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In personalized medicine, predictive biomarker testing is the basis for an appropriate choice of therapy for patients with cancer. An important tool for laboratories to ensure accurate results is participation in external quality assurance (EQA) programs. Several providers offer predictive EQA programs for different cancer types, test methods, and sample types. In 2013, a guideline was published on the requirements for organizing high-quality EQA programs in molecular pathology. Now, after six years, steps were taken to further harmonize these EQA programs as an initiative by IQNPath ABSL, an umbrella organization founded by various EQA providers. This revision is based on current knowledge, adds recommendations for programs developed for predictive biomarkers by in situ methodologies (immunohistochemistry and in situ hybridization), and emphasized transparency and an evidence-based approach. In addition, this updated version also has the aim to give an overview of current practices from various EQA providers. [ABSTRACT FROM AUTHOR]

Urologists are experts in the fields of genital and pelvic anatomy, sexual health and reproductive medicine. As such, a working understanding of urologic conditions relevant to transgender and gender diverse patients should be expected within their scope of practice. Herein, we describe an introductory framework for general urologists to grow their knowledge of the appropriate terminology, anatomy, and basic tenets of gender-affirming care to better manage the urologic needs of transgender and gender diverse patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Antibiotic stewardship in urologic reconstruction is critically important, as many patients will require indwelling catheters for days to weeks following surgery and thus are at risk of both developing catheter-associated urinary tract infections (CAUTI) as well as multi-drug resistant (MDR) uropathogens. Accordingly, limiting antibiotic use, when safe, should help reduce antibiotic resistance and the prevalence of MDR organisms. However, there is significant heterogeneity in how antibiotics are prescribed to patients who need indwelling urethral catheters post-operatively. We performed a literature review to determine if there are benefits in the use of antibiotics for various clinical scenarios that require post-operative indwelling catheters for greater than 24 h. In general, for patients undergoing prostatectomy, transurethral resection of the prostate, and/or urethroplasty, antibiotic administration may be limited without increased risk of CAUTI. However, more work is needed to identify optimal antibiotic regimens for these and alternative urologic procedures, whether certain sub-populations benefit from longer courses of antibiotics, and effective non-antibiotic or non-systemic therapies.

Background: Circulating cell free DNA (cfDNA) testing of plasma for EGFR somatic variants in lung cancer patients is being widely implemented and with any new service, external quality assessment (EQA) is required to ensure patient safety. An international consortium, International Quality Network for Pathology (IQNPath), has delivered a second round of assessment to measure the accuracy of cfDNA testing for lung cancer and the interpretation of the results., Methods: A collaboration of five EQA provider organisations, all members of IQNPath, have delivered the assessment during 2018-19 to a total of 264 laboratories from 45 countries. Bespoke plasma reference material containing a range of EGFR mutations at varying allelic frequencies were supplied to laboratories for testing and reporting according to routine procedures. The genotyping accuracy and clinical reporting was reviewed against standardised criteria and feedback was provided to participants., Results: The overall genotyping error rate in the EQA was found to be 11.1%. Low allelic frequency samples were the most challenging and were not detected by some testing methods, resulting in critical genotyping errors. This was reflected in higher false negative rates for samples with variant allele frequencies (VAF) rates less than 1.5% compared to higher frequencies. A sample with two different EGFR mutations gave inconsistent detection of both mutations. However, for one sample, where two variants were present at a VAF of less than 1% then both mutations were correctly detected in 145/263 laboratories. Reports often did not address the risk that tumour DNA may have not been tested and limitations of the methodologies provided by participants were insufficient. This was reflected in the average interpretation score for the EQA being 1.49 out of a maximum of 2., Conclusions: The variability in the standard of genotyping and reporting highlighted the need for EQA and educational guidance in this field to ensure the delivery of high-quality clinical services where testing of cfDNA is the only option for clinical management., (© 2022. The Author(s).)

