The projected impact of the COVID-19 lockdown on breast cancer deaths in England due to the cessation of population screening: a national estimation.

BACKGROUND: Population breast screening services in England were suspended in March 2020 due to the COVID-19 pandemic. Here, we estimate the number of breast cancers whose detection may be delayed because of the suspension, and the potential impact on cancer deaths over 10 years. METHODS: We estimated the number and length of screening delays from observed NHS Breast Screening System data. We then estimated additional breast cancer deaths from three routes: asymptomatic tumours progressing to symptomatically diagnosed disease, invasive tumours which remain screen-detected but at a later date, and ductal carcinoma in situ (DCIS) progressing to invasive disease by detection. We took progression rates, prognostic characteristics, and survival rates from published sources. RESULTS: We estimated that 1,489,237 women had screening delayed by around 2-7 months between July 2020 and June 2021, leaving 745,277 outstanding screens. Depending on how quickly this backlog is cleared, around 2500-4100 cancers would shift from screen-detected to symptomatic cancers, resulting in 148-452 additional breast cancer deaths. There would be an additional 164-222 screen-detected tumour deaths, and 71-97 deaths from DCIS that progresses to invasive cancer. CONCLUSIONS: An estimated 148-687 additional breast cancer deaths may occur as a result of the pandemic-related disruptions. The impact depends on how quickly screening services catch up with delays.

Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee.

BACKGROUND: Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests. METHODS: RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2. RESULTS: For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain." LIMITATIONS: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded. CONCLUSIONS: AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.

Quantitative breast density analysis to predict interval and node-positive cancers in pursuit of improved screening protocols: a case-control study.

BACKGROUND: This study investigates whether quantitative breast density (BD) serves as an imaging biomarker for more intensive breast cancer screening by predicting interval, and node-positive cancers. METHODS: This case-control study of 1204 women aged 47-73 includes 599 cancer cases (302 screen-detected, 297 interval; 239 node-positive, 360 node-negative) and 605 controls. Automated BD software calculated fibroglandular volume (FGV), volumetric breast density (VBD) and density grade (DG). A radiologist assessed BD using a visual analogue scale (VAS) from 0 to 100. Logistic regression and area under the receiver operating characteristic curves (AUC) determined whether BD could predict mode of detection (screen-detected or interval); node-negative cancers; node-positive cancers, and all cancers vs. controls. RESULTS: FGV, VBD, VAS, and DG all discriminated interval cancers (all p < 0.01) from controls. Only FGV-quartile discriminated screen-detected cancers (p < 0.01). Based on AUC, FGV discriminated all cancer types better than VBD or VAS. FGV showed a significantly greater discrimination of interval cancers, AUC = 0.65, than of screen-detected cancers, AUC = 0.61 (p < 0.01) as did VBD (0.63 and 0.53, respectively, p < 0.001). CONCLUSION: FGV, VBD, VAS and DG discriminate interval cancers from controls, reflecting some masking risk. Only FGV discriminates screen-detected cancers perhaps adding a unique component of breast cancer risk.

Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial.

BACKGROUND: The appropriate age range for breast cancer screening remains a matter of debate. We aimed to estimate the effect of mammographic screening at ages 40-48 years on breast cancer mortality. METHODS: We did a randomised, controlled trial involving 23 breast screening units across Great Britain. We randomly assigned women aged 39-41 years, using individual randomisation, stratified by general practice, in a 1:2 ratio, to yearly mammographic screening from the year of inclusion in the trial up to and including the calendar year that they reached age 48 years (intervention group), or to standard care of no screening until the invitation to their first National Health Service Breast Screening Programme (NHSBSP) screen at approximately age 50 years (control group). Women in the intervention group were recruited by postal invitation. Women in the control group were unaware of the study. The primary endpoint was mortality from breast cancers (with breast cancer coded as the underlying cause of death) diagnosed during the intervention period, before the participant's first NHSBSP screen. To study the timing of the mortality effect, we analysed the results in different follow-up periods. Women were included in the primary comparison regardless of compliance with randomisation status (intention-to-treat analysis). This Article reports on long-term follow-up analysis. The trial is registered with the ISRCTN registry, ISRCTN24647151. FINDINGS: 160 921 women were recruited between Oct 14, 1990, and Sept 24, 1997. 53 883 women (33·5%) were randomly assigned to the intervention group and 106 953 (66·5%) to the control group. Between randomisation and Feb 28, 2017, women were followed up for a median of 22·8 years (IQR 21·8-24·0). We observed a significant reduction in breast cancer mortality at 10 years of follow-up, with 83 breast cancer deaths in the intervention group versus 219 in the control group (relative rate [RR] 0·75 [95% CI 0·58-0·97]; p=0·029). No significant reduction was observed thereafter, with 126 deaths versus 255 deaths occurring after more than 10 years of follow-up (RR 0·98 [0·79-1·22]; p=0·86). INTERPRETATION: Yearly mammography before age 50 years, commencing at age 40 or 41 years, was associated with a relative reduction in breast cancer mortality, which was attenuated after 10 years, although the absolute reduction remained constant. Reducing the lower age limit for screening from 50 to 40 years could potentially reduce breast cancer mortality. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Atypical intraductal proliferation detected in prostate needle biopsy is a marker of unsampled intraductal carcinoma and other adverse pathological features: a prospective clinicopathological study of 62 cases with emphasis on pathological outcomes.

