Metastatic Prostate Cancer in a RAD51C Mutation Carrier.

A man, aged 61 years, with a history of hypogonadism and family history of cancer experienced persistent urinary difficulties with no visible prostate abnormalities. Laboratory testing and diagnostic imaging revealed a primary lesion in the prostate with lymph node involvement and multiple bone metastases. Treatment with androgen-deprivation therapy, 17,20-lyase inhibition, and bisphosphonates for 7 months was unsuccessful in preventing disease progression, but second-line chemotherapy and continued androgen-deprivation therapy improved prostate specific antigen levels. During the patient's second treatment regimen, his daughter received a diagnosis of breast cancer. The patient's daughter underwent genetic testing for oncogenic mutations, and it was discovered that she carried a mutation in RAD51C, a gene encoding a protein involved in DNA repair and genomic maintenance. Subsequent genetic testing of the patient revealed mutation in RAD51C as well. For patients with metastatic prostate cancer who are unresponsive to standard treatment and who have a positive family history of cancer, genetic testing may be warranted to develop alternative treatment regimens for the patient and guide family discussions regarding cancer risk. Targeted agents like poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors may be a consideration in prostate cancer patients with DNA repair mutations and with refractory disease.

The McGill Brisbane Symptom Score in relation to survival in pancreatic adenocarcinoma: a validation study.

PURPOSE: The McGill Brisbane Symptom Score (MBSS) is a clinical score for pancreatic cancer patients upon initial presentation that takes into account four variables (weight loss, abdominal pain, jaundice, and history of smoking) to stratify them into two MBSS intensity categories. Several studies have suggested that these categories are strongly associated with eventual survival in patients with resectable (rPCa) and unresectable (uPCa) pancreatic cancer. This study aimed to validate the MBSS in a cohort of patients with pancreatic cancer from a single institution. METHODS: Survival time by resection status and MBSS intensity category were analyzed among 633 patients from our institution between 2001 and 2010. Hazard ratios for death using Cox proportional hazards models, with age as the timescale, adjustment for sex and year of diagnosis, and stratified by adjuvant chemotherapy status were estimated. RESULTS: Median survival time was the longest in patients with low-intensity MBSS and rPCa (817 days), whereas the shortest survival time was found among patients with uPCa regardless of MBSS status (144-147 days). After consideration of age and chemotherapy status, high-intensity MBSS was associated with poorer survival for both rPCa (HR 1.64; 95 % CI 1.07-2.52) and uPCa (HR 1.35; 95 % CI 1.06-1.72). CONCLUSIONS: Preoperative MBSS intensity is a useful prognostic indicator of survival in resectable as well as unresectable pancreatic cancer.

Overview of recent trends in diagnosis and management of leptomeningeal multiple myeloma.

Neurological complications related to multiple myeloma (MM) are not uncommon; however, direct involvement of the central nervous system (CNS) is extremely rare and represents a diagnostic and therapeutic challenge. Significant survival difference has been noted with the introduction of novel therapy in patients with MM, but their effect on the incidence and their use for management of leptomeningeal myeloma (LMM) is uncertain. Analysis of published data demonstrates its recent increased incidence, median time to CNS presentation, and slight improvement in median survival after diagnosis of LMM. Less common MM isotypes have been overrepresented in LMM. CNS relapse occurred mostly in patients with Durie-Salmon stage III MM. Despite treatments, standard or experimental, the survival rates of LMM remain dismal. Monitoring high risk patients closely, even after achieving complete remission, may be useful in early detection of LMM. As we gain better understanding of LMM, we recommend that future research and clinical care focus on earlier diagnosis and development of more efficient CNS-directed therapy to improve survival in this patient population.

