Bevacizumab Treatment for Metastatic Colorectal Cancer in Real-World Clinical Practice.

Background and Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality and morbidity worldwide. Bevacizumab was approved for the treatment of metastatic colorectal cancer (mCRC) based on favorable benefit-risk assessments from randomized controlled trials, but evidence on its use in the real-world setting is limited. The aim of the current study is to evaluate the outcomes and safety profile of bevacizumab in mCRC in a real-world setting in Romania. Patients and Methods: This was an observational, retrospective, multicentric, cohort study conducted in Romania that included patients with mCRC treated with bevacizumab as part of routine clinical practice. Study endpoints were progression-free survival, overall survival, adverse events, and patterns of bevacizumab use. Results: A total of 554 patients were included in the study between January 2008 and December 2018. A total of 392 patients (71%) received bevacizumab in the first line and 162 patients (29%) in the second line. Bevacizumab was mostly combined with a capecitabine/oxaliplatin chemotherapy regimen (31.6%). The median PFS for patients treated with bevacizumab was 8.4 months (interquartile range [IQR], 4.7-15.1 months) in the first line and 6.6 months (IQR, 3.8-12.3 months) in the second line. The median OS was 17.7 months (IQR, 9.3-30.6 months) in the first line and 13.5 months (IQR, 6.7-25.2 months) in the second line. Primary tumor resection was associated with a longer PFS and OS. The safety profile of bevacizumab combined with chemotherapy was similar to other observational studies in mCRC. Conclusions: The safety profile of bevacizumab was generally as expected. Although the PFS was generally similar to that reported in other studies, the OS was shorter, probably due to the less frequent use of bevacizumab after disease progression and the baseline patient characteristics. Patients with mCRC treated with bevacizumab who underwent resection of the primary tumor had a higher OS compared to patients with an unresected primary tumor.

Diagnosis of lung cancer by flexible fiberoptic bronchoscopy: a descriptive study.

Flexible fiberoptic bronchoscopy (FFB) remains the most important minimally invasive method for the diagnosis of lung cancer (LC). We performed a retrospective study to assess the main endoscopic findings of malignant lung tumors in the large airways in a cohort of Romanian patients. The group consisted of 32 (84.21%) men and six (15.78%) women, with an average age of 64.63±6.07 years. The bronchoscopic examination allowed the detection and biopsy of 36 malignant lung tumors, and in two other cases, due to malignant atelectasis, the patients were sent to a Department of Thoracic Surgery, to perform the biopsy following the surgery. Histopathological (HP) examination revealed the presence of squamous cell carcinoma (SCC) in 19 (50%) patients, adenocarcinoma (ADC) in 11 (28.94%) patients and small cell lung cancer (SCLC) in eight (21.05%) patients. The macroscopic and microscopic analysis of the lung tumors showed that infiltrative forms were found in most cases (58.33%), followed by exophytic (mass) endobronchial lesions (22.22%) and mixed forms (19.44%). If most infiltrative forms were SCC (66.66%), the exophytic and mixed lesions were most frequently ADC (50% and 57.14%). The tumor lesions caused both malignant bronchial stenosis (57.89%) and malignant atelectasis (42.1%). The main mechanisms involved in bronchial malignant obstruction were endoluminal (50%), mixed (31.57%) and extraluminal (18.42%) mechanisms. In conclusion, FFB remains the main method of diagnosing LC in the large airways. The most common macroscopic appearance of lung tumors revealed by bronchoscopy was the infiltrative appearance. In half of our patients, the malignant bronchial obstruction was achieved by endoluminal mechanism. The most common pathological form found in our patients was the SCC, as described in half of the investigated patients.

Circulating Angiogenic Markers in Gastroenteropancreatic Neuroendocrine Neoplasms: A Systematic Review.

