Mousumi Banerjee

Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments

Th17 cells play an active role in autoimmune diseases. However, the nature of Th17 cells is poorly understood in cancer patients. We studied Th17 cells, the associated mechanisms, and clinical significance in 201 ovarian cancer patients. Tumor-infiltrating Th17 cells exhibit a polyfunctional effector T-cell phenotype, are positively associated with effector cells, and are negatively associated with tumor-infiltrating regulatory T cells. Tumor-associated macrophages promote Th17 cells through interleukin-1beta (IL-1beta), whereas tumor-infiltrating regulatory T cells inhibit Th17 cells through an adenosinergic pathway. Furthermore, through synergistic action between IL-17 and interferon-gamma, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced diseases and positively predict patient outcome. Altogether, Th17 cells may contribute to protective human tumor immunity through inducing Th1-type chemokines and recruiting effector cells to the tumor microenvironment. Inhibition of Th17 cells represents a novel immune evasion mechanism. This study thus provides scientific and clinical rationale for developing novel immune-boosting strategies based on promoting the Th17 cell population in cancer patients.

Surgical Skill and Complication Rates after Bariatric Surgery

BACKGROUND Clinical outcomes after many complex surgical procedures vary widely across hospitals and surgeons. Although it has been assumed that the proficiency of the operating surgeon is an important factor underlying such variation, empirical data are lacking on the relationships between technical skill and postoperative outcomes. METHODS We conducted a study involving 20 bariatric surgeons in Michigan who participated in a statewide collaborative improvement program. Each surgeon submitted a single representative videotape of himself or herself performing a laparoscopic gastric bypass. Each videotape was rated in various domains of technical skill on a scale of 1 to 5 (with higher scores indicating more advanced skill) by at least 10 peer surgeons who were unaware of the identity of the operating surgeon. We then assessed relationships between these skill ratings and risk-adjusted complication rates, using data from a prospective, externally audited, clinical-outcomes registry involving 10,343 patients. RESULTS Mean summary ratings of technical skill ranged from 2.6 to 4.8 across the 20 surgeons. The bottom quartile of surgical skill, as compared with the top quartile, was associated with higher complication rates (14.5% vs. 5.2%, P<0.001) and higher mortality (0.26% vs. 0.05%, P=0.01). The lowest quartile of skill was also associated with longer operations (137 minutes vs. 98 minutes, P<0.001) and higher rates of reoperation (3.4% vs. 1.6%, P=0.01) and readmission (6.3% vs. 2.7%) (P<0.001). CONCLUSIONS The technical skill of practicing bariatric surgeons varied widely, and greater skill was associated with fewer postoperative complications and lower rates of reoperation, readmission, and visits to the emergency department. Although these findings are preliminary, they suggest that peer rating of operative skill may be an effective strategy for assessing a surgeons proficiency.

Race, socioeconomic status and stage at diagnosis for five common malignancies

Background: African-Americans are more likely than Caucasians to be diagnosed at an advanced stage of colorectal, lung, breast, cervical, and prostate cancers. This study explores if racial differences in stage at diagnosis can be explained by socioeconomic status (SES) differences. Previous studies investigating this association have used aggregate SES indicators from census tract of residence; we used census block-group data, representing a smaller, potentially more homogenous group. Methods: We included all African-American and Caucasian invasive cancers of the colon and rectum, lung and bronchus, female breast, cervix uteri, and prostate that were diagnosed between January 1, 1988 and December 31, 1992 in the Detroit area. Stage of disease at diagnosis was grouped as local or non-local. An SES value was calculated for each case using aggregate 1990 US Census data for education, poverty status, and occupation specific to each cases census block-group. Logistic regression analysis was used to model the probability of non-local stage using SES, race, age group, and sex as covariates. Results: SES was an independent predictor of stage at diagnosis for each cancer site, with cases from the highest SES block-group more likely to present with local stage disease than those from the lowest SES group. Race independently predicted stage only for breast and prostate cancers; African-Americans presented with more advanced stage than Caucasians. Conclusions: Based on census block-group aggregate data, SES is an important predictor of stage at diagnosis, most likely accounting for much of the disparity in stage between African-Americans and Caucasians for colorectal, lung, and cervical cancers. Biological factors may play a role in racial disparities for breast and prostate cancer stage at diagnosis.

