Anjali S. Kumar

Breast Cancer Growth Prevention by Statins

Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation reactions and reduction of signals driving cell proliferation and survival responses. The objectives of this study were to examine the effects of statins on breast cancer cells, both in vitro and in vivo, and to begin to determine their mechanism of action. We evaluated the effects of statins on breast cancer cell growth, phosphoprotein signaling intermediates, survival/apoptosis regulators, cell cycle regulators, and activated transcription factors. We also examined the in vivo effect of statin administration in a mouse ErbB2(+) breast cancer model. Only lipophilic statins had direct anticancer activity in vitro. Breast cancer cells with activated Ras or ErbB2 pathways seemed to be more sensitive than those overexpressing estrogen receptor, and this correlated with endogenous levels of activated nuclear factor kappaB (NF-kappaB). Key intermediates regulating cell survival by NF-kappaB activation, as well as cell proliferation by the mitogen activated protein kinase cascade, were among the earliest phosphoproteins influenced by statin treatment. These early effects were followed by declines in activator protein-1 and NF-kappaB activation and concordant changes in other mediators of proliferation and apoptosis. In vivo results showed that oral dosing of statins significantly inhibited the growth of a mouse mammary carcinoma. Lipophilic statins can exert direct anticancer activity in vitro by reducing proliferation and survival signals in susceptible breast cancer phenotypes. Tumor growth inhibition in vivo using a clinically relevant statin dose also seems to be associated with reduced tumor cell proliferation and survival. These findings provide supporting rationale for future statin trials in breast cancer patients.

Optimizing the total skin-sparing mastectomy.

HYPOTHESIS Dissection of subnipple tissue to spare the entire skin envelope of the breast (total skin-sparing mastectomy) is a feasible option in appropriately selected patients and yields an excellent final cosmetic outcome. DESIGN Prospective surgical technique outcomes study. SETTING University-based breast care referral center. PATIENTS Total skin-sparing mastectomy with preservation of the nipple-areola complex was performed in 64 breasts in 43 women. Indications for total skin-sparing mastectomy included prophylaxis (n = 29), invasive carcinoma (n = 24), and ductal carcinoma in situ (n = 11). INTERVENTIONS Preoperative magnetic resonance imaging was used to select patients and to confirm absence of disease within 2 cm of the nipple. Nipple tissue was serially sectioned at pathologic analysis. Circumareolar/nipple-areola free graft, inframammary, crescentic mastopexy, areola crossing, and radial incisions were used. Immediate reconstruction was performed with implant or tissue expander placement or latissimus dorsi muscle, transverse rectus abdominis muscle, or deep inferior epigastric perforator muscle flaps. MAIN OUTCOME MEASURES Nipple-areola complex skin survival, implant loss, skin flap necrosis, wound infection, and occult neoplasm. RESULTS Nipple-areola complex skin survival was complete in 80% of patients (n = 51) and partial in 16% (n = 10); it was highest with the radial incision at 97% survival (n = 34). Occult ductal carcinoma in situ in the nipple-areola complex was found in 2 patients (3%), and the affected nipple-areola complex was subsequently removed. Other complications included implant loss, total skin-sparing skin flap necrosis, and infection. Although follow-up is limited, no patients have exhibited cancer recurrence. CONCLUSIONS Total skin-sparing mastectomy is a viable surgical option in selected patients with breast neoplasm and those who choose prophylactic mastectomy, and may increase the willingness of women to consider mastectomy to reduce their risk of breast cancer.

Magnetic Resonance Imaging Captures the Biology of Ductal Carcinoma In Situ

PURPOSE Magnetic resonance imaging (MRI) is an important tool for characterizing invasive breast cancer but has proven to be more challenging in the setting of ductal carcinoma in situ (DCIS). We investigated whether MRI features of DCIS reflect differences in biology and pathology. PATIENTS AND METHODS Forty five of 100 patients with biopsy-proven DCIS who underwent MRI and had sufficient tissue to be characterized by pathologic (nuclear grade, presence of comedo necrosis, size, and density of disease) and immunohistochemical (IHC) findings (proliferation, Ki67; angiogenesis, CD34; and inflammation, CD68). Pathology and MRI features (enhancement patterns, distribution, size, and density) were analyzed using pairwise and canonical correlations. RESULTS Histopathologic and IHC variables correlated with MRI features (r = 0.73). The correlation was largely due to size, density (by either MRI or pathology), and inflammation (P < .05). Most small focal masses were estrogen receptor-positive. MRI enhancement patterns that were clumped were more likely than heterogeneous patterns to be high-grade lesions. Homogenous lesions were large, high grade, and rich in macrophages. Presence of comedo necrosis and size could be distinguished on MRI (P < .05). MRI was most likely to over-represent the size of less dense, diffuse DCIS lesions. CONCLUSION The heterogeneous presentation of DCIS on MRI reflects underlying histopathologic differences.

