Rajendra A. Badwe

Differential regulation of centrosome integrity by DNA damage response proteins

MDC1 and BRIT1 have been shown to function as key regulators in response to DNA damage. However, their roles in centrosomal regulation haven’t been elucidated. In this study, we demonstrated the novel functions of these two molecules in regulating centrosome duplication and mitosis. We found that MDC1 and BRIT1 were integral components of the centrosome that colocalize with γ-tubulin. Depletion of either protein led to centrosome amplification. However, the mechanisms that allow them to maintain centrosome integrity are different. MDC1-depleted cells exhibited centrosome overduplication, leading to multipolar mitosis, chromosome missegregation, and aneuploidy, whereas BRIT1 depletion led to misaligned spindles and/or lagging chromosomes with defective spindle checkpoint activation that resulted in defective cytokinesis and polyploidy. We further illustrated that both MDC1 and BRIT1 were negative regulators of Aurora A and Plk1, two centrosomal kinases involved in centrosome maturation and spindle assembly. Moreover, the levels of MDC1 and BRIT1 inversely correlated with centrosome amplification, defective mitosis, and cancer metastasis in human breast cancer. Together, MDC1 and BRIT1 may function as tumor-suppressor genes, at least in part by orchestrating proper centrosome duplication and mitotic spindle assembly.

Problem solving for breast health care delivery in low and middle resource countries (LMCs): consensus statement from the Breast Health Global Initiative.

International collaborations like the Breast Health Global Initiative (BHGI) can help low and middle income countries (LMCs) to establish or improve breast cancer control programs by providing evidence-based, resource-stratified guidelines for the management and control of breast cancer. The Problem Solving Working Group of the BHGI 2010 Global Summit met to develop a consensus statement on problem-solving strategies addressing breast cancer in LMCs. To better assess breast cancer burden in poorly studied populations, countries require accurate statistics regarding breast cancer incidence and mortality. To better identify health care system strengths and weaknesses, countries require reasonable indicators of true health system quality and capacity. Using qualitative and quantitative research methods, countries should formulate cancer control strategies to identify both system inefficiencies and patient barriers. Patient navigation programs linked to public advocacy efforts feed and strengthen functional early detection and treatment programs. Cost-effectiveness research and implementation science are tools that can guide and expand successful pilot programs.

Determinants of Compliance in a Cluster Randomised Controlled Trial on Screening of Breast and Cervix Cancer in Mumbai, India

Objectives: This study aims to investigate the efficacy of screening by low-cost technology in down-staging and reducing mortality due to breast and cervix cancer. Methods: The present trial is a community-based, cluster randomised controlled cohort study on screening for breast and cervix cancers (clinical breast examination and visual inspection of the cervix after application of 4% acetic acid). Univariate and multivariate logistic regression analyses are conducted to identify the predictors of participation in screening. Results: The average compliance is 71.43 and 64.93% for breast and cervix cancer screening, respectively, with the highest compliance in round 1. At the end of 3 screening rounds, 94 and 84% of the eligible women were screened at least once for breast and cervix cancer, respectively. Younger women, women from other than Hindu and Muslim communities, school level-educated women, women belonging to lower-income families, Marathi-speaking women, married women and women who had previously consulted for any breast or gynaecological complaints had higher compliance to participation in screening. Conclusions: Good compliance rates to screening have been demonstrated in the trial, reflecting acceptance of the study by the society, which has implications while translating the trial into a programme.

Sentinel-node biopsy in breast cancer.

Axillary lymph node dissection (ALND) is an important tool in staging patients with breast cancer. However, this procedure has several sequelae and complications and improvement in early diagnosis has led to an increasing number of cases of ALND in which axillary nodes are found to be negative. Sentinel node (SN) biopsy appears to be a less invasive alternative to ALND. The aim of the present study was to assess whether SN is a reliable indicator for axillary staging. We studied 126 consecutive patients with T1-T2 breast cancer and clinically negative axilla. In each case, 30-70 MBq of 99mTC-labelled colloidal albumin was injected subdermally close to the tumour and SN was visualised by lymphoscintigraphy. Surgery was performed 24 h after injection and the SN was removed under the guidance of a gamma ray-detecting probe. ALND was then undertaken in all cases. A histopathologic examination of the SNs was then made and the findings compared with the status of the other axillary nodes. SNs were identified and biopsied in 115/126 patients (91.3%) and correctly predicted the axillary status in 110/115 cases (95.6%). In five cases (4.4%), SNs were found to be negative, but other axillary nodes were positive. Our data confirm that SN biopsy is a good method for staging the axilla in patients with breast cancer. However, before SN biopsy can replace ALND in daily clinical practice, some technical aspects must be standardized, and clinical trials are required in order to clarify the prognostic impact of false-negative cases.

Revision surgery for breast cancer: single-institution experience.

