Standard Versus Modified Ipilimumab, in Combination With Nivolumab, in Advanced Renal Cell Carcinoma: A Randomized Phase II Trial (PRISM).

PURPOSE: Ipilimumab (IPI), in combination with nivolumab (NIVO), is an approved frontline treatment option for patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC). We conducted a randomized phase II trial to evaluate whether administering IPI once every 12 weeks (modified), instead of once every 3 weeks (standard), in combination with NIVO, is associated with a favorable toxicity profile. METHODS: Treatment-naïve patients with clear-cell aRCC were randomly assigned 2:1 to receive four doses of modified or standard IPI, 1 mg/kg, in combination with NIVO (3 mg/kg). The primary end point was the proportion of patients with a grade 3-5 treatment-related adverse event (trAE) among those who received at least one dose of therapy. The key secondary end point was 12-month progression-free survival (PFS) in the modified arm compared with historical sunitinib control. The study was not designed to formally compare arms for efficacy. RESULTS: Between March 2018 and January 2020, 192 patients (69.8% intermediate/poor-risk) were randomly assigned and received at least one dose of study drug. The incidence of grade 3-5 trAEs was significantly lower among participants receiving modified versus standard IPI (32.8% v 53.1%; odds ratio, 0.43 [90% CI, 0.25 to 0.72]; P = .0075). The 12-month PFS (90% CI) using modified IPI was 46.1% (38.6 to 53.2). At a median follow-up of 21 months, the overall response rate was 45.3% versus 35.9% and the median PFS was 10.8 months versus 9.8 months in the modified and standard IPI groups, respectively. CONCLUSION: Rates of grade 3-5 trAEs were significantly lower in patients receiving modified versus standard IPI. Although 12-month PFS did not meet the prespecified efficacy threshold compared with historical control, informal comparison of treatment groups did not suggest any reduction in efficacy with the modified schedule.

Real-Time Telepathology Is Substantially Equivalent to In-Person Intraoperative Frozen Section Diagnosis.

CONTEXT.­: Intraoperative diagnosis by frozen section is a mainstay of surgical pathology practice, providing immediate feedback to the surgical team. Despite good accuracy with modern methods, access to intraoperative surgical pathology with an appropriate turnaround time (TAT) has been a limiting factor for small or remote surgical centers, with negative impacts on cost and patient care. Telepathology offers immediate expert anatomic pathology consultation to sites without an in-house or subspecialized pathologist. OBJECTIVE.­: To assess the utility of live telepathology in frozen section practice. DESIGN.­: Frozen section diagnoses by telemicroscopy from 2 tertiary care centers with a combined 3 satellite hospitals were queried for anatomic site, TAT per block, pathologist, and concordance with paraffin diagnosis. TAT and concordance were compared to glass diagnoses in the same period. RESULTS.­: For 748 intraoperative diagnoses by telemicroscopy, 694 had TATs with a mean of 18 minutes 56 seconds ± 8 minutes 45 seconds, which was slower than on glass (14 minutes 25 seconds ± 7 minutes 8 seconds, P < .001). Twenty-two (2.89% of available) were discordant, which was not significantly different from the on-glass rate (P = .44) or categorical distribution (P = .31). Two cases (0.27%) had technical failures. CONCLUSIONS.­: Although in-person diagnoses were statistically faster, the great majority of telemicroscopic diagnoses were returned in less than 20 minutes. This remained true through numerous pathologists, pathology assistants and/or technicians, different hospitals, and during a combined 6 years. The concentration of discordant diagnoses among relatively few pathologists suggests individual comfort with telepathology and/or frozen section diagnosis. In rare cases, technical issues prevented telemicroscopic diagnosis. Overall, this justifies continued use and expansion of telemicroscopic services in primary intraoperative diagnoses.

Association of SARS-CoV-2 Spike Protein Antibody Vaccine Response With Infection Severity in Patients With Cancer: A National COVID Cancer Cross-sectional Evaluation.