Limited role of radionuclide bone scintigraphy in patients with prostate specific antigen elevations after radical prostatectomy

PURPOSE Bone scintigrams of patients with increasing serum prostate specific antigen (PSA) after radical prostatectomy are only rarely positive. We identify clinical parameters that would improve our ability to select patients for this imaging study. MATERIALS AND METHODS We reviewed all bone scintigrams done at our institution between 1991 and 1996 in patients with persistently increasing serum PSA after radical prostatectomy. What prompted the clinician to obtain the bone scintigram was trigger PSA (tPSA). The rate of increase in PSA to tPSA was measured by tPSA/time from radical prostatectomy (slope 1) and tPSA/time from last undetectable PSA (slope 2). These parameters were evaluated together with standard clinicopathological data in univariate and multivariate analyses to determine the ability to predict the bone scintigram result. RESULTS In univariate analysis tPSA (p = 0.003), slope 1 (p = 0.005) and slope 2 (p = 0.004) were useful in predicting the bone scintigram result but pathological stage, Gleason score, preoperative PSA and time to recurrence were not. In multivariate analysis the single most useful parameter in predicting the bone scintigram result was tPSA (p = 0.01). Based on a logistic regression model the probability of a positive bone scintigram was less than 5% until tPSA increased to 40 to 45 ng./ml. CONCLUSIONS In patients with increasing serum PSA after radical prostatectomy current serum PSA is the best predictor of the bone scintigram result. Furthermore, there is limited usefulness of bone scintigraphy until PSA increases above 30 to 40 ng./ml.

Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study

BACKGROUND During in-hospital cardiac arrests, how long resuscitation attempts should be continued before termination of efforts is unknown. We investigated whether duration of resuscitation attempts varies between hospitals and whether patients at hospitals that attempt resuscitation for longer have higher survival rates than do those at hospitals with shorter durations of resuscitation efforts. METHODS Between 2000 and 2008, we identified 64,339 patients with cardiac arrests at 435 US hospitals within the Get With The Guidelines—Resuscitation registry. For each hospital, we calculated the median duration of resuscitation before termination of efforts in non-survivors as a measure of the hospitals overall tendency for longer attempts. We used multilevel regression models to assess the association between the length of resuscitation attempts and risk-adjusted survival. Our primary endpoints were immediate survival with return of spontaneous circulation during cardiac arrest and survival to hospital discharge. FINDINGS 31,198 of 64,339 (48·5%) patients achieved return of spontaneous circulation and 9912 (15·4%) survived to discharge. For patients achieving return of spontaneous circulation, the median duration of resuscitation was 12 min (IQR 6-21) compared with 20 min (14-30) for non-survivors. Compared with patients at hospitals in the quartile with the shortest median resuscitation attempts in non-survivors (16 min [IQR 15-17]), those at hospitals in the quartile with the longest attempts (25 min [25-28]) had a higher likelihood of return of spontaneous circulation (adjusted risk ratio 1·12, 95% CI 1·06-1·18; p<0·0001) and survival to discharge (1·12, 1·02-1·23; 0·021). INTERPRETATION Duration of resuscitation attempts varies between hospitals. Although we cannot define an optimum duration for resuscitation attempts on the basis of these observational data, our findings suggest that efforts to systematically increase the duration of resuscitation could improve survival in this high-risk population. FUNDING American Heart Association, Robert Wood Johnson Foundation Clinical Scholars Program, and the National Institutes of Health.

