iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging.

The visualization of molecularly labeled structures within large intact tissues in three dimensions is an area of intense focus. We describe a simple, rapid, and inexpensive method, iDISCO, that permits whole-mount immunolabeling with volume imaging of large cleared samples ranging from perinatal mouse embryos to adult organs, such as brains or kidneys. iDISCO is modeled on classical histology techniques, facilitating translation of section staining assays to intact tissues, as evidenced by compatibility with 28 antibodies to both endogenous antigens and transgenic reporters like GFP. When applied to degenerating neurons, iDISCO revealed unexpected variability in number of apoptotic neurons within individual sensory ganglia despite tight control of total number in all ganglia. It also permitted imaging of single degenerating axons in adult brain and the first visualization of cleaved Caspase-3 in degenerating embryonic sensory axons in vivo, even single axons. iDISCO enables facile volume imaging of immunolabeled structures in complex tissues. PAPERCLIP:

Stratification of Barrett's esophagus surveillance based on p53 immunohistochemistry: a cost-effectiveness analysis by an international collaborative group.

BACKGROUND: Surveillance of nondysplastic Barrett's esophagus (NDBE) is recommended to identify progression to dysplasia; however, the most cost-effective strategy remains unclear. Mutation of TP53 or aberrant expression of p53 have been associated with the development of dysplasia in BE. We sought to determine if surveillance intervals for BE could be stratified based on p53 expression. METHODS: A Markov model was developed for NDBE. Patients with NDBE underwent p53 immunohistochemistry (IHC) and those with abnormal p53 expression underwent surveillance endoscopy at 1 year, while patients with normal p53 expression underwent surveillance in 3 years. Patients with dysplasia underwent endoscopic therapy and surveillance. RESULTS: On base-case analysis, the strategy of stratifying surveillance based on abnormal p53 IHC was cost-effective relative to conventional surveillance and a natural history model, with an incremental cost-effectiveness ratio (ICER) of $8258 for p53 IHC-based surveillance. Both the conventional and p53-stratified surveillance strategies dominated the natural history model. On probabilistic sensitivity analysis, the p53 IHC strategy ($28 652; 16.78 quality-adjusted life years [QALYs]) was more cost-effective than conventional surveillance ($25 679; 16.17 QALYs) with a net monetary benefit of $306 873 compared with conventional surveillance ($297 642), with an ICER <$50 000 in 96% of iterations. The p53-stratification strategy was associated with a 14% reduction in the overall endoscopy burden and a 59% increase in dysplasia detection. CONCLUSION: A surveillance strategy for BE based on abnormal p53 IHC is cost-effective relative to a conventional surveillance strategy and is likely to be associated with higher rates of dysplasia diagnosis.

The predicted impact and cost-effectiveness of systematic testing of people with incident colorectal cancer for Lynch syndrome.

OBJECTIVES: To evaluate the health impact and cost-effectiveness of systematic testing for Lynch syndrome (LS) in people with incident colorectal cancer (CRC) in Australia. DESIGN, SETTING, PARTICIPANTS: We investigated the impact of LS testing strategies in a micro-simulation model (Policy1-Lynch), explicitly modelling the cost of testing all patients diagnosed with incident CRC during 2017, with detailed modelling of outcomes for patients identified as LS carriers (probands) and their at-risk relatives throughout their lifetimes. For people with confirmed LS, we modelled ongoing colonoscopic surveillance. MAIN OUTCOME MEASURES: Cost-effectiveness of six universal tumour testing strategies (testing for DNA mismatch repair deficiencies) and of universal germline gene panel testing of patients with incident CRC; impact on cost-effectiveness of restricting testing by age at CRC diagnosis (all ages, under 50/60/70 years) and of colonoscopic surveillance interval (one, two years). RESULTS: The cost-effectiveness ratio of universal tumour testing strategies (annual colonoscopic surveillance, no testing age limit) compared with no testing ranged from $28 915 to $31 904/life-year saved (LYS) (indicative willingness-to-pay threshold: $30 000-$50 000/LYS). These strategies could avert 184-189 CRC deaths with an additional 30 597-31 084 colonoscopies over the lifetimes of 1000 patients with incident CRC with LS and 1420 confirmed LS carrier relatives (164-166 additional colonoscopies/death averted). The most cost-effective strategy was immunohistochemistry and BRAF V600E testing (incremental cost-effectiveness ratio [ICER], $28 915/LYS). Universal germline gene panel testing was not cost-effective compared with universal tumour testing strategies (ICER, $2.4 million/LYS). Immunohistochemistry and BRAF V600E testing was cost-effective at all age limits when paired with 2-yearly colonoscopic surveillance (ICER, $11 525-$32 153/LYS), and required 4778-15 860 additional colonoscopies to avert 46-181 CRC deaths (88-103 additional colonoscopies/death averted). CONCLUSIONS: Universal tumour testing strategies for guiding germline genetic testing of people with incident CRC for LS in Australia are likely to be cost-effective compared with no testing. Universal germline gene panel testing would not currently be cost-effective.