BACKGROUND: Neuroendocrine neoplasms are a heterogeneous group of tumors that raise challenges in terms of diagnosis, treatment and monitoring. Despite continuous efforts, no biomarker has showed satisfying accuracy in predicting outcome or response to treatment. METHODS: We conducted a systematic review to determine relevant circulating biomarkers for angiogenesis in neuroendocrine tumors. We searched three databases (Pubmed, Embase, Web of Science) using the keywords "neuroendocrine" and "biomarkers", plus specific biomarkers were searched by full and abbreviated name. From a total of 2448 publications, 11 articles met the eligibility criteria. RESULTS: VEGF is the most potent and the most studied angiogenic molecule, but results were highly controversial. Placental growth factor, Angiopoietin 2 and IL-8 were the most consistent markers in predicting poor outcome and aggressive disease behavior. CONCLUSIONS: There is no robust evidence so far to sustain the use of angiogenic biomarkers in routine practice, although the results show promising leads.

Technical Performance, Overall Accuracy and Complications of EUS-Guided Interventional Procedures: A Dynamic Landscape.

Endoscopic ultrasound (EUS) gained wide acceptance as the diagnostic and minimally invasive therapeutic approach for intra-luminal and extraluminal gastrointestinal, as well as various non-gastrointestinal lesions. Since its introduction, EUS has undergone substantial technological advances. This multi-centric study is a retrospective analysis of a prospectively maintained database of patients who underwent EUS for the evaluation of lesions located within the gastrointestinal tract and the proximal organs. It aimed to extensively assess in dynamic the dual-center EUS experience over the course of the past 20 years. Hence, we performed a population study and an overall assessment of the EUS procedures. The performance of EUS-FNA/FNB in diagnosing pancreatic neoplasms was evaluated. We also investigated the contribution of associating contrast-enhanced ultrasound imaging (CE-EUS) with EUS-FNA/FNB for differentiating solid pancreatic lesions or cystic pancreatic lesions. A total of 2935 patients undergoing EUS between 2002-2021 were included, out of which 1880 were diagnostic EUS and 1052 EUS-FNA/FNB (80% FNA and 20% FNB). Therapeutic procedures performed included endoscopic transmural drainage of pancreatic fluid collections, celiac plexus block and neurolysis, while diagnostic EUS-like CE-EUS (20%) and real-time elastography (12%) were also conducted. Most complications occurred during the first 7 days after EUS-FNA/FNB or pseudocyst drainage. EUS and the additional tools have high technical success rates and low rates of complications. The EUS methods are safe, cost effective and indispensable for the diagnostic or therapeutic management in gastroenterological everyday practice.

How Much Burnout and Coping Influence Quality of Life among Young Oncology Providers in Romania during the COVID-19 Pandemic.

This study aims to investigate the correlations between burnout, coping strategies, and quality of life among young oncology healthcare workers in Romania during the COVID-19 pandemic. We collected the data using an online questionnaire consisting of sociodemographic questions, the Maslach Burnout Inventory, the COPE questionnaire, and the 15D instrument. A total of 122 healthcare providers responded to our survey. We evaluated the differences in the scores among the three groups of healthcare workers in oncology under 40 years old: medical oncologists (n = 87), radiation oncologists (n = 11), and oncology nurses (n = 24). Finally, we conducted a correlation analysis between the dimensions of burnout, coping, and quality of life. Overall, the medical oncologists exhibited much higher burnout levels than nurses in the COVID-19 pandemic outbreak, having statistically significant higher levels of emotional exhaustion, depersonalization, and lack of personal achievement. Some factors were inversely associated with burnout: active approach, planning, positive interpretation and growth, and acceptance. Our findings illustrated a very good level of health-related quality of life (average = 0.93, SD = 0.06), and no statistically significant differences were found in the quality of life between the three groups. This study was the first to identify the profile of young oncology providers in Romania. Our findings may be relevant in creating preventive strategies for burnout and increasing the quality of life in Romanian young oncology providers in future crises.

Evaluation of MMR Status and PD-L1 Expression Using Specimens Obtained by EUS-FNB in Patients with Pancreatic Ductal Adenocarcinoma (PDAC).