While tumour mutation burden (TMB) is emerging as a possible biomarker for immune-checkpoint inhibitors (ICI), methods for testing have not been standardised as yet. In April 2019, the International Quality Network for Pathology (IQN Path) launched a survey to assess the current practice of TMB testing. Of the 127 laboratories that replied, 69 (54.3%) had already introduced TMB analysis for research purposes and/or clinical applications. Fifty laboratories (72.5%) used targeted sequencing, although a number of different panels were employed. Most laboratories tested formalin-fixed paraffin-embedded material (94.2%), while 18/69 (26%) tested also cell-free DNA. Fifty-five laboratories used both single nucleotide variants and indels for TMB calculation; 20 centers included only non-synonymous variants. In conclusion, the data from this survey indicate that multiple global laboratories were capable of rapidly introducing routine clinical TMB testing. However, the variability of testing methods raises concerns about the reproducibility of results among centers., (© 2021. The Author(s).)

Several immune checkpoint inhibitors (ICIs) have already been introduced into clinical practice or are in advanced phases of clinical experimentation. Extensive efforts are being made to identify robust biomarkers to select patients who may benefit from treatment with ICIs. Tumor mutation burden (TMB) may be a relevant biomarker of response to ICIs in different tumor types; however, its clinical use is challenged by the analytical methods required for its evaluation. The possibility of using targeted next-generation sequencing panels has been investigated as an alternative to the standard whole exome sequencing approach. However, no standardization exists in terms of genes covered, types of mutations included in the estimation of TMB, bioinformatics pipelines for data analysis, and cut-offs used to discriminate samples with high, intermediate or low TMB. Bioinformatics serve a relevant role in the analysis of targeted sequencing data and its standardization is essential to deliver a reliable test in clinical practice. In the present study, cultured and formalin-fixed, paraffin-embedded cell lines were analyzed using a commercial panel for TMB testing; the results were compared with data from the literature and public databases, demonstrating a good correlation. Additionally, the correlation between high tumor mutation burden and microsatellite instability was confirmed. The bioinformatics analyses were conducted using two different pipelines to highlight the challenges associated with the development of an appropriate analytical workflow., Competing Interests: NN has received speaker's fee and is on the advisory boards of the following companies: Astra-Zeneca, Bayer, Illumina, Incyte, MSD, Merck KgA, J&J, Qiagen, Roche, Thermo Fisher Scientific, Inc. CA, FH and RC are Thermo Fisher Scientific, Inc. employees. Thermo Fisher Scientific, Inc. is the supplier of the Oncomine Tumor Mutation Load assay used within the study. The other authors declare no competing interests., (Copyright: © Fenizia et al.)

Tumor mutation burden (TMB) is evaluated as a biomarker of response to immunotherapy. We present the efforts of the Onconetwork Immuno-Oncology Consortium to validate a commercial targeted sequencing test for TMB calculation. A three-phase study was designed to validate the Oncomine Tumor Mutational Load (OTML) assay at nine European laboratories. Phase 1 evaluated reproducibility and accuracy on seven control samples. In phase 2, six formalin-fixed, paraffin-embedded samples tested with FoundationOne were reanalyzed with the OTML panel to evaluate concordance and reproducibility. Phase 3 involved analysis of 90 colorectal cancer samples with known microsatellite instability (MSI) status to evaluate TMB and MSI association. High reproducibility of TMB was demonstrated among the sites in the first and second phases. Strong correlation was also detected between mean and expected TMB in phase 1 (r 2  = 0.998) and phase 2 (r 2  = 0.96). Detection of actionable mutations was also confirmed. In colorectal cancer samples, the expected pattern of MSI-high/high-TMB and microsatellite stability/low-TMB was present, and gene signatures produced by the panel suggested the presence of a POLE mutation in two samples. The OTML panel demonstrated robustness and reproducibility for TMB evaluation. Results also suggest the possibility of using the panel for mutational signatures and variant detection. Collaborative efforts between academia and companies are crucial to accelerate the translation of new biomarkers into clinical research., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Objectives : The National Cancer Database (NCDB) captures nearly 70% of all new cancer diagnoses in the United States, but there exists significant variation in this capture rate based on primary tumor location and other patient demographic factors. Prostate cancer has the lowest coverage rate of all major cancers, and other genitourinary malignancies likewise fall below the average NCDB case coverage rate. We aimed to explore NCDB coverage rates for patients with genitourinary cancers as a function of race. Materials and Methods : We compared the incidence of cancer cases in the NCDB with contemporary United States Cancer Statistics data. Results : Across all malignancies, American Indian/Alaskan Natives subjects demonstrated the lowest capture rates, and Asian/Pacific Islander subjects exhibited the second-lowest capture rates. Between White and Black subjects, capture rates were significantly higher for White subjects overall and for prostate cancer and kidney cancer in White males, but significantly higher for bladder cancer in Black versus White females. No significant differences were observed in coverage rates for kidney cancer in females, bladder cancer in males, penile cancer, or testicular cancer in White versus Black patients. Conclusions : Differential access to Commission on Cancer-accredited treatment facilities for racial minorities with genitourinary cancer constitutes a unique avenue for health equity research.