Importance: Accurate identification of patient groups with the lowest level of protection following COVID-19 vaccination is important to better target resources and interventions for the most vulnerable populations. It is not known whether SARS-CoV-2 antibody testing has clinical utility for high-risk groups, such as people with cancer. Objective: To evaluate whether spike protein antibody vaccine response (COV-S) following COVID-19 vaccination is associated with the risk of SARS-CoV-2 breakthrough infection or hospitalization among patients with cancer. Design, Setting, and Participants: This was a population-based cross-sectional study of patients with cancer from the UK as part of the National COVID Cancer Antibody Survey. Adults with a known or reported cancer diagnosis who had completed their primary SARS-CoV-2 vaccination schedule were included. This analysis ran from September 1, 2021, to March 4, 2022, a period covering the expansion of the UK's third-dose vaccination booster program. Interventions: Anti-SARS-CoV-2 COV-S antibody test (Elecsys; Roche). Main Outcomes and Measures: Odds of SARS-CoV-2 breakthrough infection and COVID-19 hospitalization. Results: The evaluation comprised 4249 antibody test results from 3555 patients with cancer and 294 230 test results from 225 272 individuals in the noncancer population. The overall cohort of 228 827 individuals (patients with cancer and the noncancer population) comprised 298 479 antibody tests. The median age of the cohort was in the age band of 40 and 49 years and included 182 741 test results (61.22%) from women and 115 737 (38.78%) from men. There were 279 721 tests (93.72%) taken by individuals identifying as White or White British. Patients with cancer were more likely to have undetectable anti-S antibody responses than the general population (199 of 4249 test results [4.68%] vs 376 of 294 230 [0.13%]; P < .001). Patients with leukemia or lymphoma had the lowest antibody titers. In the cancer cohort, following multivariable correction, patients who had an undetectable antibody response were at much greater risk for SARS-CoV-2 breakthrough infection (odds ratio [OR], 3.05; 95% CI, 1.96-4.72; P < .001) and SARS-CoV-2-related hospitalization (OR, 6.48; 95% CI, 3.31-12.67; P < .001) than individuals who had a positive antibody response. Conclusions and Relevance: The findings of this cross-sectional study suggest that COV-S antibody testing allows the identification of patients with cancer who have the lowest level of antibody-derived protection from COVID-19. This study supports larger evaluations of SARS-CoV-2 antibody testing. Prevention of SARS-CoV-2 transmission to patients with cancer should be prioritized to minimize impact on cancer treatments and maximize quality of life for individuals with cancer during the ongoing pandemic.

COVID-19: Third dose booster vaccine effectiveness against breakthrough coronavirus infection, hospitalisations and death in patients with cancer: A population-based study.

PURPOSE: People living with cancer and haematological malignancies are at an increased risk of hospitalisation and death following infection with acute respiratory syndrome coronavirus 2. Coronavirus third dose vaccine boosters are proposed to boost waning immune responses in immunocompromised individuals and increase coronavirus protection; however, their effectiveness has not yet been systematically evaluated. METHODS: This study is a population-scale real-world evaluation of the United Kingdom's third dose vaccine booster programme for cancer patients from 8th December 2020 to 7th December 2021. The cancer cohort comprises individuals from Public Health England's national cancer dataset, excluding individuals less than 18 years. A test-negative case-control design was used to assess the third dose booster vaccine effectiveness. Multivariable logistic regression models were fitted to compare risk in the cancer cohort relative to the general population. RESULTS: The cancer cohort comprised of 2,258,553 tests from 361,098 individuals. Third dose boosters were evaluated by reference to 87,039,743 polymerase chain reaction coronavirus tests. Vaccine effectiveness against breakthrough infections, symptomatic infections, coronavirus hospitalisation and death in cancer patients were 59.1%, 62.8%, 80.5% and 94.5%, respectively. Lower vaccine effectiveness was associated with a cancer diagnosis within 12 months, lymphoma, recent systemic anti-cancer therapy (SACT) or radiotherapy. Patients with lymphoma had low levels of protection from symptomatic disease. In spite of third dose boosters, following multivariable adjustment, individuals with cancer remain at an increased risk of coronavirus hospitalisation and death compared to the population control (OR 3.38, 3.01, respectively. p < 0.001 for both). CONCLUSIONS: Third dose boosters are effective for most individuals with cancer, increasing protection from coronavirus. However, their effectiveness is heterogenous and lower than the general population. Many patients with cancer will remain at the increased risk of coronavirus infections even after 3 doses. In the case of patients with lymphoma, there is a particularly strong disparity of vaccine effectiveness against breakthrough infection and severe disease. Breakthrough infections will disrupt cancer care and treatment with potentially adverse consequences on survival outcomes. The data support the role of vaccine boosters in preventing severe disease, and further pharmacological intervention to prevent transmission and aid viral clearance to limit the disruption of cancer care as the delivery of care continues to evolve during the coronavirus pandemic.