[Immunohistochemistry using clone VE1 is an economic, specific and sensitive method for detecting the presence of BRAFV600E mutations in melanoma]. / L'immunohistochimie (clone VE1) est une méthode économique, spécifique et sensible pour détecter la présence d'une mutation BRAFV600E dans le mélanome.

BACKGROUND: Determination of BRAF mutation status is mandatory in the management of patients with inoperable stage IIIC or stage IV melanoma. Currently, molecular biology (MB) has been validated for detecting the presence of BRAF mutations. OBJECTIVE: To compare the sensitivity, specificity and cost of immunohistochemistry (IHC) (clone VE1) versus BM methods (qPCR and Sanger sequencing). PATIENTS AND METHODS: All the samples for which BRAF mutation status was requested between March 2013 and February 2015 at the cellular and molecular analysis laboratory of the Angers Hospital were included retrospectively and consecutively. The IHC (clone VE1) and BM analyses were performed with the same formalin-fixed paraffin embedded tumour samples. The cost of these two methods was determined on the basis of the cost for the French Health Insurance. RESULTS: Two hundred and seven samples were subjected to a determination of BRAF mutational status in IHC and BM. Only one sample was discordant between these two methods (positive in IHC, negative in BM). The sensitivity and specificity of the IHC was 100% and 99.25% respectively. The ratio of the cost of IHC/BM testing was 1:2.1. CONCLUSION: IHC (clone VE1) is a specific, sensitive and economic method for determining BRAFV600E mutation status. Nevertheless, this method must be validated in order to be integrated into a decisional algorithm, alongside BM methods, to determine whether targeted BRAF-inhibitor therapy is indicated.

Low cost immunohistochemistry bench for developing countries.

No abstract available.

Quality control in diagnostic immunohistochemistry: integrated on-slide positive controls.

Standardization in immunohistochemistry is a priority in modern pathology and requires strict quality control. Cost containment has also become fundamental and auditing of all procedures must take into account both these principles. Positive controls must be routinely performed so that their positivity guarantees the appropriateness of the immunohistochemical procedure. The aim of this study is to develop a low cost (utilizing a punch biopsy-PB-tool) procedure to construct positive controls which can be integrated in the patient's tissue slide. Sixteen frequently used control blocks were selected and multiple cylindrical samples were obtained using a 5-mm diameter punch biopsy tool, separately re-embedding them in single blocks. For each diagnostic immunoreaction requiring a positive control, an integrated PB-control section (cut from the appropriate PB-control block) was added to the top right corner of the diagnostic slide before immunostaining. This integrated control technique permitted a saving of 4.75% in total direct lab costs and proved to be technically feasible and reliable. Our proposal is easy to perform and within the reach of all pathology labs, requires easily available tools, its application costs is less than using external paired controls and ensures that a specific control for each slide is always available.

A new scenario in the immunohistochemical diagnosis of cutaneous leishmaniasis.

