Validation and real-world clinical application of an artificial intelligence algorithm for breast cancer detection in biopsies.

Breast cancer is the most common malignant disease worldwide, with over 2.26 million new cases in 2020. Its diagnosis is determined by a histological review of breast biopsy specimens, which can be labor-intensive, subjective, and error-prone. Artificial Intelligence (AI)-based tools can support cancer detection and classification in breast biopsies ensuring rapid, accurate, and objective diagnosis. We present here the development, external clinical validation, and deployment in routine use of an AI-based quality control solution for breast biopsy review. The underlying AI algorithm is trained to identify 51 different types of clinical and morphological features, and it achieves very high accuracy in a large, multi-site validation study. Specifically, the area under the receiver operating characteristic curves (AUC) for the detection of invasive carcinoma and of ductal carcinoma in situ (DCIS) are 0.99 (specificity and sensitivity of 93.57 and 95.51%, respectively) and 0.98 (specificity and sensitivity of 93.79 and 93.20% respectively), respectively. The AI algorithm differentiates well between subtypes of invasive and different grades of in situ carcinomas with an AUC of 0.97 for invasive ductal carcinoma (IDC) vs. invasive lobular carcinoma (ILC) and AUC of 0.92 for DCIS high grade vs. low grade/atypical ductal hyperplasia, respectively, as well as accurately identifies stromal tumor-infiltrating lymphocytes (TILs) with an AUC of 0.965. Deployment of this AI solution as a real-time quality control solution in clinical routine leads to the identification of cancers initially missed by the reviewing pathologist, demonstrating both clinical utility and accuracy in real-world clinical application.

[PERSONALIZED MEDICINE IN ONCOLOGY REQUIRES TEAMWORK BETWEEN MEDICAL ONCOLOGISTS AND MOLECULAR PATHOLOGISTS].

INTRODUCTION: The systemic anti-cancer approach is based on medical/pharmaceutical interventions affecting cancer cells at multiple sites, including local and distant regions. Interventions include: cytotoxic chemotherapy agents used for direct extermination of proliferating cells, hormonal interventions altering the tumor environment and affecting its ability to survive and thrive, biological drugs restoring the function defective proteins in mutated tumors, and immunological medications encouraging effective immune recognition of tumor cells and associated immune response. "Personalized medicine in oncology" aims to make anti-cancer treatment more effective and with less side effects. Potential candidates are identified both clinically per indication for therapy and ability to tolerate it, and pathologically-molecularly assessing unique biological changes in the tumor cells and/or their immediate environment. Safe and effective treatment directed to the dominant biological changes is essential as well. The biological changes in the tumor and/or its immediate environment are referred to as "bio-markers", and point to pathological changes accumulated in the tissue during the malignant transformation and tumor progression. The relevant tests for biomarker assessment are performed at the protein level or on genetic material (DNA or RNA); they require high levels of accuracy and reliability and short turnover time for results. Communication between teams assessing the molecular results and a general pathologist may facilitate high quality assessment. Laboratory tests with accurate assessment of biomarkers in over 500 genes are available in the pathology laboratories in Israel since 2020.

Biplanar Lipoabdominoplasty: Introducing the Subscarpal Lipo Aponeurotic System.

Preservation of Scarpa's fascia in abdominoplasty has been previously presented. Herein we introduce the subscarpal lipo aponeurotic system (SLAS) and the technique of preserving the SLAS and its tightening in lipoabdominoplasty. METHODS: A retrospective cohort study of patients who underwent lipoabdominoplasty performed by a single plastic surgeon (YW) between 2014 and 2019 was conducted. We compared postoperative complications, aesthetic outcomes, and procedure lengths between standard and biplanar lipoabdominoplasty with SLAS tightening. Supra-scarpal fat and SLAS tissue specimens were obtained for histological analysis. RESULTS: In total, 179 patients underwent biplanar lipoabdominoplasty with SLAS tightening and were compared with a control group of 65 patients who underwent standard lipoabdominoplasty. Fifty-four patients (29.9%) underwent concomitant umbilical, epigastric, or postoperative ventral hernia (POVH) repair. No major complications were encountered other than one skin necrosis in a standard lipoabdominoplasty. Moderate complication rate was 10.05% in the biplanar group, compared with 16.92% in the standard lipoabdominoplasty. The average length of the procedure and overall aesthetic results were equivalent. CONCLUSIONS: The SLAS can be individually dissected and used during abdominoplasty. No statistically significant differences were found in complication rates, length of procedure, or aesthetic outcomes between standard and biplanar lipoabdominoplasty with SLAS tightening. Further investigation is needed. Nonetheless, we postulate that patients who would benefit the most from this procedure are those with weakening of the abdominal wall, and with some fullness of the hip line, as this technique adds reinforcement to the lower abdomen and "pulls in" the flanks.