Deficient DNA mismatch repair status (dMMR)/high microsatellite instability have been shown to be predictive biomarkers for immune checkpoint inhibitor drugs which block the programmed death protein-1/programmed death ligand-1 (PD-1/PD-L1) interaction between tumor cells and activated T cells. The aim of this study was to determine the prevalence of MMR status and quantification of PD-L1 expression in pancreatic endoscopic ultrasound-guided fine-needle biopsy (EUS FNB) specimens. Immunochemistry (IHC) was performed on consecutive archived treatment-naïve formalin-fixed paraffin-embedded EUS-FNB samples. The specimens were considered to have PD-L1 expression if PD-L1 was expressed in ≥1% of tumor cells and a high level of expression if ≥50%. Tumors with absent nuclear staining of DNA mismatch repair proteins (MLH1, MSH2, MSH6, or PMS2) were classified as dMMR. A total of 28 treatment-naïve patients who underwent EUS-FNB and had a final diagnosis of pancreatic ductal adenocarcinoma (PDAC) were included in the study. All the EUS-FNB samples were adequate for the evaluation of MMR and PD-L1 expression. None of the patients with PDAC included in the study had a dMMR tumor. PD-L1 expression was identified in 39% of the cohort (n = 11). Expression thresholds of ≥1%, ≥10%, and ≥50% in tumor cells were identified in 11 (39%), 4 (14%), and 1 (4%) patients, respectively. The evaluation of MMR status and PD-L1 can be successfully performed on EUS-FNB pancreatic specimens. Furthermore, MMR expression failed to show utility in recognizing immunotherapy vulnerability in pancreatic cancer; the only recommendation for testing remains for patients with heritable cancers. Meanwhile high PD-L1 expression was correlated with poor prognosis. This association may identify a subgroup of patients where immune checkpoints inhibitors could provide therapeutic benefits, spotlighting the role of EUS-FNB in the field of immune-oncology.

An Insight into Deficient Mismatch Repair Colorectal Cancer Screening in a Romanian Population-A Bi-Institutional Pilot Study.

Background and Objectives: Colorectal cancer (CRC) can be classified as mismatch-repair-deficient (dMMR) with high levels of microsatellite instability (MSI-H), or mismatch-repair-proficient (pMMR) and microsatellite stable (MSS). Approximately 15% of patients have microsatellite instability (MSI). MSI-H tumors are associated with a high mutation burden. Monoclonal antibodies that block immune checkpoints can induce long-term durable responses in some patients. Pembrolizumab is the first checkpoint inhibitor approved in the EU to treat dMMR-MSI-H metastatic CRC. Materials and Methods: Our study assesses the regional variability of MSI-H colorectal cancer tumors in Romania. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks containing tumor samples from 90 patients diagnosed with colorectal cancer were collected from two tertiary referral Oncology Centers from Romania. Tissues were examined for the expression loss of MMR proteins (MLH1, PMS2, MSH2, MSH6) using immunohistochemistry or MSI status using polymerase chain reaction (PCR), respectively. Results: MSI-H was detected in 19 (21.1%) patients. MSI-H was located more in ascending colon (36.8% vs. 9.9%, p-value = 0.0039) and less in sigmoid (5.3% vs. 33.8%, p-value = 0.0136) than MSS patients. Most patients were stage II for MSI-H (42.1%) as well as for MSS (56.3%), with significant more G1 (40.9% vs. 15.8%, p-value = 0.0427) for MSS patients. Gender, N stage, and M stage were identified as significant prognostic factors in multivariate analysis. MSI status was not a statistically significant predictor neither in univariate analysis nor multivariate analysis. Conclusion: Considering the efficacy of PD-1 inhibitor in metastatic CRC with MSI-H or dMMR, and its recent approval in EU, it is increasingly important to understand the prevalence across tumor stage, histology, and demographics, since our study displayed higher regional MSI-H prevalence (21%) compared to the literature.

Real-time computer-aided diagnosis of focal pancreatic masses from endoscopic ultrasound imaging based on a hybrid convolutional and long short-term memory neural network model.