AIMS: Intraductal proliferations of the prostate with more complexity and/or cytological atypia than high-grade prostate intra-epithelial neoplasia (HGPIN), but falling short of intraductal carcinoma (IDC-P), are described as 'atypical intraductal proliferation' (AIP). When present in needle biopsy (NBX) without IDC-P, the clinical significance is not known. METHODS AND RESULTS: Sixty-two NBX cases were diagnosed as AIP over 7 years with estimated incidence of 1%. AIP was characterised by loose cribriform architecture (90%) or non-cribriform architecture exhibiting significant nuclear atypia that fell short of IDC-P. Fifty patients had concomitant PCa (20% grade group (GG) 1, 48% GG2, 14% GG3, 8% GG4 and 10% GG 5), and 12 had AIP alone. Of 40 patients who were candidates for no therapy (AIP alone) or active surveillance (AIP with GG1 or GG2 PCa without cribriform pattern 4), 20 had subsequent follow-up pathology [seven NBXs and 13 radical prostatectomy (RP)]. Of the 12 AIP only patients, six had a subsequent biopsy diagnosis of: benign prostate (two), IDC-P with PCa (one) and PCa (three). One or more adverse pathological features at subsequent RP were present in 93% of patients with AIP and GG1 or GG2 PCa, defined as: GG ≥ 3 (15%), IDC-P (77%), cribriform Gleason pattern 4 (69%), pT3a (77%) or pT3b (8%). CONCLUSIONS: AIP in NBX may be a marker of unsampled IDC-P and/or other adverse pathological features in suspected low- to intermediate-risk PCa. AIP should be considered distinct from HGPIN for risk assessment and warrant consideration for further work-up to detect unsampled high-risk PCa.

Current CPT Coding and Payment Policy Implications for Immunohistology Services.

Immunohistology is essential to the practice of modern surgical and cytopathology. There are 3 major types of immunohistologic services provided in clinical practice: traditional immunohistochemistry, morphometric analysis of tumor immunohistochemistry, and immunofluorescence. Proper Current Procedural Terminology coding for these services has been updated to reflect current medical practice. Subsequent to changes in the Current Procedural Terminology coding structure for these services, the valuation of these services have been reviewed by the American Medical Association/Specialty Society Relative Value Update Committee and new valuations instituted by the Centers for Medicare and Medicaid Services. Although valuations for services may be established, the circumstances of payment may be affected by Medicare Contractor's Local Coverage Determinations or service limits imposed by the National Correct Coding Initiative.

Current Valuation of Pathology Service.

Health care reform has accelerated as the existing health care system undergoes continuing financial stress. Medicare's new value-based payment system, commonly referred to as MACRA, provides opportunities for physicians to participate in this new system in a variety of ways. However, many of the value-based adjustments are based on existing valuations of services through traditional mechanisms. To achieve appropriate valuation of pathologist's services in the new payment models, it is imperative that we continue to achieve proper valuation of services through the traditional mechanisms.

Impact of pathologic re-review on grade, clinical stage, and risk stratification for patients with nonmuscle invasive bladder cancer.