Cutaneous lesions of leishmaniasis are easy to diagnose when clinically obvious or when amastigotes are numerous in the biopsy. However, this is not always the case. In difficult cases, the diagnosis of leishmaniasis requires a reliable tool to identify the microorganisms. The identification of the parasite via microscope has a superior sensitivity to that of culture, and molecular techniques, such as polymerase chain reaction (PCR), highly improve the sensitivity of the diagnosis. Alternatively, immunohistochemistry has emerged as an affordable alternative to PCR. Several laboratories have produced their own antibodies against Leishmania and seem satisfied with the results. Nevertheless, most of these antibodies are not commercialized or standardized. Pathology also welcomed the unexpected positivity of amastigotes with certain clones of anti-CD1a. The latter does not universally stain all species of Leishmania, with a low sensitivity for New World species. In conclusion, although anti-CD1a is a reliable complementary tool in the diagnosis of leishmaniasis, pathologists should familiarize themselves with one of the specific antibodies against Leishmania and globalize its use, standardizing and adapting the technique.

Optimal use of colonoscopy and fecal immunochemical test for population-based colorectal cancer screening: a cost-effectiveness analysis using Japanese data.

OBJECTIVE: There have been few cost-effectiveness analyses of population-based colorectal cancer screening in Japan, and there is no consensus on the optimal use of total colonoscopy and the fecal immunochemical test for colorectal cancer screening with regard to cost-effectiveness and total colonoscopy workload. The present study aimed to examine the cost-effectiveness of colorectal cancer screening using Japanese data to identify the optimal use of total colonoscopy and fecal immunochemical test. METHODS: We developed a Markov model to assess the cost-effectiveness of colorectal cancer screening offered to an average-risk population aged 40 years or over. The cost, quality-adjusted life-years and number of total colonoscopy procedures required were evaluated for three screening strategies: (i) a fecal immunochemical test-based strategy; (ii) a total colonoscopy-based strategy; (iii) a strategy of adding population-wide total colonoscopy at 50 years to a fecal immunochemical test-based strategy. RESULTS: All three strategies dominated no screening. Among the three, Strategy 1 was dominated by Strategy 3, and the incremental cost per quality-adjusted life-years gained for Strategy 2 against Strategies 1 and 3 were JPY 293 616 and JPY 781 342, respectively. Within the Japanese threshold (JPY 5-6 million per QALY gained), Strategy 2 was the most cost-effective, followed by Strategy 3; however, Strategy 2 required more than double the number of total colonoscopy procedures than the other strategies. CONCLUSIONS: The total colonoscopy-based strategy could be the most cost-effective for population-based colorectal cancer screening in Japan. However, it requires more total colonoscopy procedures than the other strategies. Depending on total colonoscopy capacity, the strategy of adding total colonoscopy for individuals at a specified age to a fecal immunochemical test-based screening may be an optimal solution.

Universal Versus Targeted Screening for Lynch Syndrome: Comparing Ascertainment and Costs Based on Clinical Experience.

BACKGROUND: Strategies to screen colorectal cancers (CRCs) for Lynch syndrome are evolving rapidly; the optimal strategy remains uncertain. AIM: We compared targeted versus universal screening of CRCs for Lynch syndrome. METHODS: In 2010-2011, we employed targeted screening (age < 60 and/or Bethesda criteria). From 2012 to 2014, we screened all CRCs. Immunohistochemistry for the four mismatch repair proteins was done in all cases, followed by other diagnostic studies as indicated. We modeled the diagnostic costs of detecting Lynch syndrome and estimated the 5-year costs of preventing CRC by colonoscopy screening, using a system dynamics model. RESULTS: Using targeted screening, 51/175 (29 %) cancers fit criteria and were tested by immunohistochemistry; 15/51 (29 %, or 8.6 % of all CRCs) showed suspicious loss of ≥1 mismatch repair protein. Germline mismatch repair gene mutations were found in 4/4 cases sequenced (11 suspected cases did not have germline testing). Using universal screening, 17/292 (5.8 %) screened cancers had abnormal immunohistochemistry suspicious for Lynch syndrome. Germline mismatch repair mutations were found in only 3/10 cases sequenced (7 suspected cases did not have germline testing). The mean cost to identify Lynch syndrome probands was ~$23,333/case for targeted screening and ~$175,916/case for universal screening at our institution. Estimated costs to identify and screen probands and relatives were: targeted, $9798/case and universal, $38,452/case. CONCLUSIONS: In real-world Lynch syndrome management, incomplete clinical follow-up was the major barrier to do genetic testing. Targeted screening costs 2- to 7.5-fold less than universal and rarely misses Lynch syndrome cases. Future changes in testing costs will likely change the optimal algorithm.

