even if all women infected by HPV will not develop the disease. This article reviews aspects of HPV molecular biology and the mechanisms of cancerogenesis in HPV infected females.

Psychological and behavioural aspects of patients with Turner syndrome from childhood to adulthood: a review of the clinical literature.

Turner syndrome (TS) is a chromosomal abnormality, which occurs in approximately one of every 2500 female births. Short stature, infertility, additional physical abnormalities, skeletal and medical problems may be present. Genetic, hormonal, and medical problems associated with TS are likely to affect psychosexual development of female adolescent patients, and thus influence their psychological functioning, behavior patterns, social interactions and learning ability. Although TS constitutes a chronic medical condition, with possible physical, social and psychological complications in a woman's life, hormonal and estrogen replacement therapy and assisted reproduction, are treatments that can be helpful for TS patients and improve their quality of life. Authors report on a review of the research literature clinical aspects of the syndrome as well as the beneficial effect of hormonal therapy in such patients.