Vaccine effectiveness against COVID-19 breakthrough infections in patients with cancer (UKCCEP): a population-based test-negative case-control study.

BACKGROUND: People with cancer are at increased risk of hospitalisation and death following infection with SARS-CoV-2. Therefore, we aimed to conduct one of the first evaluations of vaccine effectiveness against breakthrough SARS-CoV-2 infections in patients with cancer at a population level. METHODS: In this population-based test-negative case-control study of the UK Coronavirus Cancer Evaluation Project (UKCCEP), we extracted data from the UKCCEP registry on all SARS-CoV-2 PCR test results (from the Second Generation Surveillance System), vaccination records (from the National Immunisation Management Service), patient demographics, and cancer records from England, UK, from Dec 8, 2020, to Oct 15, 2021. Adults (aged ≥18 years) with cancer in the UKCCEP registry were identified via Public Health England's Rapid Cancer Registration Dataset between Jan 1, 2018, and April 30, 2021, and comprised the cancer cohort. We constructed a control population cohort from adults with PCR tests in the UKCCEP registry who were not contained within the Rapid Cancer Registration Dataset. The coprimary endpoints were overall vaccine effectiveness against breakthrough infections after the second dose (positive PCR COVID-19 test) and vaccine effectiveness against breakthrough infections at 3-6 months after the second dose in the cancer cohort and control population. FINDINGS: The cancer cohort comprised 377 194 individuals, of whom 42 882 had breakthrough SARS-CoV-2 infections. The control population consisted of 28 010 955 individuals, of whom 5 748 708 had SARS-CoV-2 breakthrough infections. Overall vaccine effectiveness was 69·8% (95% CI 69·8-69·9) in the control population and 65·5% (65·1-65·9) in the cancer cohort. Vaccine effectiveness at 3-6 months was lower in the cancer cohort (47·0%, 46·3-47·6) than in the control population (61·4%, 61·4-61·5). INTERPRETATION: COVID-19 vaccination is effective for individuals with cancer, conferring varying levels of protection against breakthrough infections. However, vaccine effectiveness is lower in patients with cancer than in the general population. COVID-19 vaccination for patients with cancer should be used in conjunction with non-pharmacological strategies and community-based antiviral treatment programmes to reduce the risk that COVID-19 poses to patients with cancer. FUNDING: University of Oxford, University of Southampton, University of Birmingham, Department of Health and Social Care, and Blood Cancer UK.

Digital Pathology Transformation in a Supraregional Germ Cell Tumour Network.

BACKGROUND: In this article we share our experience of creating a digital pathology (DP) supraregional germ cell tumour service, including full digitisation of the central laboratory. METHODS: DP infrastructure (Philips) was deployed across our hospital network to allow full central digitisation with partial digitisation of two peripheral sites in the supraregional testis germ cell tumour network. We used a survey-based approach to capture the quantitative and qualitative experiences of the multidisciplinary teams involved. RESULTS: The deployment enabled case sharing for the purposes of diagnostic reporting, second opinion, and supraregional review. DP was seen as a positive step forward for the departments involved, and for the wider germ cell tumour network, and was completed without significant issues. Whilst there were challenges, the transition to DP was regarded as worthwhile, and examples of benefits to patients are already recognised. CONCLUSION: Pathology networks, including highly specialised services, such as in this study, are ideally suited to be digitised. We highlight many of the benefits but also the challenges that must be overcome for such clinical transformation. Overall, from the survey, the change was seen as universally positive for our service and highlights the importance of engagement of the whole team to achieve success.