Why and how immunohistochemistry should now be used to screen for the BRAFV600E status in metastatic melanoma? The experience of a single institution (LCEP, Nice, France).

BACKGROUND: Knowledge of the BRAFV600E status is mandatory in metastatic melanoma patients (MMP). Molecular biology is currently the gold standard method for status assessment. OBJECTIVES: We assessed and compared the specificity, sensibility, cost-effectiveness and turnaround time (TAT) of immunohistochemistry (IHC) and molecular biology for detection of the BRAFV600E mutation in 188 MMP. METHODS: IHC, with the VE1 antibody, and pyrosequencing analysis were performed with formalin fixed paraffin embedded tumour samples. RESULTS: The BRAFV600E mutation was detected by pyrosequencing in 91/188 (48%) patients. IHC was strongly positive (3+) in all of these 91 cases. IHC was strongly positive in 9/188 (5%) cases in which the molecular testing failed due to non-amplifiable DNA. Weak or moderate staining was noted in 10/188 (5%) cases in which the molecular biology identified BRAF wild-type tumours. The ratio of the global cost for IHC/molecular biology testing was 1 : 2.2. The average TAT was 48 h vs. 96 h, for IHC vs. molecular biology testing, respectively. CONCLUSIONS: This study showed that VE1 IHC should be a substitute for molecular biology in the initial assessment of the BRAFV600E status in MPP. This methodology needs to be set up in pathology laboratories in accordance with quality control/quality assurance accreditation procedures. Under these strict conditions the question is to know if BRAFV600E-IHC can serve not only as a prescreening tool, but also as a stand-alone test (at least in cases displaying an unequivocally staining pattern) as well as an alternative predictive test for samples for which the molecular biology failed.

A low cost rapid urease test to detect Helicobacter pylori infection in resource limited settings.

The aim of the study was to evaluate the suitability of a modified one minute rapid urease test (one day rapid urease test) as a low cost H. pylori detection method. A sample of 205 patients clinically suspected of having H. pylori infection was tested. One day rapid urease test and histology based H. pylori tests (the gold standard) were performed on endoscopic antral biopsies. There were 6 true positives, 191 true negatives, 8 false positives and zero false negatives. The sensitivity, specificity and positive (PPV) and negative predictive values (NPV) of the test were 100%, 96%, 42.9%, and 100% respectively. The cost per patient was 0.3US$. High sensitivity, specificity and NPV, low cost and simplicity of method were the advantages of the test and the main limitation was low PPV. Hence, one day rapid urease test can be considered as a suitable low cost method to detect H. pylori infection in resource limited settings.

Rate of detection of advanced neoplasms in proximal colon by simulated sigmoidoscopy vs fecal immunochemical tests.

BACKGROUND & AIMS: We compared the ability of biennial fecal immunochemical testing (FIT) and one-time sigmoidoscopy to detect colon side-specific advanced neoplasms in a population-based, multicenter, nationwide, randomized controlled trial. METHODS: We identified asymptomatic men and women, 50-69 years old, through community health registries and randomly assigned them to groups that received a single colonoscopy examination or biennial FIT. Sigmoidoscopy yield was simulated from results obtained from the colonoscopy group, according to the criteria proposed in the UK Flexible Sigmoidoscopy Trial for colonoscopy referral. Patients who underwent FIT and were found to have ≥75 ng hemoglobin/mL were referred for colonoscopy. Data were analyzed from 5059 subjects in the colonoscopy group and 10,507 in the FIT group. The main outcome was rate of detection of any advanced neoplasm proximal to the splenic flexure. RESULTS: Advanced neoplasms were detected in 317 subjects (6.3%) in the sigmoidoscopy simulation group compared with 288 (2.7%) in the FIT group (odds ratio for sigmoidoscopy, 2.29; 95% confidence interval, 1.93-2.70; P = .0001). Sigmoidoscopy also detected advanced distal neoplasia in a higher percentage of patients than FIT (odds ratio, 2.61; 95% confidence interval, 2.20-3.10; P = .0001). The methods did not differ significantly in identifying patients with advanced proximal neoplasms (odds ratio, 1.17; 95% confidence interval, 0.78-1.76; P = .44). This was probably due to the lower performance of both strategies in detecting patients with proximal lesions (sigmoidoscopy detected these in 19.1% of patients and FIT in 14.9% of patients) vs distal ones (sigmoidoscopy detected these in 86.8% of patients and FIT in 33.5% of patients). Sigmoidoscopy, but not FIT, detected proximal lesions in lower percentages of women (especially those 50-59 years old) than men. CONCLUSIONS: Sigmoidoscopy and FIT have similar limitations in detecting advanced proximal neoplasms, which depend on patients' characteristics; sigmoidoscopy underperforms for women 50-59 years old. Screening strategies should be designed on the basis of target population to increase effectiveness and cost-effectiveness. ClinicalTrials.gov number: NCT00906997.