Partial nephrectomy (PN) is the gold standard treatment for appropriately selected renal masses. Recent surgical advancements and adoption of the robotic technique has led to greater adoption of nephron-sparing surgery. Robotic PN was initially described via the transperitoneal (TP) approach, however, retroperitoneal (RP) access is possible and in some cases more desirable. In the RP approach, the kidney is accessed from its posterior surface and the intraperitoneal space is avoided. The RP approach to PN has the benefit of avoiding intraperitoneal viscera and colonic mobilization in patients with extensive prior abdominal surgery. The technique also eliminates the need for renal unit rotation in patients with posterior tumors and affords access to masses directly posterior to the renal hilum. The RP and TP approach to PN have shown similar oncologic and perioperative outcomes. Several recent studies have reported shorter operative times and lengths of stay (LOS) with comparable warm ischemia times for the RP approach when compared to transperitoneal PN (tPN). Given the indispensable deliverables of this approach in select patients, robotic retroperitoneal PN (rPN) should be in the armamentarium of a versatile urologic kidney surgeon. This review describes the current state of rPN and compares the indications and outcomes of the TP and RP approaches., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau.2019.12.09). The series “Controversies in Minimally Invasive Urologic Oncology” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2021 Translational Andrology and Urology. All rights reserved.)

In personalized medicine, predictive biomarker testing is the basis for an appropriate choice of therapy for patients with cancer. An important tool for laboratories to ensure accurate results is participation in external quality assurance (EQA) programs. Several providers offer predictive EQA programs for different cancer types, test methods, and sample types. In 2013, a guideline was published on the requirements for organizing high-quality EQA programs in molecular pathology. Now, after six years, steps were taken to further harmonize these EQA programs as an initiative by IQNPath ABSL, an umbrella organization founded by various EQA providers. This revision is based on current knowledge, adds recommendations for programs developed for predictive biomarkers by in situ methodologies (immunohistochemistry and in situ hybridization), and emphasized transparency and an evidence-based approach. In addition, this updated version also has the aim to give an overview of current practices from various EQA providers.