Differential diagnosis of focal pancreatic masses is based on endoscopic ultrasound (EUS) guided fine needle aspiration biopsy (EUS-FNA/FNB). Several imaging techniques (i.e. gray-scale, color Doppler, contrast-enhancement and elastography) are used for differential diagnosis. However, diagnosis remains highly operator dependent. To address this problem, machine learning algorithms (MLA) can generate an automatic computer-aided diagnosis (CAD) by analyzing a large number of clinical images in real-time. We aimed to develop a MLA to characterize focal pancreatic masses during the EUS procedure. The study included 65 patients with focal pancreatic masses, with 20 EUS images selected from each patient (grayscale, color Doppler, arterial and venous phase contrast-enhancement and elastography). Images were classified based on cytopathology exam as: chronic pseudotumoral pancreatitis (CPP), neuroendocrine tumor (PNET) and ductal adenocarcinoma (PDAC). The MLA is based on a deep learning method which combines convolutional (CNN) and long short-term memory (LSTM) neural networks. 2688 images were used for training and 672 images for testing the deep learning models. The CNN was developed to identify the discriminative features of images, while a LSTM neural network was used to extract the dependencies between images. The model predicted the clinical diagnosis with an area under curve index of 0.98 and an overall accuracy of 98.26%. The negative (NPV) and positive (PPV) predictive values and the corresponding 95% confidential intervals (CI) are 96.7%, [94.5, 98.9] and 98.1%, [96.81, 99.4] for PDAC, 96.5%, [94.1, 98.8], and 99.7%, [99.3, 100] for CPP, and 98.9%, [97.5, 100] and 98.3%, [97.1, 99.4] for PNET. Following further validation on a independent test cohort, this method could become an efficient CAD tool to differentiate focal pancreatic masses in real-time.

Endoscopic Ultrasound vs. Computed Tomography for Gastric Cancer Staging: A Network Meta-Analysis.

Gastric cancer preoperative staging is of outmost importance to assure proper management of the disease. Providing a relevant clinical stage relies on different imaging methods such as computed tomography (CT) or endoscopic ultrasound (EUS). We aimed to perform a network meta-analysis for gastric cancer clinical stage diagnostic tests, thus comparing the diagnostic accuracy of EUS vs. multidetector CT (MDCT) and EUS vs. EUS + MDCT. We plotted study estimates of pooled sensitivity and specificity on forest plots and summary receiver operating characteristic space to explore between-study variation in the performance of EUS, MDCT and EUS + MDCT for T1-T4, N0-N3, M0-M1 when data were available. Exploratory analyses were undertaken in RevMan 5. We included twelve studies with 2047 patients. Our results suggest that EUS was superior to MDCT in preoperative T1 and N staging. MDCT is more specific for the M stage but no significant difference in sensitivity was obtained. When comparing EUS vs. EUS + MDCT for T1 both sensitivity and specificity were not relevant. No significant differences were observed in T2-T4 stages. Even though EUS helped differentiate between the presence of invaded nodules, N stages should be carefully assessed by both methods since there is not sufficient data.

Prognostic biomarkers related to tumoral microenvironment in pancreatic ductal adenocarcinoma: a systematic review.

Over the past decades, pancreatic ductal adenocarcinoma (PDAC) has been coming into view due to increased mortality, the 5-year survival rate being the lowest of all cancers (around 6%). In PDAC, microenvironmental components possess prognostic relevance. The aim of this article is to perform a review of studies evaluating the composition of the tumor microenvironment to identify tumor microenvironment-related prognostic biomarkers in patients with PDAC. A literature search has been performed in three major databases PubMed®, Embase®, Web of Science® using the search terms: pancreatic adenocarcinoma in combination with one of the following: alpha-smooth muscle actin (α-SMA), collagen I, cluster of differentiation (CD)31, CD105, CD3-CD4-CD8, CD68 and CD206. Total number of articles identified through database searching was 1185. After title and abstract review, we have selected 92 articles in which the markers sought were studied. Tumor microenvironment-related biomarkers appear to also possess role in monitoring the response to treatment. Thus, CD105 angiogenetic immunomarker, stromal immunomarkers such as α-SMA and collagen I, immune cells markers represented by CD4∕CD8 ratio, CD206 and CD68 were correlated with negative prognosis, while CD3+, CD8+ immune cells markers and CD31 angiogenetic immunomarker proved to be correlated with good prognosis. Furthermore, most studies were performed on resected specimens and culture cells, while only a few studies used specimens obtained through endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). To increase the therapeutic response and reduce toxicity, prognostic targets should be determined on a large scale, not only based on resected specimens. EUS-FNB represents a feasible method to provide sufficient tissue for diagnosis and additional immunohistochemistry analysis.

