Risk factors for postpolypectomy bleeding in patients receiving anticoagulation or antiplatelet medications.

BACKGROUND AND AIMS: Balancing the risks for thromboembolism and postpolypectomy bleeding in patients requiring anticoagulation and antiplatelet agents is challenging. We investigated the incidence and risk factors for postpolypectomy bleeding on anticoagulation, including heparin bridge and other antithrombotic therapy. METHODS: We performed a retrospective cohort and case control study at 2 tertiary-care medical centers from 2004 to 2012. Cases included male patients on antithrombotics with hematochezia after polypectomy. Nonbleeding controls were matched to cases 3 to 1 by antithrombotic type, study site, polypectomy technique, and year of procedure. Our outcomes were the incidence and risk factors for postpolypectomy bleeding. RESULTS: There were 59 cases and 174 matched controls. Postpolypectomy bleeding occurred in 14.9% on bridge anticoagulation. This was significantly higher than the overall incidence of bleeding on antithrombotics at 1.19% (95% confidence interval, 0.91%-1.54%) (59/4923). We identified similarly low rates of bleeding in patients taking warfarin (0.66%), clopidogrel (0.84%), and aspirin (0.92%). Patients who bled tended to have larger polyps (13.9 vs 7.3 mm; P < .001) and more polyps ≥2 cm (41% vs 10%; P < .001). Bleeding risk was increased with restarting antithrombotics within 1 week postpolypectomy (odds ratio [OR] 4.50; P < .001), having polyps ≥2 cm (OR 5.94; P < .001), performing right-sided cautery (OR 2.61; P = .004), and having multiple large polyps (OR 2.92; P = .001). Among patients on warfarin, the presence of bridge anticoagulation was an independent risk factor for postpolypectomy bleeding (OR 12.27; P = .0001). CONCLUSION: We conclude that bridge anticoagulation is associated with a high incidence of postpolypectomy bleeding and is an independent risk factor for hemorrhage compared with patients taking warfarin alone. A higher threshold to use bridge anticoagulation should be considered in patients with an elevated bleeding risk.

Patients With Nonpolypoid (Flat and Depressed) Colorectal Neoplasms at Increased Risk for Advanced Neoplasias, Compared With Patients With Polypoid Neoplasms.

BACKGROUND & AIMS: Nonpolypoid colorectal neoplasms (NP-CRNs) are more likely to contain high-grade dysplasia or early-stage cancer than polypoid neoplasms. We aimed to determine the long-term outcomes of patients with at least 1 NP-CRN. METHODS: We performed a longitudinal cohort study of 4454 patients at a Veterans' Affairs hospital who underwent colonoscopy from 2000 through 2005; 341 were found to have 1 or more NP-CRNs and were matched (3:1) with patients found to have 1 or more polypoid neoplasms (controls, n = 1025). We collected and analyzed data on baseline colonoscopy findings and first follow-up colonoscopy results through August 2014. We calculated the incidence of advanced neoplasia at first follow-up colonoscopy, as defined by the presence of ≥1 tubular or sessile serrated adenomas ≥10 mm in diameter, tubulovillous adenoma, high-grade dysplasia, or invasive cancer. RESULTS: A significantly higher proportion of patients with 1 or more NP-CRNs (16.0%) were found to have advanced neoplasia at their first follow-up colonoscopy than controls (8.6%); the adjusted risk ratio was 1.6 (95% confidence interval, 1.05-2.6; P = .03). A significantly higher proportion of patients with 1 or more NP-CRNs were found to have additional NP-CRNs at the follow-up colonoscopy (17%) than controls (7%; relative risk, 2.3; 95% confidence interval, 1.5-3.5; P < .001). Similar proportions of patients in each group developed cancers after colonoscopy. CONCLUSIONS: In a longitudinal cohort study, we found that patients with NP-CRN were more likely to develop additional NP-CRNs and to have advanced neoplasms at their first follow-up colonoscopy than patients with only polypoid neoplasms. However, patients with NP-CRN were not more likely to develop cancers after colonoscopy when surveillance guidelines were followed. Larger studies are needed to determine risk of colorectal cancer in patients with NP-CRN.

Large Sessile Serrated Polyps Can Be Safely and Effectively Removed by Endoscopic Mucosal Resection.

