Deepak Vangala

Blood‐based detection of RAS mutations to guide anti‐EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue‐based RAS testing

An accurate blood‐based RAS mutation assay to determine eligibility of metastatic colorectal cancer (mCRC) patients for anti‐EGFR therapy would benefit clinical practice by better informing decisions to administer treatment independent of tissue availability. The objective of this study was to determine the level of concordance between plasma and tissue RAS mutation status in patients with mCRC to gauge whether blood‐based RAS mutation testing is a viable alternative to standard‐of‐care RAS tumor testing. RAS testing was performed on plasma samples from newly diagnosed metastatic patients, or from recurrent mCRC patients using the highly sensitive digital PCR technology, BEAMing (beads, emulsions, amplification, and magnetics), and compared with DNA sequencing data of respective FFPE (formalin‐fixed paraffin‐embedded) tumor samples. Discordant tissue RAS results were re‐examined by BEAMing, if possible. The prevalence of RAS mutations detected in plasma (51%) vs. tumor (53%) was similar, in accord with the known prevalence of RAS mutations observed in mCRC patient populations. The positive agreement between plasma and tumor RAS results was 90.4% (47/52), the negative agreement was 93.5% (43/46), and the overall agreement (concordance) was 91.8% (90/98). The high concordance of plasma and tissue results demonstrates that blood‐based RAS mutation testing is a viable alternative to tissue‐based RAS testing.

Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes: CNV analysis and targeted NGS in suspected Lynch syndrome patients

In many families with suspected Lynch syndrome (LS), no germline mutation in the causative mismatch repair (MMR) genes is detected during routine diagnostics. To identify novel causative genes for LS, the present study investigated 77 unrelated, mutation‐negative patients with clinically suspected LS and a loss of MSH2 in tumor tissue. An analysis for genomic copy number variants (CNV) was performed, with subsequent next generation sequencing (NGS) of selected candidate genes in a subgroup of the cohort. Genomic DNA was genotyped using Illuminas HumanOmniExpress Bead Array. After quality control and filtering, 25 deletions and 16 duplications encompassing 73 genes were identified in 28 patients. No recurrent CNV was detected, and none of the CNVs affected the regulatory regions of MSH2. A total of 49 candidate genes from genomic regions implicated by the present CNV analysis and 30 known or assumed risk genes for colorectal cancer (CRC) were then sequenced in a subset of 38 patients using a customized NGS gene panel and Sanger sequencing. Single nucleotide variants were identified in 14 candidate genes from the CNV analysis. The most promising of these candidate genes were: (i) PRKCA, PRKDC, and MCM4, as a functional relation to MSH2 is predicted by network analysis, and (ii) CSMD1, as this is commonly mutated in CRC. Furthermore, six patients harbored POLE variants outside the exonuclease domain, suggesting that these might be implicated in hereditary CRC. Analyses in larger cohorts of suspected LS patients recruited via international collaborations are warranted to verify the present findings.

Screening and surveillance in hereditary gastrointestinal cancers: Recommendations from the European Society of Digestive Oncology (ESDO) expert discussion at the 20th European Society for Medical Oncology (ESMO)/World Congress on Gastrointestinal Cancer, Barcelona, June 2018

Patients with hereditary gastrointestinal (GI) cancers represent a substantial fraction of the overall affected population. Although awareness for hereditary GI cancer syndromes is on the rise, identification of patients and measures of surveillance are often unclear in everyday clinical routine. Therefore, the European Society of Digestive Oncology expert discussion 2018 at the World Congress on Gastrointestinal Cancer focussed on screening and surveillance of hereditary colorectal, gastric and pancreatic cancers. An international panel of experts and opinion leaders developed the here presented recommendations based on published evidence and on profound clinical expertise to facilitate clinical routine in identification and caretaking of patients with familial GI cancers.

Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo

BackgroundFormer studies already revealed the anti-neoplastic properties of the anti-infective agent Taurolidine (TRD) against many tumor species in vitro and in vivo. Its anti-proliferative and cell death inducing capacity is largely due to its main derivative Taurultam (TRLT). In this study it could be demonstrated, that substance 2250 - a newly defined innovative structural analogue of TRLT - exhibits an anti-neoplastic effect on malignant pancreatic carcinoma in vitro and in vivo.MethodsThe anti-neoplastic potential of substance 2250 as well as its mode of action was demonstrated in extensive in vitro analysis, followed by successful and effective in vivo testings, using xenograft models derived from established pancreatic cancer cell lines as well as patient derived tissue.ResultsOur functional analysis regarding the role of oxidative stress (ROS) and caspase activated apoptosis showed, that ROS driven programmed cell death (PCD) is the major mechanisms induced by substance 2250 in pancreatic carcinoma. What is strongly relevant towards clinical practice is especially the observed inhibition of patient derived pancreatic cancer tumor growth in mice treated with this new substance in combination with its sharply higher metabolic stability.ConclusionThese encouraging results provide new therapeutical opportunities in pancreatic cancer treatment and build the basis for further functional analysis as well as first clinical studies for this promising agent.