OBJECTIVES: Pathologic re-review of transurethral resection of bladder tumor (TURBT) specimen is a common practice at our tertiary care center, but its impact on disease risk stratification remains unknown. We sought to determine how pathologic re-review of specimen initially read at an outside institution changed grade, clinical T (cT) stage, and AUA non-muscle-invasive bladder cancer (NMIBC) risk stratification. METHODS AND MATERIALS: The laboratory information system was searched for patients who underwent TURBT from 2021 to 2022, yielding 561 records. 173 patients met inclusion criteria: 113 with

Using ISARIC 4C mortality score to predict dynamic changes in mortality risk in COVID-19 patients during hospital admission.

As SARS-CoV-2 infections continue to cause hospital admissions around the world, there is a continued need to accurately assess those at highest risk of death to guide resource use and clinical management. The ISARIC 4C mortality score provides mortality risk prediction at admission to hospital based on demographic and physiological parameters. Here we evaluate dynamic use of the 4C score at different points following admission. Score components were extracted for 6,373 patients admitted to Barts Health NHS Trust hospitals between 1st August 2020 and 19th July 2021 and total score calculated every 48 hours for 28 days. Area under the receiver operating characteristic (AUC) statistics were used to evaluate discrimination of the score at admission and subsequent inpatient days. Patients who were still in hospital at day 6 were more likely to die if they had a higher score at day 6 than others also still in hospital who had the same score at admission. Discrimination of dynamic scoring in those still in hospital was superior with the area under the curve 0.71 (95% CI 0.69-0.74) at admission and 0.82 (0.80-0.85) by day 8. Clinically useful changes in the dynamic parts of the score are unlikely to be associated with subject-level measurements. Dynamic use of the ISARIC 4C score is likely to provide accurate and timely information on mortality risk during a patient's hospital admission.

Donor-Derived Renal Cell Carcinoma in a Kidney Allograft: A Case Report.

Renal cell carcinoma (RCC) in the kidney allograft is a relatively rare complication most commonly seen approximately a decade or more after transplant. We report a case of diffuse multifocal RCC within 6 months of transplant. The initial signal leading to an abnormality in the graft was an elevated routine cell-free DNA. Initial imaging findings appeared consistent with post-transplant lymphoproliferative disorder; however, biopsy would ultimately yield RCC. The patient's diffuse disease necessitated radical nephrectomy. Tumor DNA fingerprinting was employed in this case to show the tumor originated from donor tissue rather than host, indicating primary rather than metastatic disease. Early RCC is a rare complication. Most cases are detected at an early stage, likely as a result of increased surveillance with ultrasound imaging. A donor's social history including significant tobacco use should be considered when evaluating the risk of malignancy transmission in the allograft. Clinicians should be aware of multifocal RCC as a potential differential diagnosis for diffuse nodular infiltrates in the allograft.

Laboratory and Clinical Implications of Incidental and Secondary Germline Findings During Tumor Testing.

CONTEXT.­: Next-generation sequencing is a powerful clinical tool for cancer management but can produce incidental/secondary findings that require special consideration. OBJECTIVE.­: To discuss clinical and laboratory issues related to incidental or secondary germline findings in the clinical setting of tumor testing and inform future guidelines in this area. DESIGN.­: A College of American Pathologists workgroup including representation from the American Society of Clinical Oncology, the Association for Molecular Pathology, and the American College of Medical Genetics and Genomics created a review of items that should be considered when developing guidelines for incidental or secondary findings when performing clinical tumor testing. RESULTS.­: Testing recommendations should be cognizant of the differences among anticipated incidental, unanticipated incidental, and secondary findings, and whether normal tissue is also tested. In addition to defining which variants will be reported, robust recommendations must also take into account test design and validation, reimbursement, cost, infrastructure, impact on reflex testing, and maintenance of proficiency. Care providers need to consider the potential of a test to uncover incidental or secondary findings, the recommendation of upfront counseling, the need for consent, the timing of testing and counseling, and that the exact significance of a finding may not be clear. CONCLUSIONS.­: As clinical oncology testing panels have become a mainstay of clinical cancer care, guidelines addressing the unique aspects of incidental and secondary findings in oncology testing are needed. This paper highlights clinical and laboratory considerations with regard to incidental/secondary findings and is a clarion call to create recommendations.

Papillary Renal Cell Carcinoma With Microcystic Architecture Is Strongly Associated With Extrarenal Invasion and Metastatic Disease.