Estrogen Receptor–Negative Breast Cancer Is Less Likely to Arise among Lipophilic Statin Users

Background: Preclinical studies have shown the anticancer potential of HMG-CoA reductase enzyme inhibitors (statins), whereas epidemiologic studies remain controversial. Because lipophilic statins show preclinical anticancer activity against hormone receptor [estrogen receptor (ER)/progesterone receptor (PR)]–negative breast cancer models, we explored the hormone receptor phenotype of breast cancers that arise in statin users. Methods: We did a retrospective cohort analysis via electronic pharmacy records from the Kaiser Permanente Northern California Cancer Registry on 2,141 female patients listed in 2003 as incident cases of breast malignancy. Measures included tumor grade, stage, and receptor phenotype in statin users versus nonusers and controlled for hormone replacement therapy and race. Results: 387 of the 2,141 breast cancer patients used lipophilic statins [lovastatin (85%), simvastatin, and atorvastatin]. Fifty-one women developed ER/PR-negative tumors. The age-adjusted odds ratio (OR) of developing an ER/PR negative tumor was 0.63 (95% confidence interval, 0.43-0.92; P = 0.02) for statin use ≥1 year before breast cancer diagnosis compared with statin use <1 year (including nonuse). Breast cancers in patients with ≥1 year of statin use were more likely to be low grade (OR, 1.44) and less invasive stage (OR, 1.42). Conclusions: Breast cancer patients with exposure to statins have proportionately fewer ER/PR-negative tumors that are of lower grade and stage. Although our data set cannot address whether statins affect the incidence of breast cancer, we show that statin use may influence the phenotype of tumors. This suggests a new potential strategy for breast cancer prevention, that of combining statins with agents that prevent ER-positive cancer (tamoxifen, aromatase inhibitors). (Cancer Epidemiol Biomarkers Prev 2008;17(5):1028–33)

Complications of transanal endoscopic microsurgery are rare and minor: a single institution's analysis and comparison to existing data.

BACKGROUND: Transanal endoscopic microsurgery, a minimally invasive procedure for treatment of early-stage rectal cancer, carcinoid tumors, and adenomas, is shown to be a safe procedure with very low perioperative morbidity. OBJECTIVE: We aimed to compare the outcomes of transanal endoscopic microsurgery at a large volume tertiary care center with the existing literature. DESIGN: We retrospectively reviewed a prospectively collected database of 325 transanal endoscopic microsurgery procedures and looked for risk factors associated with complications. Indications for transanal endoscopic microsurgery included rectal adenocarcinomas, adenomas, and carcinoids. SETTING: Procedures were performed by a single surgeon at a large-volume tertiary care center. PATIENTS: Patients were enrolled over a 20-year period, and data were collected on demographics, perioperative details, tumor characteristics, and complications. INTERVENTIONS: Transanal endoscopic microsurgery was performed on all 325 patients. MAIN OUTCOME MEASURES: Main outcome measures were urinary retention, late bleeding requiring intervention, dehiscence, peritoneal cavity entry, conversion to abdominal approach, fecal soiling, and rectovaginal fistula. RESULTS: Intraoperative bleeding was associated with larger tumor size, whereas postoperative bleeding requiring intervention was not associated with any factors studied. Peritoneal cavity entry and urinary retention were more likely if the tumor was in either the anterior or lateral position in the rectum. The peritoneal cavity was entered in 9 patients, and conversion to abdominal approach occurred in 1 patient. Intraoperative bleeding, by surgeon’s choice, and urinary retention, by patient’s choice, were associated with a greater likelihood of admission to the inpatient ward. Fecal soiling was not reported by patients and not recorded. LIMITATIONS: This study was limited because it was a retrospective analysis CONCLUSIONS: Transanal endoscopic microsurgery is an extremely safe procedure, offering very low perioperative morbidity. The overall morbidity found in our study was 10.5%, on par with published data for large series of 21%, 7.7%, and 14.9%. In contrast, complications from radical resection are reported at 18% to 55%.