BACKGROUND & AIMS: As many as 50% of large sessile serrated adenomas/polyps (SSPs) are removed incompletely, which is significant because SSPs have been implicated in the development of interval cancers. It is unclear if endoscopic mucosal resection (EMR) is an optimal method for removal of SSPs. We assessed the efficacy and safety of removal of SSPs 10 mm and larger using a standardized inject-and-cut EMR technique. METHODS: We performed a retrospective analysis of colonoscopy data, collected over 7 years (2007-2013) at 2 centers, from 199 patients with proximal colon SSPs 10 mm and larger (251 polyps) removed by EMR by 4 endoscopists. The primary outcome measure was local recurrence. The secondary outcome measure was safety. RESULTS: At the index colonoscopy, patients had a median of 1 serrated lesion (range, 1-12) and 1 nonserrated neoplastic lesion (range, 0-15). The mean SSP size was 15.9 ± 5.3 mm; most were superficially elevated (84.5%) and located in the ascending colon (51%), and 3 SSPs (1.2%) had dysplasia. Surveillance colonoscopies were performed on 138 patients (69.3%) over a mean follow-up period of 25.5 ± 17.4 months. Of these patients, 5 had local recurrences (3.6%; 95% confidence interval, 0.5%-6.7%), detected after 17.8 ± 15.4 months, with a median size of 4 mm. No patients developed postprocedural bleeding, perforation, or advanced colon cancer, or had a death related to the index colorectal lesion during the study period. CONCLUSIONS: Inject-and-cut EMR is a safe and effective technique for the resection of SSPs. Less than 5% of patients have a local recurrence, which is usually small and can be treated endoscopically.

Intraoperative Optical Biopsy during Robotic Assisted Radical Prostatectomy Using Confocal Endomicroscopy.

PURPOSE: Intraoperative optical biopsy technologies may aid in the identification of important anatomical landmarks and improve surgical outcomes of robotic assisted radical prostatectomy. We evaluate the feasibility of confocal laser endomicroscopy during robotic assisted radical prostatectomy. MATERIALS AND METHODS: A total of 21 patients with biopsy proven prostate cancer scheduled for robotic assisted radical prostatectomy were recruited. After intravenous administration of fluorescein 15 patients underwent in vivo intraoperative confocal laser endomicroscopy of prostatic and periprostatic structures using a 2.6 or 0.85 mm imaging probe. Standard robotic instruments were used to grasp and maneuver the confocal laser endomicroscopy probes for image acquisition. Confocal laser endomicroscopy imaging was performed ex vivo on fresh prostate specimens from 20 patients. Confocal video sequences acquired in vivo and ex vivo were reviewed and analyzed, with additional image processing using a mosaicing algorithm. Processed confocal images were compared with standard hematoxylin and eosin analysis of imaged regions. RESULTS: Confocal laser endomicroscopy was successfully integrated with robotic surgery, including co-registration of confocal video sequences with white light and probe handling with standard robotic instrumentation. Intraoperative confocal laser endomicroscopy imaging of the neurovascular bundle before and after nerve sparing dissection revealed characteristic features including dynamic vascular flow and intact axon fibers. Ex vivo confocal imaging of the prostatic parenchyma demonstrated normal prostate glands, stroma and prostatic carcinoma. CONCLUSIONS: We report the initial feasibility of optical biopsy of prostatic and periprostatic tissue during robotic assisted radical prostatectomy. Image guidance and tissue interrogation using confocal laser endomicroscopy offer a new intraoperative imaging method that has the potential to improve the functional and oncologic outcomes of prostate cancer surgery.

Does Better Specimen Orientation and a Simplified Grading System Promote More Reliable Histologic Interpretation of Serrated Colon Polyps in the Community Practice Setting? Results of a Nationwide Study.