Papillary renal cell carcinoma (PRCC) is well-recognized as a morphologically and molecularly heterogenous group of kidney tumors with variable clinical behavior. Our goal was to analyze a unique histologic pattern of PRCC we have observed in routine practice to evaluate for potential clinical significance or distinct molecular signature. We identified 42 cases of PRCC showing a morphologically distinct architecture characterized by numerous epithelial-lined cysts containing the papillary tumor (herein called "microcysts"), which are typically separated by fibrous stroma. Of the initial 42 case test set with microcystic features, 23 (55%) were stage pT3a or higher. Most tumors had strong and diffuse cytoplasmic immunoreactivity for CK7 (93%, 37/40) and AMACR (100%, 40/40). Fumarate hydratase staining was retained in all cases tested (39/39). We performed next-generation sequencing on 15 of these cases with available tissue and identified chromosomal alterations commonly reported in historically "type 1" PRCC, notably multiple chromosomal gains, particularly of chromosomes 7 and 17, and MET alterations. However, alterations in pathways associated with more aggressive behavior (including SETD2, CDKN2A, and members of the NRF pathway) were also identified in 6 of 15 cases tested (40%). Given this molecular and immunophenotypic data, we subsequently reviewed an additional group of 60 consecutive pT2b-pT3 PRCCs to allow for comparisons between cases with and without microcysts, to assess for potential associations with other recently described histologic patterns (ie, "unfavorable architecture": micropapillary, solid, and hobnail), and to assess interobserver reproducibility for diagnosing architectural patterns and grade. Of the total combined 102 PRCCs, 67 (66%) had microcystic architecture within the intrarenal component but were commonly admixed with other patterns (39% had micropapillary, 31% solid, and 31% hobnail). Twenty-seven cases (26%) had metastatic disease, and 24 of these 27 (89%) had microcystic architecture in the intrarenal tumor. Within the pT3 subset, 21 of 22 cases with metastases (95%) had extrarenal invasion as either individual microcysts in renal sinus fat or aggregates of microcysts bulging beyond the confines of the capsule. Backward elimination and stepwise regression methods to detect features significantly associated with adverse outcome identified solid architecture (hazard ratio [HR]: 6.3; confidence interval [CI]: 2.1-18.8; P=0.001), hobnail architecture (HR: 5.3; CI: 1.7-16.7; P=0.004), and microcystic architecture at the tumor-stromal interface (HR: 4.2; CI: 1.1-16.7; P=0.036) as strongest. Of architectural patterns and grade, the microcystic pattern had a substantial interobserver agreement (κ score=0.795) that was highest among the 6 observers. In summary, PRCCs with microcystic architecture represents a subset of historically "type 1" PRCC with a predilection for morphologically distinctive extrarenal involvement and metastatic disease. Microcysts co-vary with other "unfavorable" architectural patterns also associated with higher risk for aggressive disease (ie, micropapillary, hobnail, and solid), but microcysts were more common and have superior interobserver reproducibility. These findings suggest that microcystic PRCC should be recognized as a potentially aggressive histologic pattern of growth in PRCC.

Proceedings From the ASCO/College of American Pathologists Immune Checkpoint Inhibitor Predictive Biomarker Summit.

PURPOSE: Immune checkpoint inhibition (ICI) therapy represents one of the great advances in the field of oncology, highlighted by the Nobel Prize in 2018. Multiple predictive biomarkers for ICI benefit have been proposed. These include assessment of programmed death ligand-1 expression by immunohistochemistry, and determination of mutational genotype (microsatellite instability or mismatch repair deficiency or tumor mutational burden) as a reflection of neoantigen expression. However, deployment of these assays has been challenging for oncologists and pathologists alike. METHODS: To address these issues, ASCO and the College of American Pathologists convened a virtual Predictive Factor Summit from September 14 to 15, 2021. Representatives from the academic community, US Food and Drug Administration, Centers for Medicare and Medicaid Services, National Institutes of Health, health insurance organizations, pharmaceutical companies, in vitro diagnostics manufacturers, and patient advocate organizations presented state-of-the-art predictive factors for ICI, associated problems, and possible solutions. RESULTS: The Summit provided an overview of the challenges and opportunities for improvement in assay execution, interpretation, and clinical applications of programmed death ligand-1, microsatellite instability-high or mismatch repair deficient, and tumor mutational burden-high for ICI therapies, as well as issues related to regulation, reimbursement, and next-generation ICI biomarker development. CONCLUSION: The Summit concluded with a plan to generate a joint ASCO/College of American Pathologists strategy for consideration of future research in each of these areas to improve tumor biomarker tests for ICI therapy.