Systemic Chemotherapy prior to Cytoreductive Surgery and HIPEC for Carcinomatosis from Appendix Cancer: Impact on Perioperative Outcomes and Short-Term Survival

Background and Objectives. Systemic chemotherapy administered prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mucinous adenocarcinoma of appendiceal origin (PMCA) is associated with a significant rate of histological response. The impact of preoperative systemic chemotherapy (PSC) on intraperitoneal tumor burden, completeness of cytoreduction, and perioperative complications is unknown. Methods. We analyzed prospectively collected data from our HIPEC database. Thirty-four patients with PMCA were prospectively recruited and treated with PSC. Perioperative variables and survival in this group of patients were compared against 24 patients with PMCA who did not receive PSC. Results. Ten of 34 patients (29%) receiving PSC had a complete or near complete histological response. Patients receiving PSC had a lower peritoneal carcinomatosis index, required fewer peritonectomies and visceral resections, and achieved complete cytoreduction more frequently compared to patients with no preoperative chemotherapy. The incidence of perioperative complications and survival were not significantly different between the two groups. However, patients with complete histological response had better overall survival compared to patients without complete response. Conclusions. Preoperative systemic chemotherapy in appendix-originated PMCA is associated with a significant rate of histological response which may reduce the tumor burden, facilitate less aggressive and more complete CRS, and improve short-term survival in patients with a significant histological response.

Liposome Bupivacaine for Postsurgical Analgesia in Adult Patients Undergoing Laparoscopic Colectomy: Results from Prospective Phase IV Sequential Cohort Studies Assessing Health Economic Outcomes

Background Opioid-based postsurgical analgesia exposes patients undergoing laparoscopic colectomy to elevated risk for gastrointestinal motility problems and other opioid-related adverse events (ORAEs). The purpose of our research was to investigate postsurgical outcomes, including opioid consumption, hospital length of stay, and ORAE risk associated with a multimodal analgesia regimen, employing a single administration of liposome bupivacaine as well as other analgesics that act by different mechanisms. Methods We analyzed combined results from 6 Phase IV, prospective, single-center studies in which patients undergoing laparoscopic colectomy received opioid-based intravenous patient-controlled analgesia (PCA) or multimodal analgesia incorporating intraoperative administration of liposome bupivacaine. As-needed rescue therapy was available to all patients. Primary outcome measures were postsurgical opioid consumption, hospital length of stay, and hospitalization costs. Secondary measures included time to first rescue opioid use, patient satisfaction with analgesia (assessed using a 5-point Likert scale), and ORAEs. Results Eighty-two patients underwent laparoscopic colectomy and did not meet intraoperative exclusion criteria (PCA n = 56; multimodal analgesia n = 26). Compared with the PCA group, the multimodal analgesia group had significantly lower mean total postsurgical opioid consumption (96 vs 32 mg, respectively; P < 0.0001) and shorter median postsurgical hospital length of stay (3.0 vs 4.0 days; P = 0.0019). Geometric mean costs were

Transanal endoscopic microsurgery for rectal carcinoids: the largest reported United States experience

11,234 and

Overdiagnosis and overtreatment of breast cancer: Rates of ductal carcinoma in situ: a US perspective

13,018 in the multimodal analgesia and PCA groups, respectively (P = 0.2612). Median time to first rescue opioid use was longer in the multimodal analgesia group versus PCA group (1.1 hours vs 0.6 hours, respectively; P=0.0003). ORAEs were experienced by 41% of patients receiving intravenous opioid PCA and 8% of patients receiving multimodal analgesia (P = 0.0019). Study limitations included use of an open-label, nonrandomized design; small population size; and the inability to isolate treatment-related effects specifically attributable to liposome bupivacaine. Conclusions Compared with intravenous opioid PCA, a liposome bupivacaine-based multimodal analgesia regimen reduced postsurgical opioid use, hospital length of stay, and ORAEs, and may lead to improved postsurgical outcomes following laparoscopic colectomy.

Bowel Preparation before Elective Surgery

Aim  Rectal carcinoids are often inadequately resected by snare excision during colonoscopy. Transanal endoscopic microsurgery is a minimally invasive procedure with low morbidity that offers full‐thickness excision with a low rate of negative margins. It presents an excellent alternative to radical surgery for mid and proximally located lesions. We report the largest United States (US) experience in the use of transanal endoscopic microsurgery for rectal carcinoids.