Dyspnoe und Gewichtsverlust bei einem 70-jährigen Patienten@@@Dyspnea and weight loss in a 70-year-old man

A 70-year-old man presented with subacute dyspnea, cough, weight loss, and mild fever. Blood analysis revealed an elevated C-reactive protein level. Chest x-ray and CT of the chest showed alveolar opacities with a migratory tendency during the clinical course. After extensive diagnostics, treatment with prednisolone under the presumed diagnosis of a cryptogenic organizing pneumonia was started, which lead to a rapid clinical response.ZusammenfassungWir berichten über einen 70-jährigen Patienten, der sich bei uns mit Dyspnoe, Husten, Gewichtsverlust und subfebrilen Temperaturen vorstellte. Laborchemisch war das C-reaktive Protein erhöht. Die konventionelle Röntgenuntersuchung des Thorax ergab infiltrative Veränderungen mit im Verlauf migratorischer Tendenz, die sich in der Computertomographie des Thorax als alveoläre Anschoppungen mit frischen und alten Anteilen darstellten. Nach extensiver Diagnostik erfolgte unter der Verdachtsdiagnose einer kryptogen organisierenden Pneumonie die Einleitung einer Prednisolontherapie, die rasch zu einer klinischen Besserung führte.AbstractA 70-year-old man presented with subacute dyspnea, cough, weight loss, and mild fever. Blood analysis revealed an elevated C-reactive protein level. Chest x-ray and CT of the chest showed alveolar opacities with a migratory tendency during the clinical course. After extensive diagnostics, treatment with prednisolone under the presumed diagnosis of a cryptogenic organizing pneumonia was started, which lead to a rapid clinical response.

[Dyspnea and weight loss in a 70-year-old man].

A 70-year-old man presented with subacute dyspnea, cough, weight loss, and mild fever. Blood analysis revealed an elevated C-reactive protein level. Chest x-ray and CT of the chest showed alveolar opacities with a migratory tendency during the clinical course. After extensive diagnostics, treatment with prednisolone under the presumed diagnosis of a cryptogenic organizing pneumonia was started, which lead to a rapid clinical response.ZusammenfassungWir berichten über einen 70-jährigen Patienten, der sich bei uns mit Dyspnoe, Husten, Gewichtsverlust und subfebrilen Temperaturen vorstellte. Laborchemisch war das C-reaktive Protein erhöht. Die konventionelle Röntgenuntersuchung des Thorax ergab infiltrative Veränderungen mit im Verlauf migratorischer Tendenz, die sich in der Computertomographie des Thorax als alveoläre Anschoppungen mit frischen und alten Anteilen darstellten. Nach extensiver Diagnostik erfolgte unter der Verdachtsdiagnose einer kryptogen organisierenden Pneumonie die Einleitung einer Prednisolontherapie, die rasch zu einer klinischen Besserung führte.AbstractA 70-year-old man presented with subacute dyspnea, cough, weight loss, and mild fever. Blood analysis revealed an elevated C-reactive protein level. Chest x-ray and CT of the chest showed alveolar opacities with a migratory tendency during the clinical course. After extensive diagnostics, treatment with prednisolone under the presumed diagnosis of a cryptogenic organizing pneumonia was started, which lead to a rapid clinical response.

Dyspnoe und Gewichtsverlust bei einem 70-jährigen Patienten

A 70-year-old man presented with subacute dyspnea, cough, weight loss, and mild fever. Blood analysis revealed an elevated C-reactive protein level. Chest x-ray and CT of the chest showed alveolar opacities with a migratory tendency during the clinical course. After extensive diagnostics, treatment with prednisolone under the presumed diagnosis of a cryptogenic organizing pneumonia was started, which lead to a rapid clinical response.ZusammenfassungWir berichten über einen 70-jährigen Patienten, der sich bei uns mit Dyspnoe, Husten, Gewichtsverlust und subfebrilen Temperaturen vorstellte. Laborchemisch war das C-reaktive Protein erhöht. Die konventionelle Röntgenuntersuchung des Thorax ergab infiltrative Veränderungen mit im Verlauf migratorischer Tendenz, die sich in der Computertomographie des Thorax als alveoläre Anschoppungen mit frischen und alten Anteilen darstellten. Nach extensiver Diagnostik erfolgte unter der Verdachtsdiagnose einer kryptogen organisierenden Pneumonie die Einleitung einer Prednisolontherapie, die rasch zu einer klinischen Besserung führte.AbstractA 70-year-old man presented with subacute dyspnea, cough, weight loss, and mild fever. Blood analysis revealed an elevated C-reactive protein level. Chest x-ray and CT of the chest showed alveolar opacities with a migratory tendency during the clinical course. After extensive diagnostics, treatment with prednisolone under the presumed diagnosis of a cryptogenic organizing pneumonia was started, which lead to a rapid clinical response.