HPV Screening Test for the Detection of Precancerous Cervical Lesions and Cervical Cancer in Israeli Women.

OBJECTIVES: This work is aimed to summarize the first year of the high-risk human papillomavirus (hrHPV) screening test and compare it to the cytology screening test, regarding positivity rates and premalignant lesions diagnosed in the Israeli population. A specific consideration is for the age group 25-30 that is not considered mandatory for the HPV primary screening testing. METHODS: A retrospective study was performed in women who were screened for prevention of cervical cancer in Maccabi HealthCare HMO from March 2017 to March 2019. Screening methods included hrHPV typing for types 16, 18, and the other 12 hrHPV types and the PAP LBC test. RESULTS: A total of 115,807 cervical samples were tested for HPV presence and 91% (105,225) were found negative for hrHPV. The other 9% (10,582) were positive for one or more of the 14 hrHPV types tested, and 37% (3,916) of them showed abnormal PAP LBC results. In the age group of 25-30, 3,104 (17.5%) women were found positive for hr-HPV (825 had hrHPV types 16 and/or 18), of which 42% (1,293) of them showed abnormal PAP LBC results. During the hrHPV versus PAP LBC screening era, 258 more women were diagnosed with precancerous cervical lesions (CIN2/3), 70% increased detection versus cytology screening. CONCLUSIONS: The hrHPV screening test is currently the best method for the detection of precancerous cervical lesions and cervical cancer, and it is better started at age 25.

An artificial intelligence algorithm for prostate cancer diagnosis in whole slide images of core needle biopsies: a blinded clinical validation and deployment study.

BACKGROUND: There is high demand to develop computer-assisted diagnostic tools to evaluate prostate core needle biopsies (CNBs), but little clinical validation and a lack of clinical deployment of such tools. We report here on a blinded clinical validation study and deployment of an artificial intelligence (AI)-based algorithm in a pathology laboratory for routine clinical use to aid prostate diagnosis. METHODS: An AI-based algorithm was developed using haematoxylin and eosin (H&E)-stained slides of prostate CNBs digitised with a Philips scanner, which were divided into training (1 357 480 image patches from 549 H&E-stained slides) and internal test (2501 H&E-stained slides) datasets. The algorithm provided slide-level scores for probability of cancer, Gleason score 7-10 (vs Gleason score 6 or atypical small acinar proliferation [ASAP]), Gleason pattern 5, and perineural invasion and calculation of cancer percentage present in CNB material. The algorithm was subsequently validated on an external dataset of 100 consecutive cases (1627 H&E-stained slides) digitised on an Aperio AT2 scanner. In addition, the AI tool was implemented in a pathology laboratory within routine clinical workflow as a second read system to review all prostate CNBs. Algorithm performance was assessed with area under the receiver operating characteristic curve (AUC), specificity, and sensitivity, as well as Pearson's correlation coefficient (Pearson's r) for cancer percentage. FINDINGS: The algorithm achieved an AUC of 0·997 (95% CI 0·995 to 0·998) for cancer detection in the internal test set and 0·991 (0·979 to 1·00) in the external validation set. The AUC for distinguishing between a low-grade (Gleason score 6 or ASAP) and high-grade (Gleason score 7-10) cancer diagnosis was 0·941 (0·905 to 0·977) and the AUC for detecting Gleason pattern 5 was 0·971 (0·943 to 0·998) in the external validation set. Cancer percentage calculated by pathologists and the algorithm showed good agreement (r=0·882, 95% CI 0·834 to 0·915; p<0·0001) with a mean bias of -4·14% (-6·36 to -1·91). The algorithm achieved an AUC of 0·957 (0·930 to 0·985) for perineural invasion. In routine practice, the algorithm was used to assess 11 429 H&E-stained slides pertaining to 941 cases leading to 90 Gleason score 7-10 alerts and 560 cancer alerts. 51 (9%) cancer alerts led to additional cuts or stains being ordered, two (4%) of which led to a third opinion request. We report on the first case of missed cancer that was detected by the algorithm. INTERPRETATION: This study reports the successful development, external clinical validation, and deployment in clinical practice of an AI-based algorithm to accurately detect, grade, and evaluate clinically relevant findings in digitised slides of prostate CNBs. FUNDING: Ibex Medical Analytics.

Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression.

Fusobacterium nucleatum is an oral anaerobe recently found to be prevalent in human colorectal cancer (CRC) where it is associated with poor treatment outcome. In mice, hematogenous F. nucleatum can colonize CRC tissue using its lectin Fap2, which attaches to tumor-displayed Gal-GalNAc. Here, we show that Gal-GalNAc levels increase as human breast cancer progresses, and that occurrence of F. nucleatum gDNA in breast cancer samples correlates with high Gal-GalNAc levels. We demonstrate Fap2-dependent binding of the bacterium to breast cancer samples, which is inhibited by GalNAc. Intravascularly inoculated Fap2-expressing F. nucleatum ATCC 23726 specifically colonize mice mammary tumors, whereas Fap2-deficient bacteria are impaired in tumor colonization. Inoculation with F. nucleatum suppresses accumulation of tumor infiltrating T cells and promotes tumor growth and metastatic progression, the latter two of which can be counteracted by antibiotic treatment. Thus, targeting F. nucleatum or Fap2 might be beneficial during treatment of breast cancer.

Re-Examining Distal Resection in Colon Cancer.

BACKGROUND: In colon cancer, data regarding proximal and distal metastasis to lymph nodes remains scarce. OBJECTIVES: To evaluate lymph node distribution along the longitudinal axis of the colon as related to a tumor to re-examine the common practice of 5 cm proximal and 2 cm distal resection margins. METHODS: We studied 106 patients (53 males and 53 females, mean age 67.9 ± 10 years) who had undergone left hemicolectomy or sigmoidectomy. Colonic cancer specimens were divided into five zones proximally and distally to the tumor. For each zone, overall lymph node evaluation and ratio was performed. RESULTS: The mean number of retrieved lymph nodes per patient was 24.3 ± 12, with 54.9% of the nodes concentrated in zone I, 22.1% in zone II, 9.5% in zone III, 10.3% in zone IV, and 3% in zone V. While most positive nodes were found in zone I, significant numbers were also detected in both directions proximally and distally to the tumor. CONCLUSIONS: It seems that longer colonic segments proximally, and especially distally, should be considered for resection to significantly reduce the chances of finding involved lymph node.

Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2',2'-difluorodeoxycytidine) into its inactive form, 2',2'-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.

Mapping breast tissue types by miniature radio-frequency near-field spectroscopy sensor in ex-vivo freshly excised specimens.

BACKGROUND: Receiving real-time information on tissue properties while performing biopsy procedures has the potential of improving biopsy accuracy. The study goal was to test the ability of a miniature flexible Radio-Frequency (RF) sensor (Dune Medical Devices), designed to be mounted on the surface of surgical tools, in measuring and mapping the various breast tissue types and abnormalities in terms of electrical properties. METHODS: Between January and October 2012, 102 patients undergoing lumpectomy, open-biopsy or mastectomy, in 3 medical centers, were enrolled in this study. The device was applied to freshly excised specimens, with registration between device measurements and histology analysis. Based on histology, the dielectric properties of the various tissue types were derived. Additionally, the ability of the device to differentiate between malignant and non-malignant tissue was assessed. RESULTS: A total of 4322 measurements from 106 specimens from 102 patients were analyzed. The dielectric properties of 10 tissue types in the low RF-frequency range were measured, showing distinct differences between the various types. Based on the dielectric properties, a score variable was derived, which showed a correlation of 90 % between the RF measurements and the tissue types. Differentiation ability between tissue types was characterized using ROC curve analysis, with AUC of 0.96, and sensitivity and specificity of 90 and 91 % respectively, for tissue feature sizes at or above 0.8 mm. CONCLUSIONS: Using a radio-frequency near-field spectroscopy miniature flexible sensor the dielectric properties of multiple breast tissue types, both normal and abnormal, were evaluated. The results show promise in differentiating between various breast tissue types, and specifically for differentiation between cancer and normal tissues.

A Harmonization Study for the Use of 22C3 PD-L1 Immunohistochemical Staining on Ventana's Platform.

