Vitamin D Receptor Gene Polymorphisms Predict Acquired Resistance to Clodronate Treatment in Patients with Paget’s Disease of Bone

Bisphosphonates are first-choice drugs for treatment of Paget’s disease of bone (PDB); nevertheless, acquired resistance to bisphosphonate therapy has been described in PDB patients. The 1,25(OH)₂D₃/vitamin D receptor (VDR) system influences the effectiveness of antiresorptive treatments in metabolic bone disorders. This study evaluated the relationship between acquired resistance to clodronate treatment and BsmI, TaqI, and FokI VDR polymorphisms in Caucasian patients with polyostotic PDB (n = 84). We also evaluated the influence of mutations in exons 7 and 8 of the sequestosome 1 (SQSTM1) gene on the occurrence of this phenomenon. All patients were treated from diagnosis for several cycles with intravenous clodronate infusion (1500 mg/cycle). Acquired resistance to clodronate treatment was defined as the failure of total alkaline phosphatase serum levels to be suppressed to at least 50% of the patient’s previous highest levels during a subsequent treatment course with the same compound, which produced a >50% response after the first exposure. During an observation period of 10.6 ± 2.7 years, 31 PDB patients (36.9%) showed acquired resistance to clodronate. It was observed that the bb and TT VDR genotypes as well as a lower persistence of the biochemical response to the first treatment course were significantly and independently associated with the risk of developing resistance to clodronate treatment. SQSTM1 gene mutations, considered altogether, did not influence the occurrence of this phenomenon. Our results indicate that 3′VDR allelic variants and duration of biochemical response to the first treatment course are independent predictors of acquired resistance to clodronate treatment in patients with polyostotic PDB.     

Outcomes of Delays in Time to Treatment in Triple Negative Breast Cancer

Background

Compared with other breast cancer subtypes, triple negative breast cancers (TNBC) are associated with higher recurrence rates and worse survival. Because of the aggressive nature of TNBC, outcomes may be more sensitive to delays in time to treatment. This study evaluates whether delays from diagnosis to initial treatment in TNBC impacts survival or locoregional recurrence (LRR).

Methods

Retrospective review of TNBC patients treated between January 2004 and January 2011 at an academic center was performed. Data collected included demographics, pathology, treatment, recurrence, and survival. Interval to treatment was defined as days from pathologic diagnosis to first local or systemic treatment. The t test, Cox regression, and Kaplan–Meier analyses were used to evaluate impact of time to treatment on overall survival and LRR.

Results

Median follow-up was 40 months for 301 TNBC patients. Mean interval to treatment was 46 ± 2 days. Higher initial stage yielded worse survival (p < .0001). Interval to treatment did not impact overall survival (p = .24), although there was a trend toward worse survival with delays of >90 days (p = .06). LRR was seen in 20 patients (7 %). Median time to recurrence was 15 months. Time to treatment was 38 ± 6 days for patients with LRR versus 44 ± 2 days without a recurrence (p = .37). Short delay in time to treatment did not impact LRR (p = .54).

Conclusions

In TNBC, a short delay from pathologic diagnosis to initial treatment does not appear to adversely affect survival or LRR. Appropriate time to perform evaluations such as genetic testing, imaging, or additional consultation can be taken to guide optimal treatment options.     

Treatment of Bone Metastases in Patients with Advanced Breast Cancer

Bone metastases are usually associated with a variety of skeletal related events (SREs), a term covering both complications (pathological fractures, spinal cord compression) and the need for therapeutic intervention (radiotherapy, surgery to bone) for painful bone lesions and/or lesions carrying a high risk of fracture by which the patient's quality of life, functioning, and independence may be compromised. In view of the availability of improved therapeutic approaches for oncological diseases and the resulting improvements of median overall survival, the aim of preventing and delaying the occurrence of SREs becomes more important. To avoid, wherever possible, therapies requiring hospitalization, is another relevant goal. In recent years, bisphosphonates, along with available tumor-specific medication (chemotherapy, hormone therapy), constituted the standard of care for preventing skeletal complications in treating patients with bone metastases. Recently, a therapeutical alternative with potentially superior efficacy has been found in denosumab, a fully human monoclonal antibody that binds to the receptor activator of nuclear factor-κB ligand (RANKL), thus preventing osteoclast-mediated bone resorption and specifically interfering with bone metabolism.     

Long-Term Outcomes in Patients with Radiation-Associated Angiosarcomas of the Breast Following Surgery and Radiotherapy for Breast Cancer

Background

Radiation-associated angiosarcoma (RAAS) is a devastating disease occasionally observed in breast cancer patients treated with radiation. Due to its rarity, our knowledge—of disease risk factors, epidemiology, treatment, and outcome—is extremely limited. Therefore, we sought to identify clinicopathologic factors associated with local and distant recurrence and disease-specific survival (DSS).

Methods

Radiation-associated angiosarcoma was defined as pathologically confirmed breast or chest wall angiosarcoma arising within a previously irradiated field. A comprehensive search of our institutional tumor registry (1/1/93 through 2/28/11) was used to identify patients (n = 95 females). Patient, original tumor, RAAS treatment, and outcome variables were retrospectively retrieved and assembled into a database.

Results

The median follow-up for all RAAS patients was 10.3 (range, 2.4–31.8) years. The latency period following radiation exposure ranged from 1.4 to 26 (median, 7) years. One-year and 5-year DSS rates were 93.5 and 62.6 %, respectively. Reduced risk of local recurrence was observed in patients who received chemotherapy (P = 0.0003). In multivariable analysis, size was found to be an independent predictor of adverse outcome (P = 0.015).