Prognostic significance of full-length estrogen receptor beta expression in stage I-III triple negative breast cancer.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which there is a need to identify new therapeutic targets. Full-length estrogen receptor beta (ERß1) may be a possible target given its antiproliferative effects on breast cancer cells. The prognostic significance of ERß in breast cancer subtypes has remained elusive, and disparate results observed across previously published reports might be due to the detection of multiple ERß isoforms, the lack of specific antibodies and the use of different cutoffs to define ERßpositivity. The objective of this retrospective study was to determine the association between ERß1 expression and disease-free and overall survival, as well as Ki67 expression, in non-metastatic TNBC. Immunohistochemical protocols were optimized using xenograft tissues obtained from a breast cancer cell line with inducible ERß1 expression. ERß1 localization and expression were assessed in two cohorts of TNBC using the VECTRA(TM) platform. There was a close relationship between nuclear and cytoplasmic ERß1 expression. ERß1 was expressed in a subset of TNBCs, but its expression was significantly associated with Ki67 in only one of the cohorts. There was no significant association between ERß1 expression and disease-free and overall survival in either cohort. Although these results suggest that ERß1 expression alone may not be informative in TNBCs, this study provides a new strategy for optimizing and objectively measuring ERß1 expression in tissues, which may provide a standard for ERß1 immunohistochemistry in future large-scale clinical studies aimed at better understanding the role of ERß1 in breast cancer.

All-cause mortality is decreased in women undergoing annual mammography before breast cancer diagnosis.

OBJECTIVE: The value of annual mammography remains an area of debate because of concerns regarding risk versus benefit. The potential for harm due to overdiagnosis and treatment of clinically insignificant cancers may not be captured by breast cancer-specific mortality. Instead, we examined all-cause mortality as a function of missed annual mammography examinations before breast cancer diagnosis. MATERIALS AND METHODS: Primary breast cancer cases diagnosed in the Marsh-field Clinic Health System from 2002 through 2008 were identified for retrospective review, and whether annual mammography examinations had been performed in the 5 years before diagnosis was assessed. RESULTS: Analyses were performed on 1421 women with breast cancer. After adjustment of data for age, comorbidity status, a family history of breast cancer, insurance status, medical encounter frequency, and the calendar year, women who had missed any of the previous five annual mammography examinations had a 2.3-fold increased risk of all-cause mortality compared with subjects with no missed mammography examinations (hazard ratio=2.28; 95% CI, 1.58-3.30; p<0.0001). Additionally, an analysis by the number of missed annual mammography examinations showed a progressive increase in hazard as the number of missed mammography studies increased. CONCLUSION: These results suggest that annual mammography before breast cancer diagnosis is predictive of increased overall survival. A stepwise decline in overall survival was noted for each additional missed mammography examination. These results are similar to findings in the literature for breast cancer-specific mortality and illustrate the importance of recommending annual mammography to all eligible women.

Survival Comparisons for Breast Conserving Surgery and Mastectomy Revisited: Community Experience and the Role of Radiation Therapy.

OBJECTIVES: Evidence suggests superiority of breast conserving surgery (BCS) plus radiation over mastectomy alone for treatment of early stage breast cancer. Whether the superiority of BCS plus radiation is related to the surgical approach itself or to the addition of adjuvant radiation therapy following BCS remains unclear. MATERIALS AND METHODS: We conducted a retrospective cohort study of women with breast cancer diagnosed from 1994-2012. Data regarding patient and tumor characteristics and treatment specifics were captured electronically. Kaplan-Meier survival analyses were performed with inverse probability of treatment weighting to reduce selection bias effects in surgical assignment. RESULTS: Data from 5335 women were included, of which two-thirds had BCS and one-third had mastectomy. Surgical decision trends changed over time with more women undergoing mastectomy in recent years. Women who underwent BCS versus mastectomy differed significantly regarding age, cancer stage/grade, adjuvant radiation, chemotherapy, and endocrine treatment. Overall survival was similar for BCS and mastectomy. When BCS plus radiation was compared to mastectomy alone, 3-, 5-, and 10-year overall survival was 96.5% vs 93.4%, 92.9% vs 88.3% and 80.9% vs 67.2%, respectively. CONCLUSION: These analyses suggest that survival benefit is not related only to the surgery itself, but that the prognostic advantage of BCS plus radiation over mastectomy may also be related to the addition of adjuvant radiation therapy. This conclusion requires prospective confirmation in randomized trials.

Cardiovascular toxicity associated with adjuvant trastuzumab therapy: prevalence, patient characteristics, and risk factors.