INTRODUCTION: Immunotherapy is a novel treatment for lung cancer. Pembrolizumab (Merck Sharp and Dohme, Kenilworth, NJ) is a monoclonal antibody against programmed cell death 1 that has been approved for use with NSCLC together with a companion diagnostic by Dako (Carpinteria, CA). Ventana's BenchMark XT (Ventana Medical Systems, Tucson, AZ) is a widely used immunohistochemical (IHC) platform. However, data on its reliability and reproducibility with the 22C3 antibody are scant. METHODS: We performed a comprehensive calibration of 22C3 programmed cell death ligand 1 (PD-L1) staining on the BenchMark XT platform using Dako's prediluted 22C3 anti-PD-L1 primary antibody with two of Ventana's detection systems. Forty-one random cases of NSCLC were then independently evaluated by two pathologists. Each case was scored using Dako- or Ventana-stained slides. The scores obtained with the two 22C3 Ventana assays were compared with those obtained using the Dako 22C3 IHC platform. RESULTS: The Dako IHC platform stratified eight, seven, and 26 cases as being strongly positive, weakly positive, and negative for PD-L1, respectively, whereas 36 of 41 cases (87.8%) had the same results with Ventana's UltraView 22C3 protocol (Pearson's correlation score 0.91, p < 0.0001). Moreover, 35 of 41 cases (85.3%) had the same results with Ventana's OptiView 22C3 protocol (Pearson's correlation score 0.89, p < 0.0001). CONCLUSIONS: The results of this study demonstrate that the same PD-L1 IHC algorithm can be reliably applied to Ventana's BenchMark XT platform. Furthermore, we were able to detect all of the strongly positive cases with high interobserver and intraobserver agreement by using the Ventana platform. These findings suggest that the Ventana platform can be used to stratify patients for pembrolizumab-based immunotherapy.

Geriatric nutritional risk index, muscle function, quality of life and clinical outcome in hemodialysis patients.

BACKGROUND & AIMS: The geriatric nutritional risk index (GNRI) has been reported as a useful predictor of prognosis in maintenance hemodialysis (MHD) patients, demonstrating GNRI less than 90 as a marker of a poorer nutritional status and significantly increased mortality. We tested whether GNRI as a whole associated stronger with clinical and laboratory surrogates of nutrition and inflammation, muscle function, health-related quality of life (QoL), and predicts all-cause and cardiovascular (CV) morbidity and mortality in this population better than its individual components (albumin and body weight to ideal body weight ratio). METHODS: A prospective observational study with a median follow-up of 30 months (interquartile range - 19-41 months) was performed on 352 MHD outpatients (38.0% women) with a mean age of 67.4 ± 13.2 years. All-cause and cardiovascular hospitalization and mortality, GNRI, handgrip strength (HGS), body composition parameters (anthropometry and bioimpedance) and short form 36 (SF-36) quality-of-life scores were measured. Multivariate linear regression analyses were performed to obtain adjusted correlations. Receiver operating characteristic (ROC) curves were generated and multivariate Cox proportional hazards models were applied to identify the predictive value of GNRI and its components separately. RESULTS: GNRI positively correlated with total score (r = 0.15, P < 0.05), the physical health dimension (r = 0.14, P < 0.05), the general health (r = 0.18, P < 0.01) and some other scales of the SF-36. A significant correlation of GNRI with HGS in male patients didn't stand up to multivariable adjustments. For each one unit increase in baseline GNRI levels, the first hospitalization hazard ratio (HR) after adjustments for confounders was 0.98 (95% confidence interval (CI), 0.97 to 0.99) and the first CV event HR was 0.98 (95% CI, 0.97 to 0.99); all-cause death HR was 0.97 (95% CI, 0.96 to 0.99) and CV death HR was 0.97 (95% CI, 0.95-0.99). Albumin was related to QoL and clinical outcomes with higher strength and magnitude than GNRI. CONCLUSIONS: Despite the significant relationship with clinical outcomes and QOL, GNRI is not better and is even slightly worse than albumin's performance. This raises doubts as to the clinical utility of GNRI as a prognostic tool in the MHD population.

An intraoperative MRI system for margin assessment in breast conserving surgery: Initial results from a novel technique.