Cost analysis of different cervical cancer screening strategies in Mexico.

OBJECTIVE: To compare the costs and number of undetected cases of four cervical cancer screening strategies (CCSS) in Mexico. MATERIALS AND METHODS: We estimated the costs and outcomes of the following CCSS: a) conventional Papanicolaou smear (Pap) alone; b) high-risk human papilloma virus testing (HR-HPV) as primary screening with Pap as reflex triage; c) HR-HPV as primary screening with HPV-16/18 typing, liquid-based cytology (LBC) and immunostaining for p16/Ki67 testing as reflex triage, and d) co-testing with HR-HPV and LBC with HPV-16/18 typing and immunostaining for p16/Ki67 as reflex triage. The outcome of interest was high-grade cervical lesions or cervical cancer. RESULTS: HR-HPV testing, HPV typing, LBC testing and immunostaining is the best alternative because it is the least expensive option with an acceptable number of missed cases. CONCLUSIONS: The opportunity costs of a poor quality CCSS is many false negatives. Combining multiple tests may be a more cost-effective way to screen for cervical cancer in Mexico.

Cost-effectiveness of one versus two sample faecal immunochemical testing for colorectal cancer screening.

OBJECTIVE: The sensitivity and specificity of a single faecal immunochemical test (FIT) are limited. The performance of FIT screening can be improved by increasing the screening frequency or by providing more than one sample in each screening round. This study aimed to evaluate if two-sample FIT screening is cost-effective compared with one-sample FIT. DESIGN: The MISCAN-colon microsimulation model was used to estimate costs and benefits of strategies with either one or two-sample FIT screening. The FIT cut-off level varied between 50 and 200 ng haemoglobin/ml, and the screening schedule was varied with respect to age range and interval. In addition, different definitions for positivity of the two-sample FIT were considered: at least one positive sample, two positive samples, or the mean of both samples being positive. RESULTS: Within an exemplary screening strategy, biennial FIT from the age of 55-75 years, one-sample FIT provided 76.0-97.0 life-years gained (LYG) per 1000 individuals, at a cost of € 259,000-264,000 (range reflects different FIT cut-off levels). Two-sample FIT screening with at least one sample being positive provided 7.3-12.4 additional LYG compared with one-sample FIT at an extra cost of € 50,000-59,000. However, when all screening intervals and age ranges were considered, intensifying screening with one-sample FIT provided equal or more LYG at lower costs compared with two-sample FIT. CONCLUSION: If attendance to screening does not differ between strategies it is recommended to increase the number of screening rounds with one-sample FIT screening, before considering increasing the number of FIT samples provided per screening round.

Update on immunohistochemistry in bone and soft tissue tumors: Cost-effectively replacing molecular testing with immunohistochemistry.

Soft tissue tumors form part of a challenging domain in diagnostic pathology owing to their comparative rarity, astonishing histologic diversity, and overlap between entities. Many of these tumors are now known to be defined by highly recurrent, or, in some instances, unique molecular alterations. Insights from gene profiling continue to elucidate the wider molecular landscape of soft tissue tumors; many of these advances have been co-opted by immunohistochemistry (IHC) for diagnostic applications. There now exists a multitude of antibodies serving as surrogate markers of recurrent gene fusions, amplifications, and point mutations, which, in certain settings, can replace the need for more resource and time-intensive cytogenetic and molecular genetic analyses. IHC presents many advantages including rapid turnaround time, cost-effectiveness, and interpretative reproducibility. A sensible application of these immunohistochemical markers complemented by a working knowledge of the molecular pathogenesis of bone and soft tissue tumors permits accurate diagnosis in the majority of cases. In this review, we will outline some of these biomarkers while emphasizing molecular correlates and highlighting interpretative challenges and pitfalls.