Including a general practice endorsement letter with the testing kit in the Bowel Cancer Screening Programme: Results of a cluster randomised trial.

OBJECTIVES: To evaluate the effect of general practitioner endorsement accompanying the screening kit rather than with the invitation letter on participation in the NHS Bowel Cancer Screening Programme and on the socioeconomic gradient in participation in the Programme. METHODS: The NHS Bowel Cancer Screening Programme in England is delivered via five regional hubs. In early 2016, we carried out a cluster-randomised trial, with hub-day of invitation as the randomisation unit. We randomised 150 hub-days of invitation to the intervention group, GP endorsement on the letter accompanying the guaiac faecal occult blood testing kit (75 hub-days, 197,366 individuals) or control, usual letter (75 hub-days, 197,476 individuals). The endpoint was participation, defined as return of a valid kit within 18 weeks of initial invitation. Because of the cluster randomisation, data were analysed by a hierarchical logistic regression, allowing a random effect for date of invitation. Socioeconomic status was represented by the index of multiple deprivation. RESULTS: Participation was 59.4% in the intervention group and 58.7% in the control group, a significant difference (p = 0.04). There was no heterogeneity of the effect of intervention by index of multiple deprivation. We found that there was some confounding between date and screening episode order (first or subsequent screen). This in turn may have induced confounding with age and slightly diluted the result. CONCLUSIONS: General practitioner endorsement induces a modest increase in participation in bowel cancer screening, but does not affect the socioeconomic gradient. When considering cluster randomisation as a research method, careful scrutiny of potential confounding is indicated in advance if possible and in analysis otherwise.

The physicians quality reporting initiative: measure development, implementation and current procedural terminology coding.

The Physicians Quality Reporting Initiative (PQRI) was instituted in the latter half of 2007. PQRI is a voluntary reporting system in which the aim is to improve patient care, whereas at the same time, an eligible practitioner may receive an incentive payment for successful participation. Two pathology-specific measures were instituted in 2008; 1 for breast cancer reporting and the other for colon cancer reporting. In 2009, Current Procedural Terminology Category II code 3250F was instituted, which allows proper coding of cases from metastatic sites when ICD 9 code and Current Procedural Terminology Category I inclusion criteria are met. After the review of the 2007 data obtained from other specialties, submission of invalid codes was predominantly attributed to failure to adhere to measurement specifications. With increased awareness and experience, the amount of invalid code submission will decrease. More performance measures would be needed to make the program available to more pathologists. PQRI is thought by many to be the first step in transforming to a Pay for Performance Program.

Annual mammographic screening to reduce breast cancer mortality in women from age 40 years: long-term follow-up of the UK Age RCT.