Before the advent of the human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody trastuzumab, HER2-positive breast cancers were difficult to treat and had a poor prognosis. Adjuvant trastuzumab is now an important part of the treatment regimen for many women with HER2-positive breast cancer and has undoubtedly resulted in a significant improvement in prognosis, but it is associated with a risk for cardiotoxicity. In this review, we describe the prevalence, patient characteristics, and risk factors for cardiotoxicity associated with use of adjuvant trastuzumab. Understanding risk factors for trastuzumab-induced cardiotoxicity and appropriate patient monitoring during trastuzumab treatment allows for safe and effective use of this important adjuvant therapy.

Geographical and seasonal barriers to mammography services and breast cancer stage at diagnosis.

INTRODUCTION: Routine mammography screening and early detection are important prognostic indicators for breast cancer. Geographical and seasonal barriers to mammography services and relationship to breast cancer stage at diagnosis were examined. METHODS: Travel time to mammography center, seasonal distribution of mammogram use, mammography frequency, and stage of cancer were retrospectively examined in 1428 female patients diagnosed with primary breast cancer at a tertiary care clinic system in Wisconsin, USA, from 2002 to 2008. RESULTS: Women with no missed mammograms before diagnosis lived a median of 15 minutes from the nearest facility, while those who missed five of their past five annual mammograms lived nearly twice as far, with a median travel time of 27 minutes (p<0.0001). There was a direct relationship between travel time to nearest mammogram facility and stage of breast cancer at diagnosis, with travel time increasing from 17 to 24 minutes for stage 0 and stage 4 breast cancers, respectively (p=0.0586). Women were less likely to undergo mammography screening during the winter months (p<0.0001), especially women with greater than 30 mi (48.3 km) to travel to the nearest mammogram facility (p=0.0448). CONCLUSIONS: In the studied service area, travel time to nearest mammogram center appears inversely related to regular mammography screening and breast cancer stage at diagnosis. Mammograms are less common in the winter, especially in women with further to travel. This is the first study to demonstrate that inclement winter weather may impact on screening behaviors in rural areas and demonstrates the importance of considering climate as part of geographical access to preventative care.

Antithrombin levels are unaffected by warfarin use.

CONTEXT: The results of studies among patients with antithrombin deficiency have suggested that the use of warfarin will increase the level of antithrombin. OBJECTIVE: To reevaluate the effect of warfarin on antithrombin levels using an automated amidolytic method in current use. DESIGN: Antithrombin levels were measured in patients who were receiving warfarin for atrial fibrillation and were compared with antithrombin levels in preoperative patients who had not received warfarin. RESULTS: Patients receiving warfarin had a mean antithrombin level of 100.40% (range, 81%-153%). Patients not receiving warfarin had a mean antithrombin level of 99.97% (range, 79%-120%). The Student t test was not significant for a difference between the mean antithrombin levels of the 2 populations. CONCLUSIONS: The use of warfarin does not increase the level of antithrombin in patients receiving the drug.

A novel method for studying the temporal relationship between type 2 diabetes mellitus and cancer using the electronic medical record.

BACKGROUND: We developed an algorithm for the identification of patients with type 2 diabetes and ascertainment of the date of diabetes onset for examination of the temporal relationship between diabetes and cancer using data in the electronic medical record (EMR). METHODS: The Marshfield Clinic EMR was searched for patients who developed type 2 diabetes between January 1, 1995 and December 31, 2009 using a combination of diagnostic codes and laboratory data. Subjects without diabetes were also identified and matched to subjects with diabetes by age, gender, smoking history, residence, and date of diabetes onset/reference date. RESULTS: The final cohort consisted of 11,236 subjects with and 54,365 subjects without diabetes. Stringent requirements for laboratory values resulted in a decrease in the number of potential subjects by nearly 70%. Mean observation time in the EMR was similar for both groups with 13-14 years before and 5-7 years after the reference date. The two cohorts were largely similar except that BMI and frequency of healthcare encounters were greater in subjects with diabetes. CONCLUSION: The cohort described here will be useful for the examination of the temporal relationship between diabetes and cancer and is unique in that it allows for determination of the date of diabetes onset with reasonable accuracy.

Breast cancer incidence before and after diagnosis of type 2 diabetes mellitus in women: increased risk in the prediabetes phase.