INTRODUCTION: Colonoscopic surveillance guidelines for serrated polyps (SPs) are predicated upon the histologic characteristics of the index polyp. However, discrimination between SP subtypes [hyperplastic polyps vs. sessile serrated adenoma/polyps (SSA/P)] is often unreliable. MATERIALS AND METHODS: We studied the impact of (1) a novel tissue orientation method, performed in the endoscopy laboratory, whereby polyps are flattened in a small paper envelope immediately after resection (modified protocol); and (2) 2012 consensus-modified criteria (CM-2012). These interventions were compared with conventional tissue-handling protocol (CP) and traditional 2008 World Health Organization criteria (WHO). Twenty blinded community pathologists from around the United States scored 100, independent, 0.5 to 2.0 cm, proximal colonic SPs randomly selected from a 2-site tissue section archive. We compared interobserver agreement and diagnostic grading. RESULTS: Interobserver agreement was higher using CM-2012 than WHO criteria (absolute agreement: 13% vs. 4%, P<0.01; 75% agreement: 54% vs. 38%, P<0.01). Interobserver agreement was higher with the modified protocol than with CP (WHO absolute agreement: 6% vs. 2%, P>0.05; WHO 75% agreement: 46% vs. 30%, P>0.05, and CM-2012 absolute agreement: 20% vs. 6%, P=0.07; CM-2012 75% agreement: 66% vs. 42%, P=0.03). Compared with WHO, use of CM-2012 criteria resulted in fewer diagnoses of "indeterminate"; more diagnoses of SSA/P (P<0.01); and "upgraded" the diagnosis from hyperplastic polyps to SSA/P in approximately 7% of cases. These observations were independent of polyp size, patient gender, and study site. CONCLUSIONS: Simple enhancements to postresection SP handling and diagnostic criteria markedly improve interobserver agreement of SP diagnosis among nongastrointestinal community pathologists. This finding, if confirmed, has important implications for SP colonoscopy surveillance guidelines.

Real-time optical diagnosis for diminutive colorectal polyps using narrow-band imaging: the VALID randomised clinical trial.

BACKGROUND: Diminutive (≤ 5 mm) colorectal polyps are common, and overwhelmingly benign. Routinely, after polypectomy, they are examined pathologically to determine the surveillance intervals. Advances in equipment and techniques, such as narrow-band imaging (NBI) colonoscopy, now permit reliable real-time optical diagnosis. METHODS: We conducted a randomised single-masked study involving three institutions to determine whether optical diagnosis of diminutive colorectal polyps meets clinical practice standards and reduces the need for histopathology. We randomly assigned eligible patients undergoing routine high-definition colonoscopy to optical diagnosis using near focus versus standard view, using computer-generated block sequence. By validated criteria, we rendered an optical diagnosis and a confidence level (high vs low) for all polyps, using NBI. Our primary endpoint was the number of accurate high-confidence optical diagnoses compared with central blinded pathology in the two groups. We analysed data using intention to treat. FINDINGS: We enrolled 558 subjects, and randomly assigned 281 to near focus and 277 to standard view optical diagnosis. We detected 1309 predominantly diminutive (74.5%) and neoplastic (60.0%) polyps. Endoscopists were significantly more likely, OR 2.2 (95% CI 1.6 to 3.0, p<0.0001), to make a high-confidence optical diagnosis with near focus (85.1%) than standard (72.6%) view. High-confidence diagnoses had 96.4% and 92.0% negative predictive value, respectively. Of all polyps, 75.3% (95% CI71.3% to 78.9%) had a high-confidence accurate prediction using near focus, compared with 63.1% (95% CI 58.5% to 67.6%) using standard view. Optical versus histopathological diagnosis showed excellent agreement between the surveillance intervals, 93.5% in near focus and 92.2% in standard view. The median diagnosis time was 14 s. CONCLUSIONS: Real-time optical diagnosis using NBI colonoscopy may replace the pathology diagnosis for the majority of diminutive colorectal polyps. Using colonoscopy with near focus view increases the confidence level of the optical diagnosis. Optical diagnosis would be a paradigm shift in clinical practice of colonoscopy for colorectal cancer screening. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01288833.

Endoscopists can sustain high performance for the optical diagnosis of colorectal polyps following standardized and continued training.