Soy Isoflavones in the Treatment of Prostate Cancer

Epidemiological studies suggest an inverse association between soy intake and prostate cancer (Pca) risk. We have previously observed that soy isoflavone genistein induces apoptosis and inhibits growth of both androgen-sensitive and androgen-independent Pca cells in vitro. To determine the clinical effects of soy isoflavones on Pca we conducted a pilot study in patients with Pca who had rising serum prostate-specific antigen (PSA) levels. Patients with Pca were enrolled in the study if they had either newly diagnosed and untreated disease under watchful waiting with rising PSA (group I) or had increasing serum PSA following local therapy (group II) or while receiving hormone therapy (group III). The study intervention consisted of 100 mg of soy isoflavone (Novasoy®) taken by mouth twice daily for a minimum of 3 or maximum of 6 mo. Forty-one patients were enrolled (4 in group I, 18 in group II, and 19 in group III) and had a median PSA level of 13.3 ng/ml. Thirty-nine patients could be assessed for response. Soy isoflavone supplementation was given for a median of 5.5 (range 0.8-6) mo per patient. Although there were no sustained decreases in PSA qualifying for a complete or partial response, stabilization of the PSA occurred in 83% of patients in hormone-sensitive (group II) and 35% of hormone-refractory (group III) patients. There was a decrease in the rate of the rise of serum PSA in the whole group (P = 0.01) with rates of rise decreasing from 14 to 6% in group II (P = 0.21) and from 31 to 9% in group III (P = 0.05) following the soy isoflavone intervention. Serum genistein and daidzein levels increased during supplementation from 0.11 to 0.65 αM (P = 0.00002) and from 0.11 to 0.51 αM (P = 0.00001), respectively. No significant changes were observed in serum levels of testosterone, IGF-1, IGFBP-3, or 5-OHmdU. These data suggest that soy isoflavones may benefit some patients with Pca.

Predicting risk for serious complications with bariatric surgery: results from the Michigan Bariatric Surgery Collaborative.

Objectives:To develop a risk prediction model for serious complications after bariatric surgery. BackgroundDespite evidence for improved safety with bariatric surgery, serious complications remain a concern for patients, providers and payers. There is little population-level data on which risk factors can be used to identify patients at high risk for major morbidity. Methods:The Michigan Bariatric Surgery Collaborative is a statewide consortium of hospitals and surgeons, which maintains an externally-audited prospective clinical registry. We analyzed data from 25,469 patients undergoing bariatric surgery between June 2006 and December 2010. Significant risk factors on univariable analysis were entered into a multivariable logistic regression model to identify factors associated with serious complications (life threatening and/or associated with lasting disability) within 30 days of surgery. Bootstrap resampling was performed to obtain bias-corrected confidence intervals and c-statistic. Results:Overall, 644 patients (2.5%) experienced a serious complication. Significant risk factors (P < 0.05) included: prior VTE (odds ratio [OR] 1.90, confidence interval [CI] 1.41–2.54); mobility limitations (OR 1.61, CI 1.23–2.13); coronary artery disease (OR 1.53, CI 1.17–2.02); age over 50 (OR 1.38, CI 1.18–1.61); pulmonary disease (OR 1.37, CI 1.15–1.64); male gender (OR 1.26, CI 1.06–1.50); smoking history (OR 1.20, CI 1.02–1.40); and procedure type (reference lap band): duodenal switch (OR 9.68, CI 6.05–15.49); laparoscopic gastric bypass (OR 3.58, CI 2.79–4.64); open gastric bypass (OR 3.51, CI 2.38–5.22); sleeve gastrectomy (OR 2.46, CI 1.73–3.50). The c-statistic was 0.68 (bias-corrected to 0.66) and the model was well-calibrated across deciles of predicted risk. Conclusions:We have developed and validated a population-based risk scoring system for serious complications after bariatric surgery. We expect that this scoring system will improve the process of informed consent, facilitate the selection of procedures for high-risk patients, and allow for better risk stratification across studies of bariatric surgery.

Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells

Identification of cancer stem cells is crucial for advancing cancer biology and therapy. Several markers including CD24, CD44, CD117, CD133, the G subfamily of ATP‐binding cassette transporters (ABCG), epithelial specific antigen (ESA) and aldehyde dehydrogenase (ALDH) are used to identify and investigate human epithelial cancer stem cells in the literature. We have now systemically analyzed and compared the expression of these markers in fresh ovarian epithelial carcinomas. Although the expression levels of these markers were unexpectedly variable and partially overlapping in fresh ovarian cancer cells from different donors, we reliably detected important levels of CD133 and ALDH in the majority of fresh ovarian cancer. Furthermore, most of these stem cell markers including CD133 and ALDH were gradually lost following in vitro passage of primary tumor cells. However, the expression of ALDH and CD133, but not CD24, CD44 and CD117, could be partially rescued by the in vitro serum‐free and sphere cultures and by the in vivo passage in the immune‐deficient xenografts. ALDH+ and CD133+ cells formed three‐dimensional spheres more efficiently than their negative counterparts. These sphere‐forming cells expressed high levels of stem cell core gene transcripts and could be expanded and form additional spheres in long‐term culture. ALDH+, CD133+ and ALDH+CD133+ cells from fresh tumors developed larger tumors more rapidly than their negative counterparts. This property was preserved in the xenografted tumors. Altogether, the data suggest that ALDH+ and CD133+ cells are enriched with ovarian cancer‐initiating (stem) cells and that ALDH and CD133 may be widely used as reliable markers to investigate ovarian cancer stem cell biology.

Downregulation of EZH2 decreases growth of estrogen receptor-negative invasive breast carcinoma and requires BRCA1

Increased levels of enhancer of zeste homolog 2 (EZH2), a critical regulator of cellular memory, are associated with negative estrogen receptor (ER) expression and disease progression in breast cancer. High levels of EZH2 signal the presence of metastasis and poor outcome in breast cancer patients. To test the hypothesis that deregulation of EZH2 contributes to ER-negative breast cancer progression, EZH2 expression was inhibited in ER-negative breast cancer cells MDA-MB-231 and CAL51 using a lentivirus system. EZH2 knockdown decreased proliferation and delayed the G2/M cell-cycle transition, although not affecting apoptosis. In vivo, EZH2 downregulation significantly decreased breast xenograft growth and improved survival. EZH2 knockdown upregulated BRCA1 protein. Of note, BRCA1 knockdown was sufficient to rescue the effects of EZH2 downregulation on proliferation, G2/M arrest, and on the levels of hyperphosphorylated mitotic Cdc25C and Cyclin B1 proteins, crucial for entry into mitosis. Invasive ER-negative breast carcinomas show significant overexpression of EZH2 and downregulation of BRCA1 proteins. Taken together, we show that EZH2 is important in ER-negative breast cancer growth in vivo and in vitro, and that BRCA1 is required for the proliferative effects of EZH2. Blockade of EZH2 may provide a prime target to prevent and/or halt ER-negative breast cancer progression.

Effects of Lycopene Supplementation in Patients with Localized Prostate Cancer

Epidemiological studies have shown an inverse association between dietary intake of lycopene and prostate cancer risk. We conducted a clinical trial to investigate the biological and clinical effects of lycopene supplementation in patients with localized prostate cancer. Twenty-six men with newly diagnosed prostate cancer were randomly assigned to receive a tomato oleoresin extract containing 30 mg of lycopene (n = 15) or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of cell proliferation and apoptosis were assessed by Western blot analysis in benign and cancerous prostate tissues. Oxidative stress was assessed by measuring the Peripheral blood lymphocyte ONA oxidation product 5-hydroxymethyl-deoxyuridine (5-OH-mdU). Usual dietary Intake of nutrients was assessed by a food frequency questionnaire at baseline. Prostatectomy specimens were evaluated for pathologic stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1, insulin-like growth factor binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. After intervention, subjects in the intervention group had smaller tumors (80% vs 45%, less than 4 ml), less involvement of surgical margins and/or extra-prostatic tissues with cancer (73% vs 18%, organ-confined disease), and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia (33% vs 0%, focal involvement) compared with subjects in the control group. Mean plasma prostate-specific antigen levels were lower in the intervention group compared with the control group. This pilot study suggests that lycopene may have beneficial effects in prostate cancer. Larger clinical trials are Warranted to investigate the potential preventive and/or therapeutic role of lycopene in prostate cancer.