The Clinical Utility of a Tiered Approach to Pediatric Glioma Molecular Characterization for Resource-Limited Settings.

PURPOSE: Molecular characterization is key to optimally diagnose and manage cancer. The complexity and cost of routine genomic analysis have unfortunately limited its use and denied many patients access to precision medicine. A possible solution is to rationalize use-creating a tiered approach to testing which uses inexpensive techniques for most patients and limits expensive testing to patients with the highest needs. Here, we tested the utility of this approach to molecularly characterize pediatric glioma in a cost- and time-sensitive manner. METHODS: We used a tiered testing pipeline of immunohistochemistry (IHC), customized fusion panels or fluorescence in situ hybridization (FISH), and targeted RNA sequencing in pediatric gliomas. Two distinct diagnostic algorithms were used for low- and high-grade gliomas (LGGs and HGGs). The percentage of driver alterations identified, associated testing costs, and turnaround time (TAT) are reported. RESULTS: The tiered approach successfully characterized 96% (95 of 99) of gliomas. For 82 LGGs, IHC, targeted fusion panel or FISH, and targeted RNA sequencing solved 35% (29 of 82), 29% (24 of 82), and 30% (25 of 82) of cases, respectively. A total of 64% (53 of 82) of samples were characterized without targeted RNA sequencing. Of 17 HGG samples, 13 were characterized by IHC and four were characterized by targeted RNA sequencing. The average cost per sample was more affordable when using the tiered approach as compared with up-front targeted RNA sequencing in LGG ($405 US dollars [USD] v $745 USD) and HGGs ($282 USD v $745 USD). The average TAT per sample was also shorter using the tiered approach (10 days for LGG, 5 days for HGG v 14 days for targeted RNA sequencing). CONCLUSION: Our tiered approach molecularly characterized 96% of samples in a cost- and time-sensitive manner. Such an approach may be feasible in neuro-oncology centers worldwide, particularly in resource-limited settings.

Assessing the potential cost-effectiveness of retesting IHC0, IHC1+, or FISH-negative early stage breast cancer patients for HER2 status.

BACKGROUND: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) tests are commonly used to assess human epidermal growth factor 2 (HER2) status of tumors in patients with breast cancer. This analysis evaluates the likely cost-effectiveness of expanded retesting to assess HER2 tumor status in women with early stage breast cancer. METHODS: We developed a decision-analytic model to estimate the incremental cost-effectiveness ratio (ICER) of expanded reflex testing from a US payer perspective. Expanded reflex testing is defined as retesting tumor specimens from patients whose tumors are IHC0, IHC1+, or FISH-negative on their first test. In the base case, we assumed that 80% of patient tumors are initially IHC-tested and 20% are FISH-tested. Testing outcomes for IHC and FISH with and without retesting were based on published meta-analyses. The cost of tests and treatment and the long-term health outcomes were obtained from the literature. RESULTS: In the base case, we estimated that 2.27% of women who received expanded reflex testing would be HER2-positive and receive trastuzumab treatment: the projected ICER was $36,721 per life year or $39,745 per quality-adjusted life year (QALY). This varied between $47,100 per QALY and $35,500 per QALY if we assumed that 1%-8% of patients retested were then HER2+, respectively. The results of deterministic and probabilistic sensitivity analysis were robust. This strategy would result in 4700 (2000-17,000) patients being eligible to receive trastuzumab treatment annually. CONCLUSIONS: Retesting patients who are IHC0, IHC1+, or FISH-negative is projected to be a cost-effective clinical strategy.

Rapid immunostaining in Mohs: current applications and attitudes.

