Baruch Shpitz

Aberrant crypt foci in human colons: distribution and histomorphologic characteristics.

Aberrant crypt foci (ACF) are one of the earliest putative preneoplastic, and in some cases, neoplastic lesions in human colons. These microscopic lesions, identified on methylene blue-stained mucosa with a low-power-magnification microscope, are thought to be closely related to the earliest steps in multistage colonic tumorigenesis. We investigated the distribution pattern and histomorphological features of ACF in 74 patients with sporadic colorectal cancer. The distribution pattern shows a slightly higher prevalence with older age. The prevalence of the ACF in sigmoid colon was significantly higher in patients with colorectal cancer as compared with patients with benign colonic diseases. Also, significantly more ACF were detected in distal parts of the large bowel (descending, sigmoid colon, and rectum) than in proximal parts. Of 42 microdissected lesions, 12 were dysplastic and 30 were hyperplastic foci. The average size of dysplastic lesions was significantly larger than hyperplastic foci. More apoptotic bodies were found in dysplastic lesions. These lesions also showed an upward expansion of proliferative compartment and higher proliferation indices expressed as proliferating cell nuclear antigen-labeling index. Lymphoid follicles were frequently observed in the base of both hyperplastic and dysplastic foci (40% and 66.6%, respectively). The coincidence of lymphoid follicles was 2.5 to 8 times higher than expected. These features may be related to further progression of selected ACF during colorectal tumorigenesis.

Proliferating cell nuclear antigen as a marker of cell kinetics in aberrant crypt foci, hyperplastic polyps, adenomas, and adenocarcinomas of the human colon*

BACKGROUND One of the first steps in multistage colonic carcinogenesis is increased cell proliferation and an upward shift of the proliferation zone of colonic crypts. In the present study, progression in cell kinetics was followed up at all sequential stages of colonic carcinogenesis, starting with aberrant crypt foci (ACF), the earliest putative preneoplastic lesions, hyperplastic and dysplastic polyps, and invasive carcinomas. MATERIALS AND METHODS Colonic tissue and tumor specimens were prospectively obtained from 65 patients treated at our hospital for adenocarcinoma or malignant polyps. For identification of ACFs, dissected mucosal strips obtained from patients with colorectal cancer were stained with 0.1% methylene blue and scanned under dissecting microscope. Paraffin-embedded ACFs and macroscopic lesions were serially sectioned, deparaffinized, and stained with a monoclonal antiproliferating cell nuclear antigen (PCNA) antibody. The PCNA-labelling index (PCNA-LI), expressed as a ratio of positively stained nuclei to total nuclei counted, was calculated separately for basal, middle, and upper colonic crypt compartments. A comparison of the PCNA-LI was made for each compartment in normal mucosa, and hyperplastic and dysplastic lesions. RESULTS A stepwise increase in the PCNA-LI was observed during neoplastic progression of colonic lesions. The two most important variables of increased cell proliferation, expressed as PCNA-LI per crypt compartment, were the presence of dysplasia and the size of dysplastic lesions. CONCLUSIONS In colorectal carcinogenesis, hyperproliferation with upward expansion of proliferative compartment is a characteristic feature at all stages of malignant progression.

Celecoxib and Curcumin Additively Inhibit the Growth of Colorectal Cancer in a Rat Model

Background: Multiple studies have indicated that specific COX-2 inhibitors may prevent CRC. However, the long-term use of COX-2 inhibitors is not toxicity-free and may be limited due to its cardiovascular side effects. The present study was carried out to examine the chemopreventive effects of celecoxib and curcumin alone and in combination using the 1,2-dimethylhydrazine (DMH) rat model. Methods: Male rats were injected with DMH and randomly divided into four groups that consumed one of the following diets: (a) AIN-076 control diet; (b) AIN-076/curcumin (0.6%); (c) AIN-076/celecoxib (0.16%), or (d) AIN-076/celecoxib (0.16%) and curcumin (0.6%). Aberrant crypt foci (ACF) were identified by intensive staining with methylene blue in comparison to the surrounding normal crypts. Results: The average number of ACF per rat colon was 64.2 ± 3 in the control group, 39 ± 5 and 47 ± 10 for the curcumin- and celecoxib-treated group, respectively, and 24.5 ± 6 in the group that had received both agents. Conclusions: In vivo, curcumin augments the growth inhibitory effect of celecoxib. This may be clinically important as this dose of celecoxib can be achieved in human serum following standard anti-inflammatory dosing of 100 mg.