The physiological changes associated with type 2 diabetes mellitus begin before disease onset, yet few have examined the incidence of cancer both before and after diabetes onset. We examined the temporal relationship between diabetes and breast cancer risk. Breast cancer risk was assessed in a retrospective cohort study using patient data from the Marshfield Clinic electronic medical record including 5423 women who developed diabetes between 1 January 1995 and 31 December 2009 (reference date) and 26 346 nondiabetic women matched by age, smoking history, residence, and reference date. Breast cancer risk was assessed before and after reference date, adjusting for matching variables, BMI, insurance status, and comorbidities. Primary outcomes included hazard ratio (HR) and number of women needed to be exposed to diabetes for one additional person to be harmed - that is, develop breast cancer (NNEH). HR for breast cancer before diabetes diagnosis was 1.16 (95% CI 1.03-1.31, P=0.0150) and NNEH was 99 at time of diabetes onset. HR for breast cancer after diabetes diagnosis was not significant at 1.07 (95% CI 0.90-1.28, P=0.422), and NNEH was 350 at 10 years post diabetes onset. Diabetic women are at the greatest increased risk of breast cancer near the time of diabetes diagnosis. The comparative NNEH increased shortly after diagnosis and as the duration of diabetes increased. Breast cancer risk appears to be increased during the prediabetes phase, waning after diagnosis, raising important issues regarding timing of breast cancer prevention interventions in women with diabetes.

Type 2 diabetes mellitus, glycemic control, and cancer risk.

Type 2 diabetes mellitus is characterized by prolonged hyperinsulinemia, insulin resistance, and progressive hyperglycemia. Disease management relies on glycemic control through diet, exercise, and pharmacological intervention. The goal of the present study was to examine the effects of glycemic control and the use of glucose-lowering medication on the risk of breast, prostate, and colon cancer. Patients diagnosed with type 2 diabetes mellitus (N=9486) between 1 January 1995 and 31 December 2009 were identified and data on glycemic control (hemoglobin A1c, glucose), glucose-lowering medication use (insulin, metformin, sulfonylurea), age, BMI, date of diabetes diagnosis, insurance status, comorbidities, smoking history, location of residence, and cancer diagnoses were electronically abstracted. Cox proportional hazards regression modeling was used to examine the relationship between glycemic control, including medication use, and cancer risk. The results varied by cancer type and medication exposure. There was no association between glycemic control and breast or colon cancer; however, prostate cancer risk was significantly higher with better glycemic control (hemoglobin A1c ≤ 7.0%). Insulin use was associated with increased colon cancer incidence in women, but not with colon cancer in men or breast or prostate cancer risk. Metformin exposure was associated with reduced breast and prostate cancer incidence, but had no association with colon cancer risk. Sulfonylurea exposure was not associated with risk of any type of cancer. The data reported here support hyperinsulinemia, rather than hyperglycemia, as a major diabetes-related factor associated with increased risk of breast and colon cancer. In contrast, hyperglycemia appears to be protective in the case of prostate cancer.

A core-item reviewer evaluation (CoRE) system for manuscript peer review.

Manuscript peer review is essential for ensuring accountability to all involved in the publication process, including authors, journals, and readers. Lack of consensus regarding what constitutes an accountable manuscript peer review process has resulted in varying practices from one journal to the next. Currently, reviewers are asked to make global judgments about various aspects of a paper for review irrespective of whether guided by a review checklist or not, and several studies have documented gross disagreement between reviewers of the same manuscript. We have previously proposed that the solution may be to direct reviewers to concrete items that do not require global judgments but rather provide a specific choice, along with referee justification for such choices. This study evaluated use of such a system via an international survey of health care professionals who had recently reviewed a health care--related manuscript. Results suggest that use of such a peer review system by reviewers does indeed improve interreviewer agreement, and thus, has the potential to support more consistent and effective peer review, if introduced into journal processes for peer review.

Utilization of neoadjuvant chemotherapy varies in the treatment of women with invasive breast cancer.