BACKGROUND: Rapid immunostaining in Mohs micrographic surgery (MMS) has been extensively reviewed in the recent literature. Despite the recent attention, there is relatively little information on how frequently these techniques are actually utilized and the current attitudes of the Mohs community towards immunohistochemical (IHC) stains. OBJECTIVE: We attempted to obtain information on the utilization and attitudes towards the use of rapid immunostaining in Mohs through a survey of fellowship-trained Mohs surgeons. MATERIALS AND METHODS: A twenty-five question survey was sent to members of the American College of Mohs Surgery (ACMS) through various methods including SurveyMonkey(®) , email, fax, and Metrofax(®) . RESULTS: A total of 378 surveys were completed. These responses represent a cross-section of fellowship-trained members of the ACMS. CONCLUSIONS: The vast majority of respondents felt as though IHC stains could be used reliably in Mohs. A subset of responses indicated that the most common reasons for not using IHC stains are time consumption, lack of education, and startup and/or maintenance costs. An increase in immunostain usage over 10 years ago appears to correlate with the activity in the literature. There may be an underutilization of IHC staining in fellowship programs, as indicated by respondents' opinions.

Prospective assessment of histological serial sectioning of pelvic lymph nodes in prostate cancer: a cost-benefit analysis.

UNLABELLED: What's known on the subject? and What does the study add? Metastatic spread to the regional lymph nodes (LNs) is the single worst predictor of survival in prostate cancer. Knowledge of the LN status is crucial, as the treatment strategy is substantially altered in non-organ-confined disease. Current routine pathological protocols for evaluation of LN resection specimens do not demand a minimum of cross-sections per LN to be examined. Depending on the LN size, usually one to two sections are examined. This might lead to underestimation of the true metastatic burden. The present study shows that additional examination of cross-sections in pelvic LNs and applying prostate cancer-specific cytokeratine immunostaining does not lead to significantly increased detection of prostate cancer metastases. However, the work-load and the expenses were significantly higher compared with routine evaluation. OBJECTIVE: To evaluate the diagnostic gain in the detection of lymph node (LN) metastases of prostate cancer and the additional expenses of histological step-section analysis, including immunohistochemistry compared with routine histopathological evaluation. PATIENTS AND METHODS: In a prospective study, 19 patients with prostate cancer at high risk of LN metastases (>cT2c and/or PSA level of >20 ng/mL and/or Gleason score >8) underwent sentinel-guided LN resection. All palpable LNs were submitted to step-section analysis in 200-µm sections and concomitant immunohistochemical staining for cytokeratine (AE1/AE3), in addition to routine histopathology of one or two haematoxylin and eosin-stained sections per LN. The number of positive LNs and LN-positive patients for each method was compared; additional expenses in labour time and material for the extended evaluation were estimated. RESULTS: In all, 413 LNs were resected; 220 LNs were palpable and were included in the study. In seven of the 19 patients routine histopathological evaluation revealed LN metastases in 24 of 220 LNs (10.9%). Extended LN evaluation with step sectioning and cytokeratin immunohistochemistry did not reveal any additional patients with LN metastases. In one patient already diagnosed with LN metastases on routine histology, four additional LN metastases were detected upon extended LN evaluation. Three LNs of two patients, one of them pN0, contained disseminated tumour cells. Compared with conventional histological evaluation, serial-section analysis and immunohistochemistry increased expenses in materials and labour time 18.7-fold. CONCLUSIONS: Serial-section analysis seems to have only a minimal diagnostic gain; however, valid conclusions cannot be drawn, as not all LNs were submitted to extended evaluation. Considering the additional expenses, extensive LN evaluation in prostate cancer cannot generally be recommended.

Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis.

BACKGROUND: Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine. OBJECTIVE: To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives. DESIGN: Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers. DATA SOURCES: Published literature. TARGET POPULATION: All persons with newly diagnosed colorectal cancer and their relatives. TIME HORIZON: Lifetime. PERSPECTIVE: Third-party payer. INTERVENTION: Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery. OUTCOME MEASURES: Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of $36,200 per life-year gained. RESULTS OF SENSITIVITY ANALYSIS: The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of $50,000 per life-year gained. Immunohistochemistry followed by BRAF mutation testing was preferred in 59% of iterations in probabilistic sensitivity analysis at a threshold of $100,000 per life-year gained. Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost $44,000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost $88,700 per incremental life-year gained compared with screening only up to age 70 years. LIMITATION: Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered. CONCLUSION: Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome. PRIMARY FUNDING SOURCE: National Institutes of Health.