Penile strangulation is an uncommon urologic emergency that requires prompt evaluation and treatment to avoid disastrous consequences. Strangulation has been reported with objects ranging from hair tourniquets, to plastic rings, to iron rings. Strangulation with these devices can result in vascular congestion of the penis, swelling and eventual gangrene of the penis distal to the constricting device. We present a case report of a 43-year-old male who had a 2-day history of penile pain and swelling secondary to a metal ring constricting the proximal phallus. Ring removal was achieved with an orthopedic bolt cutter to cut the ring in two places, using a malleable retractor to act as a "backboard" to prevent iatrogenic injury to the penis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Upper tract urothelial carcinoma (UTUC) accounts for roughly 5% of urothelial carcinomas. Historically, the gold standard for high-risk or bulky low-risk UTUC was an open radical nephroureterectomy with formal bladder cuff excision (BCE). The development of novel endoscopic, laparoscopic, and robotic techniques has transformed this operation, yet no level I evidence exists at present that demonstrates the superiority of one strategy over another. While new approaches to nephroureterectomy in the last decade have shifted the management paradigm to decrease the morbidity of surgery, controversy continues to surround the approach to the distal ureter and bladder cuff. Debate continues within the urologic community over which surgical approach is best when managing UTUC and how various approaches impact clinical outcomes such as intravesical recurrence, recurrence-free survival (RFS) and disease-specific mortality (DSM). When focusing on the existing treatment algorithm, key metrics of quality include (I) removal of the entire specimen en bloc , (II) minimizing the risk of tumor and urine spillage, (III) R0 resection, and (IV) water-tight closure allowing for early use of prophylactic intravesical chemotherapy. In the absence of robust evidence demonstrating a single superior approach, the urologic surgeon should base decisions on technical comfort and each patient's particular clinical circumstance., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau.2020.01.17). The series “Upper-Tract Urothelial Carcinoma: Current State and Future Directions” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2020 Translational Andrology and Urology. All rights reserved.)

Objective: To describe the technique of robotic remnant vaginectomy/excision of urethral diverticulum in transmen and report postoperative outcomes., Materials and Methods: Between 2015 and 2018, 4 patients underwent robotic remnant vaginectomy/excision of urethral diverticulum for relief of urinary symptoms. Patients were of mean age 36 ± 10.1 years (range 26-50) at time of vaginal remnant excision, and were 26 ± 9.1 months (range 20-39) post-op following their primary vaginectomy and radial forearm free flap (n = 3) or anterolateral thigh (n = 1) phalloplasty. All had multiple urologic complications after primary phalloplasty, most commonly urinary retention (n = 4), urethral stricture (n = 3), fistula (n = 3), dribbling (n = 2), and obstruction (n = 2). Indication for revision was obstruction and retention (n =3 ) and/or dribbling (n = 2). In each case, the robotic transabdominal dissection freed remnant vaginal tissue from the adjacent bladder and rectum without injury to these structures. Concurrent first- or second-stage urethroplasty was performed in all cases at a more distal portion of the urethra using buccal mucosa, vaginal, or skin grafts. Intraoperative cystoscopy was used in each case to confirm complete resection and closure of the diverticulum., Results: At mean follow-up of 294 ± 125.6 days (range 106-412), no patients had persistence or recurrence of vaginal cavity/urethral diverticulum on cystoscopic follow-up. Of 3 patients who wished to ultimately stand to void, 2 were able to do so at follow-up., Conclusion: Robotic transabdominal approach to remnant vaginectomy/excision of urethral diverticulum allows for excision without opening the perineal closure for management of symptomatic remnant/diverticulum in transgender men after vaginectomy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Sequencing artifacts, clonal hematopoietic mutations of indeterminate potential (CHIP) and tumor heterogeneity have been hypothesized to contribute to the low concordance between tissue and cell-free DNA (cfDNA) molecular profiling with targeted sequencing., Methods: We analyzed by targeted sequencing cfDNA from 30 healthy individuals, and cfDNA and matched tumor samples from 30 EGFR-mutant and 77 EGFR wild-type metastatic non-small-cell lung cancer (mNSCLC) patients. Discordant cases were solved by droplet digital PCR (ddPCR)., Results: By testing cfDNA from healthy donors, we developed an algorithm to recognize sequencing artifacts. Applying this method to cfDNA from mNSCLC patients, EGFR mutations were detected with a good sensitivity (76.7%) and specificity (97.4%). In contrast, sensitivity and specificity for KRAS variants were 61.5% and 93.8%, respectively. All EGFR and KRAS variants detected in plasma but not in tissue were confirmed by ddPCR, thus excluding sequencing artifacts. In a fraction of cases, KRAS mutations found in plasma samples were confirmed in tumor tissue suggesting tumor heterogeneity. KRAS variants were found to be more likely sub-clonal as compared with EGFR mutations, and a correlation between clonal origin and frequency of detection in plasma was found. In a case with both EGFR and KRAS variants in cfDNA, we could demonstrate the presence of the KRAS variant in tumor tissue associated with lack of response to tyrosine kinase inhibitors (TKIs)., Conclusions: Although sequencing artifacts can be identified in targeted sequencing of cfDNA, tumor heterogeneity and CHIP are likely to influence the concordance between plasma and tissue testing., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Previous findings suggest that metastatic colorectal carcinoma (mCRC) patients with KRAS/NRAS/BRAF/PIK3CA wild-type (quadruple-wt) tumors are highly sensitive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs). However, additional molecular alterations might be involved in the de novo resistance to these drugs. We performed a comprehensive molecular profiling of 21 quadruple-wt tumors from mCRC patients enrolled in the "Cetuximab After Progression in KRAS wild-type colorectal cancer patients" (CAPRI-GOIM) trial of first line FOLFIRI plus cetuximab. Tumor samples were analyzed with a targeted sequencing panel covering single nucleotide variants (SNVs), insertions/deletions (Indels), copy number variations (CNVs), and gene fusions in 143 cancer-related genes. The analysis revealed in all 21 patients the presence of at least one SNV/Indel and in 10/21 cases (48%) the presence of at least one CNV. Furthermore, 17/21 (81%) patients had co-existing SNVs/Indels in different genes. Quadruple-wt mCRC from patients with the shorter progression free survival (PFS) were enriched with peculiar genetic alterations in KRAS , FBXW7 , MAP2K1 , and NF1 genes as compared with patients with longer PFS. These data suggest that a wide genetic profiling of quadruple-wt mCRC patients might help to identify novel markers of de novo resistance to anti-EGFR MoAbs.