BACKGROUND AND OBJECTIVES: One of the major unmet needs in Breast Conserving Surgery (BCS) is a rapid and accurate margin assessment of the lumpectomy specimen. This study evaluates the ability of a novel MRI system (prototype of the ClearSight™ system; Clear-Cut Medical Ltd., Rehovot, Israel) to distinguish malignant and non-malignant tissues in freshly excised breast specimen by comparing MR measurements to histopathology results. METHODS: Seventy-seven samples were obtained from 22 patients undergoing BCS enrolled in the study. A T2* (T2 Star) value in milliseconds (ms) was calculated for each sample and correlated with histopathology results. RESULTS: Of the 77 samples, 35 samples were classified by histopathology as malignant and 42 as non-malignant. T2* values were significantly higher in malignant samples compared to non-malignant samples (15.3 ± 2.72 ms and 10.6 ± 1.47 ms, respectively [P < 0.00001]). Analysis for a determined cutoff of 11.7 ms revealed 91% sensitivity, 93% specificity, and 92% accuracy. ROC curve analysis yielded AUC of 0.97. CONCLUSIONS: This study demonstrates that the system is sensitive and specific in differentiating malignant and non-malignant tissues in freshly excised breast specimen. The system has the potential to be used for breast specimen margin assessment during BCS, with the goal of decreasing the need for re-operation. J. Surg. Oncol. 2016;114:22-26. © 2016 Wiley Periodicals, Inc.

Exposure to Hyperbaric Oxygen Intensified Vancomycin-Induced Nephrotoxicity in Rats.

It has been suggested that oxidative stress is a potential mechanism for vancomycin-induced nephrotoxicity and hyperbaric oxygen therapy (HBO) has been shown to be effective in treating renal toxicity that has been pharmacologically induced in animal models. The aim of this study was to investigate the effect of HBO therapy on vancomycin-induced nephrotoxicity in rats. The study group comprised 36 Sprague Dawley male rats. We treated 30 with 500 mg/kg of intraperitoneal vancomycin once a day for 7 days. Half of these rats received a daily 1-hour treatment with HBO at 2 Atmospheres (ATM) on the same 7 days and formed the HBO+ group. The other 15 subjects received no HBO treatment (HBO- group). The remaining six rats served as the control group, three received HBO treatments alone and no treatment was administered to the other three rats. Laboratory results were obtained on day 8 and the intervention and control groups were compared. Rats in the HBO+ group gained less weight than the HBO- group (11.6 grams vs 22.6 grams; P = 0,008) and had significantly higher serum blood urea nitrogen (99.6 vs 52.6 mg/dL; P<0.001), serum creatinine (0.42 vs 0.16 mg/dL; P = 0.001) and magnesium (3.6 vs 3.1 mg/dL; P = 0.014). The vancomycin blood levels were also higher in the HBO+ group (27.8 vs 6.7 µg/mL; P = 0.078). There were no pathological kidney changes in the control group. All the kidneys from the treated groups (vancomycin +HBO and vancomycin HBO-) showed moderate to severe histopathological changes with no statistical significance between them. This study demonstrated that exposure to hyperbaric oxygen intensified vancomycin-induced nephrotoxicity in rats.

Is there an association between invasive lobular carcinoma of the breast and a family history of gastric cancer?

CDH1 gene mutations have been found to be associated with diffuse type gastric cancer and invasive lobular carcinoma (ILC) of the breast. To the best of our knowledge, this is the only study relating a family history of gastric cancer to ILC of the breast. We conducted a retrospective study comparing the family history of malignancies in patients with invasive ductal carcinoma (IDC) of the breast and ILC treated in our Medical Center. The comparison was evaluated in both types of breast cancer groups, dividing the patients into two age groups, <50 and ≥50 years. One thousand one hundred and sixty-seven patients with IDC and ILC entered the study. A family history of malignancies was reported in 21.6 % of patients with IDC as opposed to 37.8 % of patients with ILC (P < 0.001). A history of gastric cancer was reported in 7.2 % in the ILC group as compared to 2.3 % in the IDC group, P < 0.008. A family history of breast cancer was more common in the ILC group as opposed to the IDC group, 18 versus 8.1 % respectively, P = 0.002 and persisted in both age groups. We conclude that a family history of malignancies in first degree relatives is more common in patients with ILC than IDC and that there is a significant association between a family history of gastric cancer and ILC.

Lymphocytic Infiltration as a Prognostic Factor in Patients With Colon Cancer.