Interferon-Gamma-Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis.

BACKGROUND & AIMS: The pathogenesis of immune checkpoint inhibitor (ICI)-colitis remains incompletely understood. We sought to identify key cellular drivers of ICI-colitis and their similarities to idiopathic ulcerative colitis, and to determine potential novel therapeutic targets. METHODS: We used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic ulcerative colitis, and healthy controls. A subset of patients with ICI-colitis were studied longitudinally. We applied a range of methods, including multiparameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, and bulk and single-cell RNA sequencing. RESULTS: We demonstrate CD8+ tissue resident memory T (TRM) cells are the dominant activated T cell subset in ICI-colitis. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and epithelial-signaling levels. CD8+ TRM cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8+ TRM cells express high levels of transcripts for checkpoint inhibitors and interferon-gamma in ICI-colitis. We demonstrate similar findings in both anti-CTLA-4/PD-1 combination therapy and in anti-PD-1 inhibitor-associated colitis. On the basis of our data, we successfully targeted this pathway in a patient with refractory ICI-colitis, using the JAK inhibitor tofacitinib. CONCLUSIONS: Interferon gamma-producing CD8+ TRM cells are a pathological hallmark of ICI-colitis and a novel target for therapy.

UniTwain: A Cost-Effective Solution for Lean Gross Imaging.

BACKGROUND: Gross imaging of surgical specimens is paramount for the accurate gross examination and diagnosis of disease. Optimized imaging workflow can facilitate consistently high-quality gross photographs, especially in high-volume, metropolitan hospitals such as ours. Most commercial medical gross imaging technology provides ergonomically well-designed hardware, remotely operated cameras, intuitive software interfaces, and automation of workflow. However, these solutions are usually cost-prohibitive and require a large sum of capital budget. MATERIALS AND METHODS: We applied lean techniques such as value stream mapping (VSM) to design a streamlined and error-free workflow for gross imaging process. We implemented a cost-effective technology, UniTwain, combined with high-resolution webcam to achieve the ideal results. RESULTS: We reduced the mean process time from 600 min to 4.0 min (99.3% decrease in duration); the median process time was reduced from 580 min to 3.0 min. The process efficiency increased from 20% to 100%. The implemented solution has a comparable durability, scalability, and archiving feasibility to commercial medical imaging systems and costs four times less. The only limitations are manual operation of the webcam and lower resolution. The webcam sensors have 8.2 megapixel (MP) resolution, approximately 12 MP less than medical imaging devices. However, we believe that this difference is not visually significant and the effect on gross diagnosis with the naked eye is minimal. CONCLUSIONS: To our knowledge, this is the first study that utilized UniTwain as a viable, low-cost solution to streamline the gross imaging workflow. The UniTwain combined with high-resolution webcam could be a suitable alternative for our institution that does not plan to heavily invest in medical imaging.

Review of Adjuvant Therapies in Renal Cell Carcinoma: Evidence to Date.

In 2018, there were 400,000 new cases of renal cell carcinoma (RCC) globally, with 175,000 deaths attributable to the disease. Three quarters of patients have potentially curable localised disease at diagnosis; however, recurrence rates are as high as 40% following surgery. There are currently no adjuvant therapies in routine clinical use which reliably improve outcomes. Effective adjuvant therapy is an urgent unmet need to reduce recurrence risk and improve outcomes. Early efforts explored chemotherapy, radiotherapy, cytokine therapy, hormonal treatments and tumour cell vaccines as adjuvant therapies, however, have yielded disappointing results. More recently, interest shifted to evaluating tyrosine kinase inhibitors (TKIs) in the adjuvant setting, as they improve outcomes in metastatic disease. Five phase III clinical trials testing adjuvant use of a range of TKIs have been performed, with the results of a sixth trial awaited. Unfortunately, these studies have thus far yielded conflicting and disappointing results, and there is currently no strong evidence for routine adjuvant TKI therapy. In parallel, novel immunotherapy treatment approaches have recently been developed, transforming the management of a range of malignancies, particularly through immune checkpoint inhibitors (ICIs). These approaches are well established in the metastatic context in RCC, as well as in the adjuvant treatment of melanoma. On this basis, five phase III trials are currently ongoing to test the efficacy of a range of ICIs in adjuvant RCC patients, with initial results expected over the next few years. In this article, we review the current evidence for adjuvant therapies in RCC, discuss ongoing clinical trials and suggest directions for future work to address this unmet need.

Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial.

BACKGROUND: Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy. METHODS: We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0-2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov, NCT03182634; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804. FINDINGS: Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96-99% (n=800, kappa 0·89-0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83-98) overall and 98% (87-100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0-23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9-49]) of 20 patients in cohort B and four (22% [6-48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3-17]) of 74 in cohort A and two (11% [1-33]) of 19 patients in cohort D having a response. The most common grade 3-4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C). INTERPRETATION: ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment. FUNDING: Cancer Research UK, AstraZeneca, and Puma Biotechnology.

Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?

BACKGROUND: Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes. METHODS: A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed. RESULTS: In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (p < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (p = 0.008) and Mayo (p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (p = 0.03). CONCLUSIONS: CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.

Case report of oxalate nephropathy in a patient with pancreatic metastases from renal carcinoma.

BACKGROUND: Patients with metastatic renal carcinoma frequently have pre-existing renal impairment and not infrequently develop worsening renal function as a complication of their treatment. The presence of pancreatic metastases in patients with metastatic renal carcinoma, often confers a more favourable prognosis and as a consequence this patient group may be exposed to such treatments for more prolonged periods of time. However, the development of renal failure may also be a consequence of the cancer itself rather than its treatment. CASE PRESENTATION: We present an 84-year-old patient receiving the tyrosine kinase inhibitor (TKI) pazopanib for metastatic renal carcinoma who developed oxalate nephropathy as a consequence of pancreatic exocrine insufficiency resulting from pancreatic metastases. CONCLUSIONS: This case demonstrates the importance of investigating unexpected toxicities and highlights the potential consequences of pancreatic insufficiency and its sequelae in patients with pancreatic metastases.

Urothelial cancer: a narrative review of the role of novel immunotherapeutic agents with particular reference to the management of non-muscle-invasive disease.

AIM: This narrative review describes current guidelines for treating NMIBC, provides an overview of the principle behind immune checkpoint inhibition, and summarizes current evidence for checkpoint inhibitors in urothelial malignancy. Further, we discuss potential strategies for immune checkpoint inhibition in the management of NMIBC. BACKGROUND: Adjuvant intravesical BCG immunotherapy has been the mainstay of treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) for decades but is associated with both a significant side effect profile and failure rate. Recently, a substantial body of trial data has been published demonstrating the successful use of systemic immunotherapy in the treatment of advanced urothelial malignancy and, in particular, a class of drugs known as 'immune checkpoint inhibitors'. This has led to the approval of a number of these drugs by the UK National Institute of Health and Care Excellence and the US Food and Drug Administration, and ongoing trials are examining use in the management of NMIBC. METHODS: To identify relevant published data, using the PubMed/ Medline search engine, an online search of the Pubmed/ Medline archives was conducted using the terms bladder cancer' in combination with 'checkpoint inhibitors', and limited to articles in English published between 1966 and September 2017.To identify ongoing trials of interest but not yet published, a further search of the clinical trials.gov search engine was conducted using the term 'non-muscle-invasive bladder cancer'. CONCLUSION: There has been little advance in available adjuvant therapy for NMIBC treated with TURBT. Current intravesical therapies are associated with a high recurrence rate and significant side effect profile. The impending publication of the wealth of ongoing trials, both into the delivery and efficacy of checkpoint inhibition will direct the future treatment of NMIBC.