Liquid biopsy testing is a new laboratory-based method that detects tumour mutations in circulating free DNA (cfDNA) derived from minimally invasive blood sampling techniques. Recognising the significance for clinical testing, in 2017, IQN Path provided external quality assessment for liquid biopsy testing. Representatives of those participating laboratories were invited to attend a workshop to discuss the findings and how to achieve quality implementation of cfDNA testing in the clinical setting, the discussion and outcomes of this consensus meeting are described below. Predictive molecular profiling using tumour tissue in order to select cancer patients eligible for targeted therapy is now routine in diagnostic pathology. If insufficient tumour tissue material is available, in some circumstances, recent European Medicines Agency (EMA) guidance recommends mutation testing with plasma cfDNA. Clinical applications of cfDNA include treatment selection based on clinically relevant mutations derived from pre-treatment samples and the detection of resistant mutations upon progression of the disease. In order to identify tumour-related mutations in amongst other nucleic acid material found in plasma samples, highly sensitive laboratory methods are needed. In the workshop, we discussed the variable approaches taken with regard to cfDNA extraction methods, the tests, and considered the impact of false-negative test results. We explored the lack of standardisation of complex testing procedures ranging from plasma collection, transport, processing and storage, cfDNA extraction, and mutation analysis, to interpretation and reporting of results. We will also address the current status of clinical validation and clinical utility, and its use in current diagnosis. This workshop revealed a need for guidelines on with standardised procedures for clinical cfDNA testing and reporting, and a requirement for cfDNA-based external quality assessment programs.

Recent findings suggest that a fraction of EGFR-mutant non-small-cell lung cancers (NSCLC) carry additional driver mutations that could potentially affect the activity of EGFR tyrosine kinase inhibitors (TKIs). We investigated the role of concomitant KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of 133 EGFR mutant patients, who received first-line therapy with EGFR TKIs between June 2008 and December 2014. Analysis of genomic DNA by Next Generation Sequencing (NGS) revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA, or MET, in 29/133 cases (21.8%). A p.T790M mutation was found in 9/133 tumour samples (6.8%). The progression free survival (PFS) of patients without other mutations was 11.3 months vs. 7 months in patients with other mutations (log-rank test univariate: p = 0.047). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status, and the presence of p.T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95% CI 1.04⁻2.58; p = 0.035). In contrast, no correlation was found between TP53 mutations and patients' outcome. These data suggest that a subgroup of EGFR mutant tumours have concomitant driver mutations that might affect the activity of first-line EGFR TKIs.