BACKGROUND: There remains disagreement on the long-term effect of mammographic screening in women aged 40-49 years. OBJECTIVES: The long-term follow-up of a randomised controlled trial that offered annual mammography to women aged 40-49 years. The estimation of the effect of these mammograms on breast cancer and other-cause mortality, and the effect on incidence, with implications for overdiagnosis. DESIGN: An individually randomised controlled trial comparing offering annual mammography with offering usual care in those aged 40-48 years, and thus evaluating the effect of annual screening entirely taking place before the age of 50 years. There was follow-up for an average of 23 years for breast cancer incidence, breast cancer death and death from other causes. We analysed the mortality and incidence data by Poisson regression and estimated overdiagnosis formally using Markov process models. SETTING: Twenty-three screening units in England, Wales and Scotland within the NHS Breast Screening Programme. PARTICIPANTS: Women aged 39-41 years were recruited between 1990 and 1997. After exclusions, a total of 53,883 women were randomised to undergo screening (the intervention group) and 106,953 women were randomised to have usual care (the control group). INTERVENTIONS: The intervention group was invited to an annual breast screen with film mammography, two view at first screen and single view thereafter, up to and including the calendar year of their 48th birthday. The control group received no intervention. Both groups were invited to the National Programme from the age of 50 years, when screening is offered to all women in the UK. MAIN OUTCOME MEASURES: The main outcome measures were mortality from breast cancers diagnosed during the intervention phase of the trial (i.e. before the first National Programme screen at 50 years), mortality from all breast cancers diagnosed after randomisation, all-cause mortality, mortality from causes other than breast cancer, and the incidence of breast cancer. RESULTS: There was a statistically significant 25% reduction in mortality from breast cancers diagnosed during the intervention phase at 10 years' follow-up (relative rate 0.75, 95% confidence interval 0.58 to 0.97; p = 0.03). No reduction was observed thereafter (relative rate 0.98, 95% confidence interval 0.79 to 1.22). Overall, there was a statistically non-significant 12% reduction (relative rate 0.88, 95% confidence interval 0.74 to 1.03; p = 0.1). The absolute benefit remained approximately constant over time, at one death prevented per 1000 women screened. There was no effect of intervention on other-cause mortality (relative rate 1.02, 95% confidence interval 0.97 to 1.07; p = 0.4). The intervention group had a higher incidence of breast cancer than the control group during the intervention phase of the trial, but incidence equalised immediately on the first National Programme screen at the age of 50-52 years. LIMITATIONS: There was 31% average non-compliance with screening and three centres had to cease screening for resource and capacity reasons. CONCLUSIONS: Annual mammographic screening at the age of 40-49 years resulted in a relative reduction in mortality, which was attenuated after 10 years. It is likely that digital mammography with two views at all screens, as practised now, could improve this further. There was no evidence of overdiagnosis in addition to that which already results from the National Programme carried out at later ages. FUTURE WORK: There is a need for research on the effects of modern mammographic protocols and additional imaging in this age group. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24647151. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 55. See the NIHR Journals Library website for further project information. Other funding in the past has been received from the Medical Research Council, Cancer Research UK, the Department of Health and Social Care, the US National Cancer Institute and the American Cancer Society.

It is known that breast cancer screening with mammography (i.e. X-ray of the breasts) in women aged ≥ 50 years leads to a reduction in the number of deaths from breast cancer. In the UK, the NHS Breast Screening Programme offers regular screening to women aged 50­70 years. There is still some disagreement about the effect of such screening on the risk of death from breast cancer for those aged 40­49 years. There is also concern about overdiagnosis, that is, the finding of breast cancer that would not have been diagnosed in a woman's lifetime if she had not been screened. This study recruited 160,921 women aged 39­41 years and randomly assigned one in three of the women to be offered annual mammographic screening from age 40 to 48 years. The women were followed up for occurrence of breast cancer, death from breast cancer and death from all other causes. We found that the women who were offered the screening were 25% less likely to die of breast cancer in the first 10 years in the trial. This mortality reduction was reduced with later follow-up, with a 12% reduction after an average of 23 years. There was no effect of offering screening on death from other causes. During the early years of the trial, the women offered screening had larger numbers of breast cancers diagnosed, but this excess disappeared after the first National Programme screen. This suggests that there is no overdiagnosis from screening those aged 40­49 years over and above that which already results from screening those aged ≥ 50 years.

Microscopic bladder neck involvement by prostate carcinoma in radical prostatectomy specimens is not a significant independent prognostic factor.

The independent prognostic importance of microscopic bladder neck involvement by prostate cancer in radical prostatectomy is questionable. We studied a cohort of 1845 patients to determine the significance of microscopic bladder neck involvement. Bladder neck involvement was defined as prostate cancer present within the coned bladder neck. We further categorized the cases as 'true bladder neck involvement' and 'false bladder neck involvement.' True bladder neck involvement required prostate cancer within thick smooth muscle bundles without intermixed benign prostatic glands. False bladder neck involvement was characterized by prostate cancer intermixed with benign prostatic glands. Bladder neck involvement was analyzed in relation to preoperative serum prostate-specific antigen (PSA) level, extraprostatic extension, seminal vesicle involvement, positive surgical margin, lymph node involvement, radical prostatectomy Gleason score, and tumor volume. Of the 90 patients (4.9%) with microscopic bladder neck involvement, 63 were further classified as true bladder neck involvement and 27 as false bladder neck involvement. In univariate model, both types of bladder neck involvement (P<0.001), true (P<0.001), and false (P=0.040), were significantly associated with increased PSA-recurrence risk compared to bladder neck negative cases. In multivariate model the PSA-recurrence relative risk associated with bladder neck involvement (true or false) was not a significant independent prognostic factor. Extraprostatic extension, seminal vesicle involvement, positive surgical margin, lymph node involvement, PSA, and Gleason score were significant independent predictors of PSA recurrence. The time to biochemical recurrence in patients with bladder neck involvement was similar to that of pT2 with positive surgical margin or pT3a with negative surgical margin patients (Kaplan-Meier curves). Bladder neck involvement was associated with other adverse pathologic features, but was not an independent predictor of PSA recurrence. In view of the previous and current data, the staging system for bladder neck involvement should be revised and patients may be best categorized as having pT3a disease.