BACKGROUND: Treatment with neoadjuvant chemotherapy (NAC) has made it possible for some women to be successfully treated with breast conservation therapy (BCT ) who were initially considered ineligible. Factors related to current practice patterns of NAC use are important to understand particularly as the surgical treatment of invasive breast cancer has changed. The goal of this study was to determine variations in neoadjuvant chemotherapy use in a large multi-center national database of patients with breast cancer. METHODS: We evaluated NAC use in patients with initially operable invasive breast cancer and potential impact on breast conservation rates. Records of 2871 women ages 18-years and older diagnosed with 2907 invasive breast cancers from January 2003 to December 2008 at four institutions across the United States were examined using the Breast Cancer Surgical Outcomes (BRCASO) database. Main outcome measures included NAC use and association with pre-operatively identified clinical factors, surgical approach (partial mastectomy [PM] or total mastectomy [TM]), and BCT failure (initial PM followed by subsequent TM). RESULTS: Overall, NAC utilization was 3.8%l. Factors associated with NAC use included younger age, pre-operatively known positive nodal status, and increasing clinical tumor size. NAC use and BCT failure rates increased with clinical tumor size, and there was significant variation in NAC use across institutions. Initial TM frequency approached initial PM frequency for tumors >30-40 mm; BCT failure rate was 22.7% for tumors >40 mm. Only 2.7% of patients undergoing initial PM and 7.2% undergoing initial TM received NAC. CONCLUSIONS: NAC use in this study was infrequent and varied among institutions. Infrequent NAC use in patients suggests that NAC may be underutilized in eligible patients desiring breast conservation.

Increased risk of colon cancer in men in the pre-diabetes phase.

BACKGROUND: Historically, studies exploring the association between type 2 diabetes mellitus (DM) and cancer lack accurate definition of date of DM onset, limiting temporal analyses. We examined the temporal relationship between colon cancer risk and DM using an electronic algorithm and clinical, administrative, and laboratory data to pinpoint date of DM onset. METHODS: Subjects diagnosed with DM (N = 11,236) between January 1, 1995 and December 31, 2009 were identified and matched at a 5∶1 ratio with 54 365 non-diabetic subjects by age, gender, smoking history, residence, and diagnosis reference date. Colon cancer incidence relative to the reference date was used to develop Cox regression models adjusted for matching variables, body mass index, insurance status, and comorbidities. Primary outcomes measures included hazard ratio (HR) and number needed to be exposed for one additional person to be harmed (NNEH). RESULTS: The adjusted HR for colon cancer in men before DM onset was 1.28 (95% CI 1.04-1.58, P = 0.0223) and the NNEH decreased with time, reaching 263 at DM onset. No such difference was observed in women. After DM onset, DM did not appear to alter colon cancer risk in either gender. CONCLUSIONS: Colon cancer risk is increased in diabetic men, but not women, before DM onset. DM did not alter colon cancer risk in men or women after clinical onset. In pre-diabetic men, colon cancer risk increased as time to DM onset decreased, suggesting that the effects of the pre-diabetes phase on colon cancer risk in men are cumulative.

Mammography utilization: patient characteristics and breast cancer stage at diagnosis.

OBJECTIVE: Missed mammograms represent missed opportunities for earlier breast cancer diagnosis. The purposes of this study were to identify patient characteristics associated with missed mammograms and to examine the association between missed mammograms and breast cancer stage at diagnosis. MATERIALS AND METHODS: Mammography frequency and cancer stage were retrospectively examined in 1368 cases of primary breast cancer diagnosed at our clinic from 2002 to 2008. RESULTS: Regardless of age (median, 62.7 years), 1428 women who underwent mammography were more likely to have early-stage (stage 0-II) breast cancer at diagnosis than were those who did not undergo mammography (p < 0.001). Similarly, the number of mammographic examinations in the 5 years before diagnosis was inversely related to stage: 57.3% (94/164) of late-stage cancers were diagnosed in women missing their last five annual mammograms. In a multivariate analysis, family history of breast cancer was most predictive of undergoing mammography (odds ratio, 3.492; 95% CI, 2.616-4.662; p < 0.0001) followed by number of medical encounters (odds ratio, 1.022; 95% CI, 1.017-1.027; p < 0.0001). Time to travel to the nearest mammography center was also predictive of missing mammograms: Each additional minute of travel time decreased the odds of undergoing at least one mammographic examination in the 5 years before cancer diagnosis (odds ratio, 0.990; 95% CI, 0.986-0.993; p < 0.0001). CONCLUSION: Missing a mammogram, even in the year before a breast cancer diagnosis, increases the chance of a cancer diagnosis at a later stage. Interventions to encourage use of mammography may be of particular benefit to women most likely to miss mammograms, including those with no family history of breast cancer, fewer encounters with the health care system, and greater travel distance to the mammography center.