Introduction: Circulating cell-free DNA (cfDNA) testing has emerged as an alternative to tumor tissue analyses for the management of metastatic non-small-cell lung cancer (NSCLC) patients. Analysis of cfDNA is a minimally invasive procedure that might better reflect tumor heterogeneity and allows repeated testing over the time. Areas covered: This review article covers the different applications of cfDNA testing in NSCLC: early diagnosis of the disease; detection of minimal residual disease in early lung cancer; identification of predictive and prognostic markers in advanced NSCLC patients; monitoring the response to therapy; assessment of tumor mutation burden. Expert commentary: The use of liquid biopsy is rapidly expanding to different applications. The combination of different circulating biomarkers (cfDNA, protein, miRNA) might improve the sensitivity and specificity of this approach in patients with low tumor burden. cfDNA testing is representing a valid source for molecular profiling in management of metastatic NSCLC patients and is providing important knowledge on tumor heterogeneity. Clinical trials are needed in order to transfer the information deriving from liquid biopsy testing in new therapeutic strategies.

The introduction in the clinic of immune checkpoint inhibitors (IOs) has represented an important improvement for the treatment of patients with advanced non-small cell lung cancer (NSCLC). These drugs have shown a higher activity as compared with chemotherapy in both first- and second-line of treatment, with some patients experiencing a long-lasting response. More recently, combinations of IOs have entered clinical trials in different tumor types including NSCLC. Nevertheless, IOs are active only in a subgroup of patients and biomarkers for appropriate patients' selection are urgently needed to offer the patients an effective therapy, and also to manage the costs. Tumor mutation burden (TMB) has powerfully emerged as a potential biomarker for immunotherapy and might enter the clinic in the next months, although different challenges are still unsolved. Different methods exist to evaluate TMB in tissue, ranging from whole exome sequencing (WES) to targeted sequencing of smaller sets of genes, which need to be fully standardized to ensure that patients receive an appropriate TMB test with clear clinical interpretation. In addition, as already happened for the implementation of liquid biopsy testing from NSCLC patients to identify targetable alterations, researchers are also evaluating the possibility to calculate TMB in blood, to further enlarge the number of NSCLC patients who may benefit from immunotherapy. Preliminary data highlight the difficulty to develop targeted sequencing panels for the assessment of TMB starting from the circulating cell free DNA (cfDNA). The applicability of TMB testing on liquid biopsy needs further investigation and may be clarified within the ongoing clinical trials., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Study Design: Retrospective analysis., Objective: To improve understanding of the impact of comorbid mental health disorders (MHDs) on long-term outcomes following cervical spinal fusion in cervical radiculopathy (CR) or cervical myelopathy (CM) patients., Summary of Background Data: Subsets of patients with CR and CM have MHDs, and their impact on surgical complications is poorly understood., Methods: Patients admitted from 2009 to 2013 with CR or CM diagnoses who underwent cervical surgery with minimum 2-year surveillance were retrospectively reviewed using New York State's Statewide Planning and Research Cooperative System. Patients with a comorbid MHD were compared against those without (no-MHD). Univariate analysis compared demographics, complications, readmissions, and revisions between MHD and no-MHD cohorts. Multivariate binary logistic regression models identified independent predictors of outcomes (covariates: age, sex, Charlson/Deyo score, and surgical approach)., Results: A total of 20,342 patients (MHD: n = 4819; no-MHD: n = 15,523) were included. MHDs identified: depressive (57.8%), anxiety (28.1%), sleep (25.2%), and stress (2.9%). CR patients had greater prevalence of comorbid MHD than CM patients (P = 0.015). Two years postoperatively, all patients with MHD had significantly higher rates of complications (specifically: device-related, infection), readmission for any indication, and revision surgery (all P < 0.05); regression modeling corroborated these findings and revealed combined surgical approach as the strongest predictor for any complication (CR, odds ratio [OR]: 3.945, P < 0.001; CM, OR: 2.828, P < 0.001) and MHD as the strongest predictor for future revision (CR, OR: 1.269, P = 0.001; CM, OR: 1.248, P = 0.008) in both CR and CM cohorts., Conclusion: Nearly 25% of patients admitted for CR and CM carried comorbid MHD and experienced greater rates of any complication, readmission, or revision, at minimum, 2 years after cervical spine surgery. Results must be confirmed with retrospective studies utilizing larger national databases and with prospective cohort studies. Patient counseling and psychological screening/support are recommended to complement surgical treatment., Level of Evidence: 3.