Seizure 6-like (SEZ6L) gene and risk for lung cancer.

DNA pooling in combination with high-throughput sequencing was done as a part of the Sequenom-Genefinder project. In the pilot study, we tested 83,715 single nucleotide polymorphisms (SNP), located primarily in gene-based regions, to identify polymorphic susceptibility variants for lung cancer. For this pilot study, 369 male cases and 287 controls of both sexes (white Europeans of Southern German origin) were analyzed. The study identified a candidate region in 22q12.2 that contained numerous SNPs showing significant case-control differences and that coincides with a region that was shown previously to be frequently deleted in lung cancer cell lines. The candidate region overlies the seizure 6-like (SEZ6L) gene. The pilot study identified a polymorphic Met430Ile substitution in the SEZ6L gene (SNP rs663048) as the top candidate for a variant modulating risk of lung cancer. Two replication studies were conducted to assess the association of SNP rs663048 with lung cancer risk. The M. D. Anderson Cancer Center study included 289 cases and 291 controls matched for gender, age, and smoking status. The Liverpool Lung Project (a United Kingdom study) included 248 cases and 233 controls. Both replication studies showed an association of the rs663048 with lung cancer risk. The homozygotes for the variant allele had more than a 3-fold risk compared with the wild-type homozygotes [combined odds ratio (OR), 3.32; 95% confidence interval (95% CI), 1.81-7.21]. Heterozygotes also had a significantly elevated risk of lung cancer from the combined replication studies with an OR of 1.15 (95% CI, 1.04-1.59). The effect remained significant after adjusting for age, gender, and pack-years of tobacco smoke. We also compared expression of SEZ6L in normal human bronchial epithelial cells (n = 7), non-small cell lung cancer (NSCLC; n = 52), and small cell lung cancer (SCLC; n = 22) cell lines by using Affymetrix HG-U133A and HG-U133B GeneChips. We found that the average expression level of SEZ6L in NSCLC cell lines was almost two times higher and in SCLC cell lines more than six times higher when compared with normal lung epithelial cell lines. Using the National Center for Biotechnology Information Gene Expression Omnibus database, we found a approximately 2-fold elevated and statistically significant (P = 0.004) level of SEZ6L expression in tumor samples compared with normal lung tissues. In conclusion, the results of these studies representing 906 cases compared with 811 controls indicate a role of the SEZ6L Met430Ile polymorphic variant in increasing lung cancer risk.

Fluorescence in situ hybridization (FISH) as primary methodology for the assessment of HER2 Status in adenocarcinoma of the breast: a single institution experience.

The demand for both reflexed and primary fluorescence in-situ hybridization (FISH) testing in the clinical setting is increasing. Relevant literature has reported the incidence of HER2 overexpression in 20% to 30% of cases, but some reports suggest that HER2 gene amplification rates are substantially lower. Published data, however, on primary FISH assessment from a single institution is limited, especially information about the frequency of the anomalous genotypes defined by FISH. We report our experience with primary FISH testing in 742 consecutive cases of breast cancer, in the calendar year 2006. Eighty percent (595/742) of the breast cancer cases were not amplified for HER2 (HER2/CEP17=0.8-1.9), whereas 19% (142/742) of cases were HER2 amplified (HER2/CEP17>or=2.0). Among the HER2-amplified cases, 3% (19/742) were low-level amplified (HER2/CEP17 ratio=2.0-2.5). Genotypic heterogeneity, defined as >5% but <50% of the tumor cells demonstrating HER2 gene amplification, was observed in 5% (40/7242) of the cases. HER2 monoallelic deletion (HER2/CEP1780% of tumor cells) was observed in 2% (13/742). Polysomy, if defined as CEP17 spot count 3.0 or more in at least 80% of tumor cells, was observed in 3% (20/742) of the cases. These data may be helpful as benchmarks for other institutions initiating primary FISH analysis for HER2 genotyping.