Host-defense mechanisms may have an important role in predicting the outcome of colorectal cancer patients. We designed our study to evaluate the possible prognostic significance of the presence of lymphocytic infiltration (LI) and subgroups of lymphocytes (CD3 and CD20) in the primary tumors. We randomly selected 195 patients operated for colorectal carcinoma from a larger cohort of 1527 patients with colorectal cancer. Histological slides were blindly reevaluated for the presence of LI that was graded 0 to 3. Immunohistochemical phenotyping of the lymphocytes was performed only for tumors with LI score 3 and included antibodies CD3 and CD20. CD3 and CD20 immunostaining were graded in the same manner as LI. The mean duration of follow-up was 63.8 months. The distribution of patients with colorectal cancer according to LI scores was as follows: score 0, 20/195 (10.2%); score 1, 61/195 (31.3%); score 2, 78/195 (40%); and score 3, 36/195 (18.5%). There was no correlation between any clinicopathological pattern and LI. Score 3 staining for CD3 was more common than for CD20 (64.7% vs 8.8%, P < .0001). Prominent lymphocytic infiltration (score 3) was associated with better disease-free survival (P = .062). Recurrence was diagnosed among 2/22 (9.1%) patients with prominent CD3 staining versus 62/171 (36.2%) of all other patient groups (P = .054) and they correspondingly had better disease-free survival (P = .018). It seems we can identify a group of patients with colorectal cancer who have an excellent prognosis according to a single immunological test unrelated to other known prognostic factors.

Influence of colectomy type and resected specimen length on number of harvested lymph nodes.

BACKGROUND: The optimal (minimal) number of harvested nodes is still a matter of debate. We prospectivly evaluated the relation between specimen length and tumor location to the number of harvested nodes and rate of node positivity. METHODS: Specimens of right hemicolectomy, left hemicolectomy, and subtotal colectomy were assessed for specimen length, overall number of harvested lymph nodes, and lymph node ratio. RESULTS: Left hemicolectomies were performed in 106 patients, right hemicolectomies in 90, and subtotal colectomies in 9. The mean number of retrieved lymph nodes was significantly higher in patients with right and subtotal colectomies compared to left colectomies: 33, 44, and 24, respectively. Positive nodes were found in 34% of the patients with right hemicolectomies, 55% in the subtotal group, and 35% in the left hemicolectomy group (not statistically significant). The length of the resected specimen was significantly longer in patients with right and subtotal colectomies compared to left colectomy: 31, 83, and 19 cm, respectively, but the ratio of lymph nodes to the length of the specimen was not statistically different: 1.19, 0.58, and 1.55, respectively. CONCLUSIONS: It appears that the additional length of resection in right colectomies compared to left colectomies leads to an increase in the average number of resected nodes, a change that did not translate into an increase in the number of positive nodes, nor in the ratio of patients with positive nodes.

A novel porcine model for chemically inducible Crohn's-like reaction.

BACKGROUND: New animal models provide insights into the pathogenesis of different types of inflammatory bowel disease as well as novel pathways for new therapeutic options. However, the scarcity of large animal models hinders the research and development of new surgical procedures and technological devices in inflammatory bowel disease surgery. Common small animal inducible models involve chemical agents that result in the development of acute intestinal inflammation. OBJECTIVES: To assess a novel method for the induction of Crohn's-like colitis using intramural injection of sclerosants in a porcine model. METHODS: Seven domestic pigs underwent several experimental protocols to assess the efficacy of intramural colonic injections of two different compounds (lauromacrogol, and phenol in almond oil).Twenty-five different large bowel segments were treated with intramural injections of the compounds. The animals were followed for 6 weeks, and treated colonic segments were resected for histopathological examination. RESULTS: Intramural injection of lauromacrogol resulted in non-specific, mild reactive foreign body changes only. Injection of various dosages of 5% phenol in almond oil caused a range of histopathological changes varying from focal fibrosis to Crohn's-like reactions com rising acute and chronic infiltrates, mucosal ulceration and focal necrosis with enteric and lymphoid non-caseating granulomas. CONCLUSIONS: Intramural colonic phenol in almond oil injection in pigs induces inflammatory reactions that histologically resemble Crohn's disease in humans.

Prevalence and correlates of human papillomavirus genotypes among patients with cervical cancer and cervical intraepithelial neoplasia 3 in Israel.