BACKGROUND AND STUDY AIMS: The learning curve for optical diagnosis of colorectal polyps with the narrow-band imaging (NBI) is unknown. To forego histological analysis of diminutive polyps diagnosed optically with high confidence, guidelines recommend ≥ 90 % negative predictive value (NPV) and concordance of ≥ 90 % for surveillance intervals predicted optically and histologically. We aimed to study the learning of optical diagnosis for colorectal polyps. PATIENTS AND METHODS: We studied five endoscopists as part of a randomized multisite trial comparing near-focus and standard-focus views for optical diagnosis. They trained using a computer-based module, followed by 10 real-time colonoscopies with pathology correlation. Endoscopists then optically diagnosed and resected all the polyps found during 558 consecutive colonoscopies, and diagnoses were compared with pathology. Endoscopists repeated the training module at the study midpoint. NPV and concordance of surveillance intervals for diminutive polyps diagnosed optically with high confidence were measured over time. RESULTS: Endoscopists showed high diagnostic performance, with a nonsignificant trend toward higher NPV in the second half of the study. For the 445 polyps in the standard-view arm, the NPV was 88.0 % (95 %CI 75.7 % - 95.5 %) in the first half and 95.8 % (88.3 % - 99.1 %) in the second; P = 0.7. Three endoscopists in the first half and four in the second achieved > 90 % NPV. Concordance of surveillance intervals was identical in the first and second halves at 98.1 % (95 %CI 93.3 % - 99.8 %). CONCLUSIONS: High NPV for the prediction of non-neoplasms with NBI was achieved and maintained in this group of endoscopists who participated in standardized and continued training. Both NPV and surveillance interval agreement indicated high performance in the optical diagnosis of colorectal polyps and exceeded thresholds.

Analysis of long-term clinical and cost impact of etranacogene dezaparvovec for the treatment of hemophilia B population in the United States.

INTRODUCTION: Etranacogene dezaparvovec (EDZ), Hemgenix, is a gene therapy recently approved for people with hemophilia B (PwHB). OBJECTIVE: To estimate long-term clinical impact and cost of EDZ in the United States (US). METHODS: A decision-analytic model was developed to evaluate the long-term impact of introducing EDZ for PwHB over a 20-year time horizon. Factor IX (FIX) prophylaxis comparator was a weighted average of different FIX prophylaxis regimens based on US market share data. We compared a scenario in which EDZ is introduced in the US versus a scenario without EDZ. Clinical inputs (annualized FIX-treated bleed rate; adverse event rates) were obtained from HOPE-B phase 3 trial. EDZ durability input was sourced from an analysis predicting long-term FIX activity with EDZ. EDZ one-time price was assumed at $3.5 million. Other medical costs, including FIX prophylaxis, disease monitoring, bleed management, and adverse events were from literature. The model estimated annual and cumulative costs, treated bleeds, and joint procedures over 20 years from EDZ introduction. RESULTS: Approximately 596 PwHB were eligible for EDZ. EDZ uptake was estimated to avert 11,282 bleeds and 64 joint procedures over 20 years. Although adopting EDZ resulted in an annual excess cost over years 1-5 (mean: $53 million annually, total $265 million), annual cost savings were achieved beginning in year 6 (mean: $172 million annually; total $2.58 billion in years 6-20). The total cumulative 20-year cost savings was $2.32 billion, with cumulative cost savings beginning in year 8. CONCLUSION: Introducing EDZ to treat PwHB is expected to result in cost savings and patient benefit over 20 years. Initiating PwHB on EDZ sooner can produce greater and earlier savings and additional bleeds avoided. These results may be a conservative estimate of the full value of EDZ, as PwHB would continue to accrue savings beyond 20 years.

This analysis assessed the long-term clinical and financial impact of introducing EDZ in the United States of America for people with severe or moderately severe hemophilia B. A decision-analytic model was developed comparing a scenario with EDZ and one without EDZ over 20 years. Introducing EDZ would avert 11,292 bleeds and 64 joint procedures over 20 years and would achieve cumulative cost savings in year 8, with a total cumulative 20-year cost saving of $2.32 billion.

Assessing health plan payer's budget impact of etranacogene dezaparvovec for the treatment of hemophilia B in the United States.