Background: Molecular analysis of circulating tumour DNA (ctDNA) is becoming increasingly important in clinical treatment decisions. A pilot External Quality Assessment (EQA) scheme for ctDNA analysis was organized by four European EQA providers under the umbrella organization IQN Path, in order to investigate the feasibility of delivering an EQA to assess the detection of clinically relevant variants in plasma circulating cell-free DNA (cfDNA) and to analyze reporting formats., Methods: Thirty-two experienced laboratories received 5 samples for EGFR mutation analysis and/or 5 samples for KRAS and NRAS mutation analysis. Samples were artificially manufactured to contain 3 mL of human plasma with 20 ng/mL of fragmented ctDNA and variants at allelic frequencies of 1 and 5%., Results: The scheme error rate was 20.1%. Higher error rates were observed for RAS testing when compared to EGFR analysis, for allelic frequencies of 1% compared to 5%, and for cases including 2 different variants. The reports over-interpreted wild-type results and frequently failed to comment on the amount of cfDNA extracted., Conclusions: The pilot scheme demonstrated the feasibility of delivering a ctDNA EQA scheme and the need for such a scheme due to high error rates in detecting low frequency clinically relevant variants. Recommendations to improve reporting of cfDNA are provided.

Molecular testing of EGFR is required to predict the response likelihood to targeted therapy in non-small cell lung cancer. Analysis of circulating tumor DNA in plasma may complement limitations of tumor tissue. This study evaluated the interlaboratory performance and reproducibility of a real-time PCR EGFR mutation test (cobas EGFR Mutation Test v2) to detect EGFR variants in plasma. Fourteen laboratories received two identical panels of 27 single-blinded plasma samples. Samples were wild type or spiked with plasmid DNA to contain seven common EGFR variants at six predefined concentrations from 50 to 5000 copies per milliliter. The circulating tumor DNA was extracted by a cell-free circulating DNA sample preparation kit (cobas cfDNA Sample Preparation Kit), followed by duplicate analysis with the real-time PCR EGFR mutation test (Roche Molecular Systems, Pleasanton, CA). Lowest sensitivities were obtained for the c.2156G>C p.(Gly719Ala) and c.2573T>G p.(Leu858Arg) variants for the lowest target copies. For all other variants, sensitivities varied between 96.3% and 100.0%. All specificities were 98.8% to 100.0%. Coefficients of variation indicated good intralaboratory and interlaboratory repeatability and reproducibility but increased for decreasing concentrations. Prediction models revealed a significant correlation for all variants between the predefined copy number and the observed semiquantitative index values, which reflect the samples' plasma mutation load. This study demonstrates an overall robust performance of the real-time PCR EGFR mutation test kit in plasma. Prediction models may be applied to estimate the plasma mutation load for diagnostic or research purposes., (Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

The optimal duration and intensity of first-line therapy in metastatic colorectal cancer patients once they have achieved an objective response is controversial. In a molecularly selected RAS and BRAF wild-type (wt) population, this concern is amplified. Once disease control has been achieved with a combination therapy including an anti-EGFR antibody, further exposure both to cytotoxic drugs and targeted therapy might result only in increased toxicity. In unresectable metastatic RAS and BRAF wt colorectal cancer patients, a deintensified therapy could represent a valuable option that might preserve quality of life. We designed a study to compare FOLFIRI/cetuximab to FOLFIRI/cetuximab for eight cycles followed by cetuximab alone in first-line treatment of RAS and BRAF (wt) metastatic colorectal cancer patients.