Changing Practice Evaluation-Stage 1 Seminoma: Outcomes With Adjuvant Treatment Versus Surveillance: Risk Factors for Recurrence and Optimizing Follow-up Protocols-Experience From a Supraregional Center.

BACKGROUND: Stage 1 seminoma is frequently cured by radical orchiectomy; however, the management strategies after this diagnosis vary in terms of the use of adjuvant treatment and the nature of the follow-up protocols. We analyzed stage 1 seminomas treated in the Thames Valley Cancer Network for outcomes to determine whether any factors are predictive of recurrence. We also studied relapses to determine the optimal follow-up schedule and protocol. MATERIALS AND METHODS: Data were obtained from centers within the Thames Valley Cancer Network for a 12-year period from 2004 to 2016. We identified 501 patients with stage 1 seminoma. RESULTS: Relapses occurred in 6.2% of the patients receiving adjuvant treatment and 6.1% of those who did not. The only statistically significant predictive factor identified for relapse was rete testis invasion, and the risk was greater when only stromal rete invasion was included, rather than pagetoid as well. A trend was seen toward an increased risk with increased tumor size, but the difference was not statistically significant. Recurrences developed within the first 2 years after surgery in nearly 75% of cases and were identified through surveillance computed tomography scans in 54.8% of the patients. All relapses were treated curatively. CONCLUSION: Active surveillance leads to excellent outcomes for stage 1 seminoma; however, adjuvant treatment should be reserved for those with high-risk disease. Follow-up schedules should include computed tomography imaging during the first 3 years, long-term measurement of tumor markers, and mechanisms for patients to be seen promptly should symptoms of tumor recurrence occur.

Whole-genome sequencing identifies homozygous BRCA2 deletion guiding treatment in dedifferentiated prostate cancer.

Whole-genome sequencing (WGS) has transformed the understanding of the genetic drivers of cancer and is increasingly being used in cancer medicine to identify personalized therapies. Here we describe a case in which the application of WGS identified a tumoral BRCA2 deletion in a patient with aggressive dedifferentiated prostate cancer that was repeat-biopsied after disease progression. This would not have been detected by standard BRCA testing, and it led to additional treatment with a maintenance poly ADP ribose polymerase (PARP) inhibitor following platinum-based chemotherapy. This case demonstrates that repeat biopsy upon disease progression and application of WGS to tumor samples has meaningful clinical utility and the potential to transform outcomes in patients with cancer.

Brain metastases in gestational trophoblast neoplasia: an update on incidence, management and outcome.

OBJECTIVE: To update the demographic data, treatment details and outcomes for GTN patients with brain metastases managed with the modern treatment protocols at the UK centre for gestational trophoblast neoplasia at Charing Cross Hospital in London. METHODS: The hospital database and pharmacy records were reviewed to identify GTN patients treated with brain metastases. Data was assembled on the specific GTN diagnosis, staging, prognostic scores, chemotherapy regimens, additional interventions and outcomes. RESULTS: During the 22 year study period, 27 GTN patients with brain metastases were treated. One case clearly resulted from a prior molar pregnancy, 3 were of uncertain aetiology and 23 cases had no prior molar pregnancy. The standard chemotherapy regimens were EMA-CO or EMA-EP given with an enhanced CNS methotrexate dose combined with intrathecal methotrexate. Five patients required emergency neurosurgery and routine radiotherapy was not employed. Twenty three (85%) patients are long term survivors and four patients died. Of the patients who died, all four had chemotherapy refractive disease and two had extended intervals of 18 and 30 years from their antecedent pregnancy. CONCLUSION: The incidence of brain metastases in postmolar pregnancy GTN is extremely low. Patients with non-molar choriocarcinoma have an approximate 20% risk of CNS disease and should have routine CNS imaging. Treatment with CNS doses of EMA-CO or EMA-EP appears curative for most patients.