Reliability of reviewer ratings in the manuscript peer review process: an opportunity for improvement.

Accountability to authors and readers cannot exist without proper peer review practices. Thus, the information a journal seeks from its peer reviewers and how it makes use of this information is paramount. Disagreement amongst peer reviewers can be considerable, resulting in very diverse comments to authors. Incorporating a clear scoring system for key concrete items and requiring referees to provide justification for scores may ensure that reviewers contribute in a consistently fair and effective manner. This article evaluates information collected from reviewers and proposes an example of a system that aims to improve accountability, while having the potential to make it easier for reviewers to perform a more objective review.

Prostate cancer risk in pre-diabetic men: a matched cohort study.

BACKGROUND: Diagnosis and duration of type 2 diabetes mellitus (DM) appear to be associated with decreased prostate cancer risk. Limitations of previous studies include methods of subject selection and accurate definition of DM diagnosis. We examined the temporal relationship between DM and prostate cancer risk exploring the period of greatest risk starting from the prediabetic to the post-diabetic period using clinical and administrative data to accurately define the date of DM diagnosis. METHODS: We identified 5,813 men who developed DM between January 1, 1995 and December 31, 2009 (reference date, date of DM onset or matched date for non-diabetic cohort) and 28,019 non-diabetic men matched by age, smoking history, residence, and reference date. Prostate cancer incidence before and after the reference date was assessed using Cox regression modeling adjusted for matching variables, body mass index, insurance status, and comorbidities. Primary outcomes included hazard ratio (HR) and number needed to be exposed to DM for one additional person to be harmed (NNEH) or benefit (NNEB) with respect to prostate cancer risk. RESULTS: After full adjustment, the HR for prostate cancer before DM diagnosis was 0.96 (95% CI 0.85-1.08; P=0.4752), and the NNEB was 974 at DM diagnosis. After the reference date, the fully-adjusted HR for prostate cancer in diabetic men was 0.84 (95% CI 0.72-0.97, P=0.0167), and the NNEB 3 years after DM onset was 425. The NNEB continued to decrease over time, reaching 63 at 15 years after DM onset, suggesting an increasing protective effect of DM on prostate cancer risk over time. No significant difference between the diabetic and non-diabetic cohort was found prior to reference date. CONCLUSION: Prostate cancer risk is not reduced in pre-diabetic men but decreases after DM diagnosis and the protective effect of DM onset on prostate cancer risk increases with DM duration.

Breast and prostate cancer survivors in a diabetic cohort: results from the Living with Diabetes Study.

OBJECTIVE: Diabetes is more common in cancer survivors than in the general population. The objective of the present study was to determine cancer frequency in a cohort of patients with diabetes and to examine demographic, clinical, and quality of life differences between cancer survivors and their cancer-free peers to inform better individualized care. METHODS: Self-reported survey data from 3,466 registrants with type 2 diabetes from Australia's National Diabetes Services Scheme (NDSS) were analyzed to compare relevant variables between cancer survivors and cancer-free patients. Analyses were focused on breast and prostate cancer to reflect the most common cancers in women and men, respectively. RESULTS: Five percent of diabetic women reported a history of breast cancer and 4.2% of men reported a history of prostate cancer. Diabetic patients with a history of breast or prostate cancer were older at time of survey and diabetes diagnosis, less likely to report metformin use (women), and more likely to have two or more comorbidities than their cancer-free peers. More diabetic prostate cancer survivors also reported problems with mobility and performing usual tasks. However, cancer-free diabetic subjects reported a lower diabetes-dependent quality of life than diabetic cancer survivors. There was no association between cancer survivorship and duration of diabetes, indices of glycemic control, obesity, or diabetic complications. CONCLUSIONS: Cancer survivors comprise a significant minority of diabetic patients that are particularly vulnerable and may benefit from interventions to increase screening and treatment of other comorbidities and promote a healthy lifestyle.