BACKGROUND: Etranacogene dezaparvovec is a recently approved gene therapy for people with hemophilia B (PwHB). Current standard of care is prophylaxis with factor IX (FIX) to prevent bleeding. Etranacogene dezaparvovec increases blood FIX levels such that FIX prophylaxis could be eliminated. OBJECTIVE: To estimate the budgetary impact of etranacogene dezaparvovec adoption and utilization in a commercial health plan of the United States. METHODS: A budget impact model was developed to evaluate the introduction of etranacogene dezaparvovec to treat severe or moderately severe hemophilia B. The model considered a hypothetical 1-million-member plan over a 5-year horizon. FIX therapy prophylaxis use was estimated based on a weighted average of relevant brands using US market share data. A scenario of etranacogene dezaparvovec adoption/utilization was compared with one without etranacogene dezaparvovec utilization. Two etranacogene dezaparvovec uptake (market share growth) analyses were performed: one with gradual uptake and alternatively assuming all eligible PwHB received etranacogene dezaparvovec in year 1. The one-time cost of etranacogene dezaparvovec was assumed to be $3.5 million. Other costs (FIX prophylaxis, disease monitoring, bleed management, and adverse events) were estimated from published literature. All costs were in 2022 US dollars. Bleed and adverse event rates were sourced from the HOPE-B trial comparing etranacogene dezaparvovec to previous FIX therapy prophylaxis. The model estimated annual and per-member per-month costs over 5 years. Secondary analyses were performed considering a 10-year horizon. RESULTS: In the 1-million-member health plan, an estimated 1.8 PwHB were eligible for treatment with etranacogene dezaparvovec. Gradual uptake of etranacogene dezaparvovec resulted in cumulative 5-year budget impact of $848,509 compared with a scenario without etranacogene dezaparvovec. In years 1-5, the incremental annual and per-member per-month costs ranged from $79,824 to $271,435 and from $0.007 to $0.023, respectively. In the alternative uptake analysis, etranacogene dezaparvovec became cost saving annually beginning in year 2 and cumulatively beginning in year 5, for a 5-year savings of $754,844. Secondary analyses over 10 years found both uptake analyses cost saving. Other scenarios considered did not affect results substantially. CONCLUSIONS: Introducing etranacogene dezaparvovec as treatment for PwHB would have a modest budget increase within 5 years after treatment but may become cost saving if all eligible PwHB were treated in year 1. Initiating PwHB on etranacogene dezaparvovec sooner may produce greater overall savings and earlier annual savings. Etranacogene dezaparvovec is a treatment option that may provide overall cost savings for US commercial health plans, which would increase as the plan size increases.

A simple tissue-handling technique performed in the endoscopy suite improves histologic section quality and diagnostic accuracy for serrated polyps.

BACKGROUND AND STUDY AIMS: Surveillance intervals after colonoscopic resection of serrated polyps are partially predicated on the histology of the polyp(s) removed during the index exam. Histologic discrimination between sessile serrated adenomas/polyps (SSA/P) and hyperplastic polyps is challenging. We devised and tested a simple tool--an envelope--that gastroenterologists can integrate into routine colonoscopy practice to address this problem. METHODS: In the "modified protocol," immediately after polypectomy each serrated polyp was flattened and enclosed in a paper envelope before being placed in formalin. In the pathology laboratory, each polyp was sectioned after processing. A two-site, prospective, randomized, single-blinded trial was performed to compare this modified protocol with the conventional protocol. Serrated polyps located proximal to the splenic flexure and 5-20 mm in diameter were included. A novel orientation score that measured the number of well-oriented crypts per unit area of polyp (higher orientation score = better orientation) was validated. Orientation score, SSA/P diagnosis rate, and inter-pathologist agreement were measured. RESULTS: A total of 375 polyps were enrolled, of which 264 were identified for analysis. The mean orientation scores in the modified and conventional protocol groups were 3.11 and 1.13, respectively (P < 0.0001). SSA/Ps were diagnosed in 103/135 cases (76.3%) in the modified protocol group vs. 54/129 (41.9%) in the conventional protocol group (P < 0.0001). Inter-pathologist agreement was higher with the modified than the conventional protocol (77.0% vs. 62.8%; P = 0.015). CONCLUSION: Standard polyp handling techniques may be sub-optimal for interpretation of serrated polyps resected at colonoscopy, and may lead to inadvertent histologic "under-grading" of many lesions. Our intervention improved histopathologic interpretation and increased the SSA/P diagnosis rate.