TRAIL-R2-specific antibodies and recombinant TRAIL can synergise to kill cancer cells.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells while sparing normal tissues. Despite promising preclinical results, few patients responded to treatment with recombinant TRAIL (Apo2L/Dulanermin) or TRAIL-R2-specific antibodies, such as conatumumab (AMG655). It is unknown whether this was due to intrinsic TRAIL resistance within primary human cancers or insufficient agonistic activity of the TRAIL-receptor (TRAIL-R)-targeting drugs. Fcγ receptors (FcγR)-mediated crosslinking increases the cancer-cell-killing activity of TRAIL-R2-specific antibodies in vivo. We tested this phenomenon using FcγR-expressing immune cells from patients with ovarian cancer. However, even in the presence of high numbers of FcγR-expressing immune cells, as found in ovarian cancer ascites, AMG655-induced apoptosis was not enabled to any significant degree, indicating that this concept may not translate into clinical use. On the basis of these results, we next set out to determine whether AMG655 possibly interferes with apoptosis induction by endogenous TRAIL, which could be expressed by immune cells. To do so, we tested how AMG655 affected apoptosis induction by recombinant TRAIL. This, however, resulted in the surprising discovery of a striking synergy between AMG655 and non-tagged TRAIL (Apo2L/TRAIL) in killing cancer cells. This combination was as effective in killing cancer cells as highly active recombinant isoleucine-zipper-tagged TRAIL (iz-TRAIL). The increased killing efficiency was due to enhanced formation of the TRAIL death-inducing signalling complex, enabled by concomitant binding of Apo2L/TRAIL and AMG655 to TRAIL-R2. The synergy of AMG655 with Apo2L/TRAIL extended to primary ovarian cancer cells and was further enhanced by combination with the proteasome inhibitor bortezomib or a second mitochondrial-derived activator of caspases (SMAC) mimetic. Importantly, primary human hepatocytes were not killed by the AMG655-Apo2L/TRAIL combination, also not when further combined with bortezomib or a SMAC mimetic. We therefore propose that clinical-grade non-tagged recombinant forms of TRAIL, such as dulanermin, could be combined with antibodies such as AMG655 to introduce a highly active TRAIL-R2-agonistic therapy into the cancer clinic.

Privacy and security of patient data in the pathology laboratory.

Data protection and security are critical components of routine pathology practice because laboratories are legally required to securely store and transmit electronic patient data. With increasing connectivity of information systems, laboratory work-stations, and instruments themselves to the Internet, the demand to continuously protect and secure laboratory information can become a daunting task. This review addresses informatics security issues in the pathology laboratory related to passwords, biometric devices, data encryption, internet security, virtual private networks, firewalls, anti-viral software, and emergency security situations, as well as the potential impact that newer technologies such as mobile devices have on the privacy and security of electronic protected health information (ePHI). In the United States, the Health Insurance Portability and Accountability Act (HIPAA) govern the privacy and protection of medical information and health records. The HIPAA security standards final rule mandate administrative, physical, and technical safeguards to ensure the confidentiality, integrity, and security of ePHI. Importantly, security failures often lead to privacy breaches, invoking the HIPAA privacy rule as well. Therefore, this review also highlights key aspects of HIPAA and its impact on the pathology laboratory in the United States.

Pathology informatics fellowship retreats: The use of interactive scenarios and case studies as pathology informatics teaching tools.

BACKGROUND: Last year, our pathology informatics fellowship added informatics-based interactive case studies to its existing educational platform of operational and research rotations, clinical conferences, a common core curriculum with an accompanying didactic course, and national meetings. METHODS: The structure of the informatics case studies was based on the traditional business school case study format. Three different formats were used, varying in length from short, 15-minute scenarios to more formal multiple hour-long case studies. Case studies were presented over the course of three retreats (Fall 2011, Winter 2012, and Spring 2012) and involved both local and visiting faculty and fellows. RESULTS: Both faculty and fellows found the case studies and the retreats educational, valuable, and enjoyable. From this positive feedback, we plan to incorporate the retreats in future academic years as an educational component of our fellowship program. CONCLUSIONS: Interactive case studies appear to be valuable in teaching several aspects of pathology informatics that are difficult to teach in more traditional venues (rotations and didactic class sessions). Case studies have become an important component of our fellowship's educational platform.