The role of IgE specific for galactose-α-1,3-galactose in predicting cetuximab induced hypersensitivity reaction: a systematic review and a diagnostic meta-analysis.

Recombinant monoclonal antibodies are used for treating various diseases, from asthma, rheumatoid arthritis, and inflammatory bowel disease to cancer. Although monoclonal antibodies are known to have fewer toxic reactions compared with the conventional cytotoxic antineoplastic drugs, the cases of severe systemic hypersensitivity reaction (HSR) should be acknowledged. Our aim was to assess the diagnostic accuracy of the anti-IgE for galactose-α-1,3-galactose in patients with HSRs to cetuximab. We searched in PubMed, Cochrane Library, Scopus, and World of Science databases to July 1st, 2020. We included a total of 6 studies, with 1074 patients. Meta-analysis was performed using bivariate analysis and the random-effect model. The pooled sensitivity was 73% (95% CI 62-81%) and the pooled specificity was 88% (95% CI 79-94%). We had not found significant heterogeneity and, despite some discrepancies in the nature of data available in the analysed studies, we draw the conclusion that the presence of cetuximab specific IgE (anti cetuximab antibody) and/or galactose-α-1,3-galactose shows moderate to high sensitivity and specificity of developing an HSR. More studies are needed to establish a protocol necessary for the proper prediction and avoidance of HSR related to cetuximab.

Psychological impact of pancreatic cancer screening by EUS or magnetic resonance imaging in high-risk individuals: A systematic review.

BACKGROUND AND OBJECTIVES: There is an increasing global interest in screening programs aiming to detect pancreatic cancer (PC) in an early and potentially curable stage. Concerns still remain as to whether screening would confer any survival benefit. Another approach to evaluate the benefits of the pancreatic screening programs would be to consider its impact on the quality of life of the individuals who at risk of developing cancer. The aim of this systematic review was to investigate the current knowledge regarding the psychological impact of participation in routine screening for PC. METHODS: A systematic literature search was carried out in January 2018 in three major databases which are as follows: PubMed, Scopus, and Web of Science. Cross-sectional and prospective studies evaluating the psychological aspects of screening in high-risk individuals were included in the study. For each study, the following data were recorded: name of first author, year of publication, study design, study population, aims, screening protocol, outcomes and instruments, main results, and summary of findings. RESULTS: Six cohort studies and one cross-sectional study that addressed the psychological aspects of PC screening were included in the analysis. Overall, studies have shown that high-risk individuals have positive psychological outcomes from participating in PC screening programs. CONCLUSIONS: Although screening might not always be reassuring, it may improve individuals' quality of life, and this should be an important aspect when considering PC screening.

Lactose intolerance but not lactose maldigestion is more frequent in patients with irritable bowel syndrome than in healthy controls: A meta-analysis.

BACKGROUND AND PURPOSE: Irritable bowel syndrome (IBS) affects 10%-20% of the adult population and is characterized by abdominal symptoms without relevant organic disease. There are numerous clinical trials available investigating the relationship between IBS, lactose maldigestion (LM), and lactose intolerance (LI), but there have been no meta-analyses on this topic yet. We aimed to assess the prevalence of LM, objective and subjective (self-reported) LI in IBS patients compared to healthy controls (HC) without IBS. METHODS: A systematic literature search was conducted up to 24 April 2018 in PubMed, Embase, and Cochrane Library. Adult IBS patients had to be diagnosed according to the Rome criteria or other well-defined criteria system. We enrolled controlled studies including healthy adult participants without IBS, as control group. Odds ratios with 95% confidence intervals were calculated. KEY RESULTS: Altogether 14 articles were suitable for statistical analyses. IBS patients reported themselves significantly more frequently lactose intolerant than HCs (odds ratio [OR] = 3.499; 95% confidence interval [CI] = 1.622-7.551). Generally, there was no significant difference in the prevalence of LM based on ingested lactose dose (OR = 1.122; 95% CI = 0.929-1.356) and test type (OR = 1.156; 95% CI = 0.985-1.356). However, significantly more IBS patients had objective LI (OR = 2.521; 95% CI = 1.280-4.965). CONCLUSIONS AND INFERENCES: Lactose intolerance, but not LM is more frequent among patients with IBS compared to HCs. According to our results, IBS among other functional bowel disorders is a possible contributing factor of LI in people with LM.