Angiogenesis, p53, and c-erbB-2 immunoreactivity and clinicopathological features in male breast cancer

p53, c‐erbB‐2, and tumor microvascular density have been shown to be potential prognostic tools in female breast cancer. Our objective was to assess the significance of these biomarkers as prognostic factors in infiltrating male breast cancer.

Should peritoneal tears be routinely closed during laparoscopic total extraperitoneal repair of inguinal hernias? A reappraisal

BackgroundPeritoneal tears (PTs) are not uncommon during the course of laparoscopic total extraperitoneal (LTEP) repair of groin hernias. Most endoscopic surgeons advocate routine closure of these tears. Our approach is not to perform routine closure of PTs. The aim of this study was to evaluate the possible effect of our approach on the intra- and postoperative course of patients in whom PTs were left opened.MethodsProspective data were collected for LTEP repairs of 298 hernias performed in 166 consecutive patients.ResultsThere were 134 primary and 34 recurrent hernias. In 23% of patients, unilateral or bilateral PTs were observed during the course of operation. Of these, the prevalence of tears was 21.8% for primary repair and 41% for recurrent repair. In 40 patients with PTs, the procedure was accomplished successfully laparoscopically. The early postoperative course was uncomplicated in all patients. Results of outpatient follow-up with a mean observation time of 16 months (range, 2–30) did not reveal any complications that could be attributed to PTs.ConclusionsThese data demonstrate that PTs do not have to be routinely closed and the majority of cases may be safely managed without peritoneal closure. We have not observed any intra- or postoperative complications that could be attributed to peritoneal tears.

LONG-TERM INCIDENCE OF ACUTE MYOCARDIAL INFARCTION AFTER OPEN AND TRANSURETHRAL RESECTION OF THE PROSTATE FOR BENIGN PROSTATIC HYPERPLASIA

PURPOSE Acute myocardial infarction was found to be the main cause of increased long-term mortality in patients after transurethral compared to open prostatectomy in various retrospective studies. We performed a randomized prospective study to compare morbidity and incidence of acute myocardial infarction in patients after transurethral compared to open prostatectomy for benign prostatic hyperplasia. MATERIALS AND METHODS We studied 365 patients who were assigned to transurethral (236) or open (129) prostatectomy only according to the size of the prostate and who were followed for 7 to 8 years. The clinical status of the patients in both groups before and after the operation was compared, and the rate of myocardial infarction and long-term mortality was studied. RESULTS More patients with a history of cerebrovascular accident (5.4 versus 0.8%) and indwelling catheters (16.3 versus 7.6%) before the operation were in the open prostatectomy group. Among the 236 patients operated on transurethrally 31 were reoperated on (6 more than once) during followup compared to 4 of the 129 patients who underwent open prostatectomy. In 15 patients from the transurethral prostatectomy group myocardial infarction developed compared to 9 patients in the open prostatectomy group. This difference was not statistically significant. The rate of acute myocardial infarction after prostatectomy, no matter which approach was used, was greater than 6% and it appeared to be higher when compared to the rate of infarction in the general population of the same age group, which is approximately 2.5% in our county. There was no statistically significant difference in the overall mortality rate between the transurethral and open prostatectomy groups, which was 14.4 and 8.5% respectively. CONCLUSIONS Open prostatectomy is more effective in overcoming urinary obstruction than the transurethral approach. No significant differences in myocardial infarction or overall mortality rates were found between the 2 groups.