At Tata Memorial Hospital, as a dedicated breast service at a tertiary cancer center in India, incompletely performed breast surgeries are encountered very frequently; however, there is a lack of published data on incompletely performed breast surgeries, revision surgeries, and their outcomes. Between March 2000 and November 2003, the authors audited 850 breast cancer patients who presented at their institute who had undergone surgery outside the institution. On the basis of study criteria, these patients were evaluated for completeness of surgery. Patients in whom the surgical intervention was considered incomplete were evaluated for a completion revision surgery. Of 850 patients, 424 (50%) had undergone surgical intervention with therapeutic intent. Of these 424 patients, 191 (45%) had received incomplete surgical intervention. Completion revision surgery was performed for 153 patients. Complete data were available for 148 patients, of which 123 patients had residual lymph nodes in the axilla. The median number of lymph nodes dissected was 8, and 64 patients had metastatic lymph node(s) left behind. A high proportion of patients with breast cancer who presented at the institute had undergone incomplete surgery outside in nonspecialty centers. Almost half of those patients who underwent incomplete surgery had surgically excisable disease left behind. The possible detrimental impact of inadequate surgical intervention may be very large in India and in other low-resource settings. Cancer 2008;113(8 suppl):2347–52.

Sentinel node biopsy versus low axillary sampling in women with clinically node negative operable breast cancer

BACKGROUNDnSentinel node biopsy (SNB) was initially conceived as excision of the first station axillary lymph node(s) (LN) identified by radioactive and/or blue dye uptake. The definition was subsequently enlarged to also include palpable lymph nodes in the vicinity of sentinel node(s) (SN). We reasoned that the excision of this combination of nodes might be best achieved by sampling the lower axilla.nnnMETHODSnEach patient underwent low axillary sampling (LAS) and identification of SN in the excised specimen followed by complete axillary lymph node dissection (ALND). LAS was defined as excision of all fibrofatty tissue overlying the second digitation of serratus anterior below the intercostobrachial nerve and was carried out following a pre-operative injection of radioactive colloid and an intra-operative injection of blue dye. Blue and/or hot nodes (B&/HN) in the dissected tissue and remaining axilla, along with any palpable nodes within the sampled tissue, were defined as SN. The primary endpoint of the study was to compare false negative rates (FNR) of SN with that of LAS in predicting axillary LN status (NCT00128362).nnnFINDINGSnThe study was performed between March 2004 and December 2011 in 478 women with clinically node negative axilla. On histopathological evaluation the median tumor size was 2.5xa0cm and axillary nodal metastases were found in 34.1% of patients. The FNR of SNB (12.7%, 95% CI 8.1-19.4) and LAS (10.5%, 95% CI 6.6-16.2) were not significantly different (pxa0=xa00.56). The FNR of B&/HN alone, without palpable nodes, (29.0%, 95% CI 22.5-36.6) was significantly inferior to those of SNB (pxa0=xa00.0007) and LAS (pxa0=xa00.0003).nnnINTERPRETATIONnLAS is as accurate as SNB in predicting axillary LN status in women with clinically node negative operable breast cancer. Confining SNB procedure to excision of B&/HN, significantly increases the risk of leaving behind metastatic lymph nodes in the axilla. LAS is an effective and low cost procedure that minimizes axillary surgery and can be implemented widely. Registry Name: Clinicaltrials.gov.nnnREGISTRATION NUMBERnNCT00128362.

Developing Countries: An Evolving Opportunity for Oncologic Research

4076. 16. Kinhikar RA, Deshpande SS, Mahantshetty U, et al. HDR brachytherapy combined with 3D conformal versus IMRT in left-sided breast cancer patients including internal mammary chain: comparative analysis of dosimetric and technical parameters. J Appl Clin Med Physics 2005;6:(3) 1–11. 1176 Badwe et al.: Oncologic Research in Developing Countries

Does primary tumor location have prognostic significance in operable breast cancer

DESIGN AND INTERVENTION Colleoni et al. performed a retrospective analysis of data from subjects with unilateral breast cancer enrolled in the International Breast Cancer Study Group (IBCSG) Trials I–VII and IX between 1978 and 1993. Patients underwent surgical resection of their primary tumors and all axillary lymph nodes; post operative radiotherapy was offered to those who had undergone a breast-conserving operation. Tumors were assigned to one of the following categories, based on location: ‘central’, ‘medial’, ‘lateral’, or ‘other’. Patients were then randomized to various adjuvant treatment regimens. Clinical and laboratory evaluations were carried out at 3 month intervals for the first 2 years, 6 month intervals for the following 3 years and annually thereafter. Multiple regression analysis was used to assess the effect of age, menopausal status, axillary node involvement, tumor size, adjuvant therapy regimen, estrogen-receptor expression, tumor grade, Does primary tumor location have prognostic significance in operable breast cancer?