Pathologic predictive factors for lymph node metastasis in submucosal invasive (T1) colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Colorectal adenocarcinoma with depth of invasion ≤1,000 µm from the muscularis mucosa and favorable histology is now considered for local resection. We aimed to examine the strength of evidence for this emerging practice. METHODS: We searched Medline, Scopus, and Cochrane (1950-2011), then performed a meta-analysis on the risk of lymph node metastasis in nonpedunculated (sessile and nonpolypoid) T1 colorectal cancers. We included studies with nonpedunculated lesions, actual invasion depth, and pathologic factors of interest. Synchronous, polyposis or secondary cancers, and chemoradiation studies were excluded. Our primary outcome was the risk of LNM. We analyzed using Review Manager; we estimated heterogeneity using Cochran Q χ(2) test and I (2). We generated summary risk ratios using a random effects model, performed sensitivity analyses, and evaluated the quality of evidence using GRADEPro. RESULTS: We identified 209 articles; 5 studies (n = 1213 patients) met the inclusion criteria. The risk of LNM in nonpedunculated ≤1,000 µm is 1.9 % (95 % confidence interval 0.5-4.8 %). The risk for all T1 is 13 % (95 % confidence interval 11.5-15.4 %). Characteristics protective against LNM were ≤1,000 µm invasion, well differentiation, absence of lymphatic and vascular invasion, and absence of tumor budding. We did not detect significant study heterogeneity. The quality of evidence was poor. CONCLUSIONS: Well-differentiated nonpedunculated T1 colorectal cancer invasive into the submucosa ≤1,000 µm, without lymphovascular involvement or tumor budding, has the lowest risk of nodal metastasis. Importantly, the risk was not zero (1.9 %), and the qualitative formal analysis of data was not strong. As such, endoscopic resection alone may be adequate in select patients with submucosal invasive colorectal cancers, but more studies are needed. Overall, the quality of evidence was poor; data were from small retrospective studies from limited geographic regions.

Specificity of brachyury in the distinction of chordoma from clear cell renal cell carcinoma and germ cell tumors: a study of 305 cases.

Brachyury is recognized as a specific marker for notochord-derived tissues and neoplasms, and has become a defining immunohistochemical feature of chordoma. The main differential diagnostic consideration for chordoma is chondrosarcoma, which is known to lack brachyury expression. However, within the spectrum of genitourinary neoplasia, metastatic germ cell tumors and clear cell renal cell carcinoma may also be close morphological mimics of chordoma, particularly given the increasing prevalence of small tissue samples from image-guided biopsies. Although immunoreactivity for brachyury has been reported in a few germ cell tumors, a thorough characterization of staining by specific subtype has not been performed in a large series. Additionally, brachyury expression in clear cell renal cell carcinoma has not been well studied. In this study, immunohistochemical expression with the brachyury antibody was evaluated in 111 germ cell tumors, 30 non-neoplastic and neoplastic (non-germ cell) testicular tissues, and 184 metastatic clear cell renal cell carcinomas using tissue microarray technology. In addition, immunoreactivity for PAX-8 and SALL-4 was evaluated in 12 chordomas on whole section. No nuclear brachyury expression was identified in any of the 101 germ cell tumors within the tissue microarray (including choriocarcinoma (1), embryonal carcinoma (20), intratubular germ cell neoplasia unclassified (2), seminoma (64), spermatocytic seminoma (1), teratoma (5) and yolk sac tumor (8)), in any of the 30 non-neoplastic and neoplastic (non-germ cell) testicular tissues, or in any of the 10 whole-section seminomas. All 184 metastatic clear cell renal cell carcinomas were also non-reactive for brachyury. All 12 chordomas showed strong nuclear immunoreactivity for brachyury, but no expression of SALL-4. In all, 1 of 12 chordoma cases showed patchy, 1+ nuclear immunoreactivity for PAX-8. This study confirms the specificity of brachyury for chordoma in the differential diagnostic distinction from the potential genitourinary mimics, germ cell tumors and metastatic clear cell renal cell carcinoma.

Immunohistochemical comparison of MUC1, CA125, and Her2Neu in invasive micropapillary carcinoma of the urinary tract and typical invasive urothelial carcinoma with retraction artifact.