The Effect of Psychoeducation on Anxiety in Women Undergoing Their Initial Breast Cancer Screening Mammography.

We conducted a prospective, randomized, single-blinded study to determine whether a psychoeducational intervention for patients undergoing screening mammography could influence the level of anxiety related to the procedure. Fifty women undergoing mammography for the first time were included in the study and randomized to two groups. In the study group, patients received a psychoeducational session before mammography. In the control group, psychoeducation was not applied. To evaluate the level of anxiety, we used the State-Trait Anxiety Inventory. State Anxiety Scale (S-Anxiety) score and Trait Anxiety Scale (T-Anxiety) scores were assessed before and after mammography in both groups. After evaluating the S-Anxiety score in the study group before mammography and after the procedure, a statistically significant difference (p = 0.043) was observed. In contrast, no statistically significant changes were noticed in the control group (p = 0.886). Our study showed that psychoeducation reduced state anxiety among the participants of a breast cancer screening.

The effect of serum triglyceride concentration on the outcome of acute pancreatitis: systematic review and meta-analysis.

Elevated serum triglyceride concentration (seTG, >1.7 mM or >150 mg/dL) or in other words hypertriglyceridemia (HTG) is common in the populations of developed countries. This condition is accompanied by an increased risk for various diseases, such as acute pancreatitis (AP). It has been proposed that HTG could also worsen the course of AP. Therefore, in this meta-analysis, we aimed to compare the effects of various seTGs on the severity, mortality, local and systemic complications of AP, and on intensive care unit admission. 16 eligible studies, including 11,965 patients were retrieved from PubMed and Embase. The results showed that HTG significantly elevated the odds ratio (OR = 1.72) for severe AP when compared to patients with normal seTG (<1.7 mM). Furthermore, a significantly higher occurrence of pancreatic necrosis, persistent organ failure and renal failure was observed in groups with HTG. The rates of complications and mortality for AP were significantly increased in patients with seTG >5.6 mM or >11.3 mM versus <5.6 mM or <11.3 mM, respectively. We conclude that the presence of HTG worsens the course and outcome of AP, but we found no significant difference in AP severity based on the extent of HTG.

Pancreatitis-Associated Genes and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this study was to evaluate the connection between pancreatic cancer (PC) and genetic variants associated with chronic pancreatitis via systematic review and meta-analysis. METHODS: The data search was performed in 3 major databases (PubMed, Embase, and Cochrane Library). The selected studies have looked into the presence of the pancreatitis-associated genes in patients with PC and in control subjects, the outcome being the frequency of the mutations in the 2 groups. For the binary outcomes, pooled odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS: Ten articles proved to be eligible for the qualitative synthesis, and 8 articles were suitable for statistical analysis. Six case-control studies, comprising 929 PC cases and 1890 control subjects for serine protease inhibitor Kazal type 1 (SPINK1) mutations, and 5 case-control studies, comprising 1674 PC cases and 19,036 control subjects for CFTR mutations, were enrolled in our analysis. SPINK1 mutations showed no association with PC (OR, 1.52; 95% CI, 0.67-3.45; P = 0.315), whereas mutations in CFTR modestly increased the risk of PC (OR, 1.41; 95% CI, 1.07-1.84; P = 0.013). CONCLUSION: Our meta-analysis showed that mutations in CFTR modestly increase the risk of PC, whereas no association was found between SPINK1 and PC.

A quarter century of EUS-FNA: Progress, milestones, and future directions.

Tissue acquisition using EUS has considerably evolved since the first EUS-FNA was reported 25 years ago. Its introduction was an important breakthrough in the endoscopic field. EUS-FNA has now become a part of the diagnostic and staging algorithm for the evaluation of benign and malignant diseases of the gastrointestinal tract and of the organs in its proximity, including lung diseases. This review aims to present the history of EUS-FNA development and to provide a perspective on the recent developments in procedural techniques and needle technologies that have significantly extended the role of EUS and its clinical applications. There is a bright future ahead for EUS-FNA in the years to come as extensive research is conducted in this field and various technologies are continuously implemented into clinical practice.