Chemopreventive effect of aspirin on growth of aberrant crypt foci in rats

Abstract Nonsteroidal anti-inflammatory drugs display a chemopreventive effect on polyps and cancer of the large bowel. This study evaluated the inhibitory effect of aspirin on the distribution and growth of aberrant crypt foci (ACF), the earliest putative preneoplastic and early neoplastic lesions in a rat model. For initiation of ACF, Sprague Dawley rats were injected with azoxymethane (30 mg/kg), a well-established rat carcinogen. After the second injection the rats were allocated to three groups, which received 0.2% or 0.6% aspirin or the solvent only (control group). After 6 weeks the animals were killed, and their colons removed, fixed in formalin, and screened for distribution and size of ACF, separately for middle and distal parts of the large intestine. The rats injected with azoxymethane showed a 100% incidence of ACF. Administration of 0.2% and 0.6% aspirin resulted in 55% and 54% reduction, respectively, in overall frequency of ACF. Aspirin significantly reduced the frequency of medium-sized (four to six crypts per focus) and large (three to six crypts per focus) but not the small (one to three crypts per focus) ACF. In the control group the ACF of the same multiplicity were larger than those in the aspirin-treated rats. No statistically significant difference in ACF-inhibiting effect was noted between 0.6% and 0.2% aspirin solution. Aspirin given at a concentration of either 0.2% of 0.6% thus has a chemopreventive effect on ACF, acting on postinitiation stage of azoxymethane-induced colonic carcinogenesis model in rats.

Definitive management of acute pilonidal abscess by loop diathermy excision

A simple technique of definitive management of acute pilonidal abscess is described. The procedure consists of incision with drainage of pus followed by controlled excision of diseased tissue and lateral sinuses, using a loop diathermy. It allows one-stage definitive management of both acute pilonidal abscess and chronic pilonidal sinuses.

Curcumin potentiates the pro-apoptotic effects of sulindac sulfone in colorectal cancer

Objective: The use of sulindac sulfone (SFN) for colorectal cancer (CRC) therapy is limited due to its toxicity. The present study was carried out to examine whether curcumin, a novel chemopreventive agent, can potentiate the effects of low dosages of SFN in CRC treatment. Methods: HT-29 CRC cells were exposed to SFN (200 – 400 microM), curcumin (5 – 10 microM) or their combination. The cytotoxic effects of the drugs were evaluated using growth inhibition assays. Annexin V/PI and cell cycle analysis were employed to study the mechanism of action of the drugs. The therapeutic efficacy of the drugs in vivo was examined using the aberrant crypt foci (ACF) model. The treatment groups included eight rats/group. Results: Treatment of cells with curcumin and SFN resulted in a synergistic inhibitory effect of 50 – 90% (p < 0.005) on cell growth. Growth inhibition was associated with inhibition of proliferation, G2/M arrest and induction of apoptosis. Administration of curcumin (0.6%) and SFN (0.06%) to 1, 2-dimethylhydrazine treated rats significantly reduced (by 75%, p < 0.01) the number of ACF. Conclusions: Curcumin augments the therapeutic effects of SFN. This may be clinically important since the addition of curcumin to low dosages of SFN may encourage a safer and potent combinatorial treatment regimen for CRC.

Altered expression of the DNA mismatch repair proteins hMLH1 and hMSH2 in cutaneous dysplastic nevi and malignant melanoma

Molecular alterations in the mismatch repair system suggest that this mechanism may be important in the evolution of cutaneous melanoma. Our current study evaluated the expression of two mismatch repair proteins, hMLH1 and hMSH2, in dysplastic nevi (DN) and cutaneous melanoma (CM). Immunohistochemical staining of these proteins was performed on 55 CM and 30 DN specimens. The staining results were divided into three groups: negative, partially positive and strongly positive. Normal adjacent skin cells served as an internal control for positive immunostaining. Altered immunoreactivity of one of the proteins was found in four (13.4%) DN and seven (12.7%) CM. Lack of staining for hMLH1 was observed in two (6.7%) cases of DN and five (9.1%) cases of CM; staining for hMSH2 was absent in two (6.7%) of the DN and two (3.6%) of the CM specimens. Partially positive staining was found in 33.3% and 53.3% for hMLH1 and hMSH2, respectively, in DN, and in 54.5% and 69.1%, respectively, in CMM. Our study shows that complete or partial loss of MMR protein expression occurs in a subset of both DN and CM and may represent a distinct pathway in the development of some DN and CM.