On the basis of recent clinical studies, some urologic oncologists do not offer bladder-sparing therapy for patients diagnosed with micropapillary carcinoma of the urinary bladder, even in the setting superficially invasive disease. Unfortunately, the distinction of invasive micropapillary carcinoma from typical invasive urothelial carcinoma with prominent retraction artifact may be difficult in some cases. In this study, we compared the immunophenotype of invasive micropapillary carcinoma to invasive urothelial carcinoma with retraction artifact using antibodies previously reported as specific for micropapillary carcinoma. Immunohistochemical staining was performed on 24 invasive micropapillary carcinomas of the urinary tract and 24 case controls of invasive urothelial carcinoma with retraction artifact using monoclonal antibodies MUC1, CA125, and Her2Neu. The staining extent and intensity for MUC1 and CA125 were scored on one representative section per case. Immunostaining for Her2Neu was scored based on the 2007 CAP/ASCO guidelines for breast carcinoma. Basal ('reverse-apical') MUC1 staining was identified in 23 of the 24 (96%) invasive micropapillary carcinomas and in 15 of the 24 (63%) invasive urothelial carcinomas with retraction artifact (P=0.0102). Membranous reactivity with CA125 was seen in 8 of the 24 (33%) invasive micropapillary carcinomas and in 3 of the 24 (13%) invasive urothelial carcinomas with retraction artifact (P=0.1681). Positive (3+) membranous Her2Neu staining was present in 6 of 24 (25%) invasive micropapillary carcinomas and in 2 of the 24 (8%) invasive urothelial carcinomas with retraction artifact (P=0.2448). The specificity for invasive micropapillary carcinoma vs invasive urothelial carcinoma with retraction artifact using antibodies MUC1, CA125, and Her2Neu was 37, 87, and 92%, respectively. Invasive micropapillary carcinoma more commonly showed immunoreactivity for MUC1, CA125, and Her2Neu compared to invasive urothelial carcinoma with retraction artifact, but only MUC1 reached statistical significance. The lack of specificity of these evaluated markers for invasive micropapillary carcinoma limits their utility in the distinction from invasive urothelial carcinoma with retraction artifact, especially given the potentially significant therapeutic implications.

Adenomatoid tumors of the female and male genital tracts: a clinicopathological and immunohistochemical study of 44 cases.

Adenomatoid tumors of the female and male genital tracts are well characterized as mesothelial in origin, but a detailed histological and immunohistochemical analysis comparing both traditional and newer mesothelial markers across gender and site has not been formally conducted. A variety of morphologic features previously described as characteristic of adenomatoid tumors were evaluated in 44 adenomatoid tumors from the male and female genital tracts. Immunohistochemical analysis with pankeratin (AE1/CAM5.2), WT-1, calretinin, CK5/6, D2-40, and caldesmon was also performed. The extent and intensity of staining were scored semiquantitatively on one representative section per case and mean value for each parameter was calculated. All (n=44) the adenomatoid tumors from both the female and male genital tracts demonstrated a distinctive thread-like bridging strand pattern. Lymphoid aggregates were seen in all 12 adenomatoid tumors of male patients, but in only 4 of 32 (13%) tumors in female patients (P<0.0001). The remaining morphologic features were variably present with no clear sex predilection. Pankeratin, calretinin, and D2-40 reactivity were identified in all female (n=32) and male (n=12) genital tract adenomatoid tumors. Adenomatoid tumors expressed WT-1 in 11/12 (92%) male patients and in 31/32 (97%) female patients. In male patients, reactivity for CK5/6 and caldesmon was found in 1/12 (8%) and 0/12 (0%) adenomatoid tumors (respectively), whereas reactivity in female patients was found in 5/32 (16%) and 1/32 (3%); respectively. Female tumors differ from their male counterparts by the frequent absence of lymphoid aggregates and the presence of a circumscribed margin when occurring in the fallopian tube. Of the putative mesothelial markers evaluated, calretinin, D2-40, and WT-1 show a similar immunoprofile and have a higher sensitivity than CK5/6 and caldesmon in genital tract adenomatoid tumors. However, the presence of additional, often strong expression of WT-1 in normal tissues of the female genital tract limits the utility of WT-1 in this setting.

A phase II study of gefitinib, 5-fluorouracil, leucovorin, and oxaliplatin in previously untreated patients with metastatic colorectal cancer.

PURPOSE: We investigated the gefitinib, 5-fluorouracil (5-FU), leucovorin and oxaliplatin (IFOX) regimen as first-line therapy in patients with metastatic colorectal cancer. EXPERIMENTAL DESIGN: Eligible patients had stage IV colorectal adenocarcinoma, and had not received prior chemotherapy for metastatic disease. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin, leucovorin, and 5-FU (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg orally daily throughout the 14-day cycle. RESULTS: Forty-five patients were enrolled and were assessable for toxicity. Forty-three patients were assessable for response. Thirty-one of the 43 patients (72%) had either a complete or partial response by the Response Evaluation Criteria in Solid Tumors. Median overall survival was 20.5 months. Median time to progression was 9.3 months. Commonly encountered grade 3 or 4 toxicities included diarrhea in 67% of patients and neutropenia in 60%. Grade 2 acneiform skin rash typical of gefitinib occurred in 60% of patients. CONCLUSIONS: IFOX is an active first-line regimen in patients with metastatic colorectal adenocarcinoma, showing higher response rates but also increased toxicities compared with FOLFOX-4 alone in a similar patient population.