OBJECTIVES: This study aimed to assess the prevalence of human papillomavirus (HPV) in Israeli patients with cervical cancer and cervical intraepithelial neoplasia 3 (CIN3), to describe the distribution of the virus genotypes among positive cases, to characterize patients positive to HPV and, in particular, patients positive to HPV-16 and/or -18, and to evaluate the possible contribution of implementing HPV vaccination in Israel. METHODS: Samples from 84 patients with cervical cancer and 886 patients with CIN3, archived at the Maccabi Institute of Pathology, were screened for HPV. DNA extraction was performed using DNeasy Blood and Tissue Kit/QIAGEN. HPV detection and typing were performed by multiplex polymerase chain reaction with primers E6/E7, using the f-HPV/Genomed kit. RESULTS: Of the samples from 84 patients with cervical cancer, 89.3% were positive for HPV. Among these positive samples, HPV-16 was found in 70.7% and HPV-18 was found in 9.3%. Of the samples from 886 patients with CIN3, 85.0% were positive for HPV. Among these positive samples, HPV-16 was found in 73.8% and HPV-18 was found in 1.1%. In the patients with CIN3, the prevalence of HPV genotypes 16 and/or 18 was higher among young women and decreased across age groups. In addition, age, being born in Israel, being born in Europe, and being born in the former Soviet Union were correlated with a low risk of being infected with genotypes 16 and/or 18. DISCUSSION: The prevalence of HPV-16 and -18 in patients with cervical cancer and CIN3 in Israel is high. It is expected that the implementation of routine vaccination against these types of HPV will significantly reduce the burden of these diseases in Israel.

Morbidity and mortality after major pulmonary resections in patients with locally advanced stage IIIA non-small cell lung carcinoma who underwent induction therapy.

BACKGROUND: The optimal treatment for patients with locally advanced stage IIIA non-small cell lung carcinoma (NSCLC) remains controversial, but induction therapy is increasingly used. The aim of this study was to evaluate mortality, morbidity, hospital stay and frequency of postoperative complications in stage IIIA NSCLC patients that underwent major pulmonary resections after neoadjuvant chemotherapy or chemoradiation. METHODS: We conducted a retrospective analysis of all patients who underwent major pulmonary resections after induction therapy for locally advanced NSCLC from October 2009 to February 2014. Forty-one patients were included in the study. RESULTS: Complete resection was achieved in 40 patients (97.5%). A complete pathologic response was seen in 10 patients (24.4%). Mean hospital stay was 17.7 days (ranged 5-129 days). Early (in-hospital) mortality occurred in 2.4% (one patient after bilobectomy), late (six months) mortality in 4.9% (two patients after right pneumonectomy and bilobectomy), and overall morbidity in 58.5% (24 patients). Postoperative complications included: bronchopleural fistula (BPF) with empyema - three patients, empyema without BPF - five patients, air leak - eight patients, atrial fibrillation - eight patients, pneumonia - eight patients, and lobar atelectasis - four patients. CONCLUSION: Following neoadjuvant therapy for stage IIIA NSCLC, pneumonectomy can be performed with low early and late mortality (0% and 5.8%, respectively), bilobectomy is a high risk operation (16.7% early and 16.7% late mortality); and lobectomy a low risk operation (0% early and late mortality). The need for major pulmonary resections should not be a reason to exclude patients from a potentially curative procedure if it can be performed with acceptable morbidity and mortality rates at an experienced medical centre.

The expression of heparanase in normal and preeclamptic placentas.

OBJECTIVE: Heparanase plays a central role in processes of placentation. Abnormal placentation may result in inadequate uteroplacental blood flow, leading to unsuccessful pregnancy outcome and preeclampsia. We aimed to evaluate heparanase expression in placentas of preeclamptic patients. MATERIALS AND METHODS: Placental tissue samples were collected immediately after delivery from 9 preeclamptic patients and 3 healthy controls at term, and were analyzed by immunohistochemistry, western blot analysis and real-time PCR, with regard to the presence of heparanase. RESULTS: Immunohistochemistry staining for heparanase did not differ between normal and preeclamptic placental sections. On the other hand, western blot analysis revealed increased expression of heparanase in preeclpamptic placentas compared to controls, p = 0.001. Similarly, RT-PCR analysis showed also an increased expression of heparanase m-RNA compared to health controls, p = 0.005. CONCLUSION: Heparanase is over expressed in preeclamptic placentas compared to normal healthy controls, suggesting its role in the development of preeclampsia.