Is lymphadenectomy indicated in patients with T1 moderately differentiated penile cancer?

OBJECTIVE: In patients with penile squamous cell carcinomas (SCCs), lymphadenectomy can be curative and should be considered in cases deemed high risk for metastatic spread to regional lymph nodes. Management of patients without palpable lymphadenopathy remains controversial. Current guidelines for T1 penile SCCs based on previous studies have suggested that moderately differentiated tumors are at low risk for metastatic disease; however given our experience with such patients we sought to examine whether such tumors were truly observable or should be treated more aggressively. MATERIALS AND METHODS: A retrospective chart review of penile cancer cases at three institutions was performed. All slides of patients diagnosed with T1 lesions were rereviewed by our reference pathologists to confirm the original diagnosis and stage. These patients were also reviewed regarding lymphadenectomy results and clinical outcomes. RESULTS: Between 1988 and 2004, a total of 34 cases of SCC of the penis were identified, of which 10 were stage T1. Of these 10 cases, seven had moderately differentiated carcinoma without vascular invasion on pathological evaluation. Metastatic disease was present in one patient at the time of diagnosis and subsequently developed in three of the remaining six patients during follow up. Thus a total of 4 (57%) of the patients developed metastatic disease. CONCLUSIONS: Current management protocols place moderately differentiated T1 penile squamous carcinoma without vascular invasion in a low risk category for metastatic disease. As such, expectant management is currently offered as a primary option for these patients. Our experience suggests that patients in this category are in fact at higher risk for metastatic disease, and may be offered early groin dissection in place of expectant management.

Real-time microfluidic system for studying mammalian cells in 3D microenvironments.

We describe a microfluidic system that can control, in real time, the microenvironments of mammalian cells in naturally derived 3D extracellular matrix (ECM). This chip combines pneumatically actuated valves with an individually addressable array of 3D cell-laden ECM; actuation of valves determines the pathways for delivering reagents through the chip and for exchanging diffusible factors between cell chambers. To promote rapid perfusion of reagents through 3D gels (with complete exchange of reagents within the gel in seconds), we created conduits above the gels for fluid flow, and microposts to stabilize the gels under high perfusion rates. As a biological demonstration, we studied spatially segregated mouse embryonic stem cells and mouse embryonic fibroblasts embedded in 3D Matrigel over days of culture. Overall, this system may be useful for high-throughput screening, single-cell analysis and studies of cell-cell communication, where rapid control of 3D cellular microenvironments is desired.

New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients.

BACKGROUND: Current practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer patients with tumor-involved sentinel lymph nodes (SLNs), although fewer than half will have non-sentinel node (NSLN) metastasis. Our goal was to develop new models to quantify the risk of NSLN metastasis in SLN-positive patients and to compare predictive capabilities to another widely used model. METHODS: We constructed three models to predict NSLN status: recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted Classification and Regression Trees (CART), and multivariate logistic regression (MLR) informed by CART. Data were compiled from a multicenter Northern California and Oregon database of 784 patients who prospectively underwent SLN biopsy and completion ALND. We compared the predictive abilities of our best model and the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram) in our dataset and an independent dataset from Northwestern University. RESULTS: 285 patients had positive SLNs, of which 213 had known angiolymphatic invasion status and 171 had complete pathologic data including hormone receptor status. 264 (93%) patients had limited SLN disease (micrometastasis, 70%, or isolated tumor cells, 23%). 101 (35%) of all SLN-positive patients had tumor-involved NSLNs. Three variables (tumor size, angiolymphatic invasion, and SLN metastasis size) predicted risk in all our models. RP-ROC and boosted CART stratified patients into four risk levels. MLR informed by CART was most accurate. Using two composite predictors calculated from three variables, MLR informed by CART was more accurate than the Nomogram computed using eight predictors. In our dataset, area under ROC curve (AUC) was 0.83/0.85 for MLR (n = 213/n = 171) and 0.77 for Nomogram (n = 171). When applied to an independent dataset (n = 77), AUC was 0.74 for our model and 0.62 for Nomogram. The composite predictors in our model were the product of angiolymphatic invasion and size of SLN metastasis, and the product of tumor size and square of SLN metastasis size. CONCLUSION: We present a new model developed from a community-based SLN database that uses only three rather than eight variables to achieve higher accuracy than the Nomogram for predicting NSLN status in two different datasets.