Conclusions

Our study demonstrates that RAAS exhibits high recurrence rates. It also highlights the need for well-designed, multicenter, clinical trials to inform the true utility of chemotherapy in this disease.     

Early Trajectories of Patient Reported Outcomes in Breast Cancer Patients Undergoing Lumpectomy Versus Mastectomy

Annals of Surgical Oncology - This study was designed to: (1) characterize longitudinal patient-reported outcomes (PROs) between breast cancer patients undergoing lumpectomy and mastectomy and (2)...     

Long-Term Comparison of Aesthetical Outcomes After Oncoplastic Surgery and Lumpectomy in Breast Cancer Patients

Annals of Surgical Oncology - Lumpectomy may result in major deformities and asymmetries in approximately one-third of patients. Although oncoplastic surgery (OP) could be a useful alternative to...     

High Hospital Volume Is Associated with Better Outcomes for Breast Cancer Surgery: Analysis of 233,247 Patients

Background: The relationship between hospital volume and outcomes needs to be further elucidated for low-risk procedures such as surgical therapy of localized breast cancer. The objective of this investigation was to assess the relationship between hospital volume and outcomes for breast cancer surgery. Methods: A total of 233,247 patients who underwent breast-conserving therapy (BCT) and breast-ablative therapy (BAT) for localized breast cancer were extracted from 13 years (1988–2000) of the Nationwide Inpatient Samples. Hospital volume was classified as low (<30 cases/year), intermediate (≥ 30 to <70cases/year), and high (≥ 70 cases/year). Multiple linear and logistic regression analyses were used to assess the risk-adjusted association between hospital volume and outcomes. Results: In risk-adjusted analyses, patients operated on at low-volume hospitals were 3.04 (p = 0.03) times more likely to die after BCT compared with patients operated on at high-volume hospitals. Similarly, low-volume hospitals had a significantly higher likelihood of postoperative complications (odds ratio [OR] = 1.73, p = 0.01 for BCT; OR = 1.44, p < 0.001 for BAT) compared with high-volume hospitals. Compared with low-volume hospitals, length of hospital stay was significantly shorter and nonroutine patient discharge significantly lower for high-volume providers for both BCT and BAT (all p < 0.001). Patients were also significantly less likely to undergo BCT if operated on in a low- or intermediate-volume hospital compared with a high-volume provider (p < 0.001). Conclusions: High-volume hospitals had significantly lower nonroutine patient discharge, postoperative morbidity and mortality, shorter length of hospital stay, and higher likelihood of performing BCT. Referral of patients with localized breast cancer to high-volume hospitals may be justified.     

CYP2D6 Genetic Polymorphisms and Phenotypes in Different Ethnicities of Malaysian Breast Cancer Patients

The cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) is an enzyme that is predominantly involved in the metabolism of tamoxifen. Genetic polymorphisms of the CYP2D6 gene may contribute to inter‐individual variability in tamoxifen metabolism, which leads to the differences in clinical response to tamoxifen among breast cancer patients. In Malaysia, the knowledge on CYP2D6 genetic polymorphisms as well as metabolizer status in Malaysian breast cancer patients remains unknown. Hence, this study aimed to comprehensively identify CYP2D6 genetic polymorphisms among 80 Malaysian breast cancer patients. The genetic polymorphisms of all the 9 exons of CYP2D6 gene were identified using high‐resolution melting analysis and confirmed by DNA sequencing. Seven CYP2D6 alleles consisting of CYP2D6*1, CYP2D6*2, CYP2D6*4, CYP2D6*10, CYP2D6*39, CYP2D6*49, and CYP2D6*75 were identified in this study. Among these alleles, CYP2D6*10 is the most common allele in both Malaysian Malay (54.8%) and Chinese (71.4%) breast cancer patients, whereas CYP2D6*4 in Malaysian Indian (28.6%) breast cancer patients. In relation to CYP2D6 genotype, CYP2D6*10/*10 is more frequently observed in both Malaysian Malay (28.9%) and Chinese (57.1%) breast cancer patients, whereas CYP2D6*4/*10 is more frequently observed in Malaysian Indian (42.8%) breast cancer patients. In terms of CYP2D6 phenotype, 61.5% of Malaysian Malay breast cancer patients are predicted as extensive metabolizers in which they are most likely to respond well to tamoxifen therapy. However, 57.1% of Chinese as well as Indian breast cancer patients are predicted as intermediate metabolizers and they are less likely to gain optimal benefit from the tamoxifen therapy. This is the first report of CYP2D6 genetic polymorphisms and phenotypes in Malaysian breast cancer patients for different ethnicities. These data may aid clinicians in selecting an optimal drug therapy for Malaysian breast cancer patients, hence improve the clinical outcome of the patients.     

A Modified Excision for Combined Reduction Mammoplasty and Breast Conservation Therapy in the Treatment of Breast Cancer

Wide local excision combined with postoperative radiotherapy is a useful technique for patients with breast cancer. For patients with macromastia whose tumor is situated in the lower pole of the breast, a breast reduction (keyhole\inverted T pattern ) can be used to achieve wide local excision. However, for patients whose tumor is not in the inferior portion of the breast, and in whom this cancer also is situated close to the skin (requiring excision of skin with a 1-cm margin for oncologic safety), the traditional keyhole pattern cannot be used. A modification of the keyhole pattern\inverted T is described. The pedicle used depends on the site of the tumor. Although the breast scars are in different positions, a similar breast shape as well as symmetry still can be achieved. This is a useful technique for a select subgroup of patients. The outcomes for three patients are presented.     

Polymorphisms in the Serotonin Transporter Protein (SERT) Gene in Patients With Pulmonary Arterial Hypertension

Serotonin is a potent vasoconstrictor and pulmonary vascular growth factor whose concentration is increased in patients with pulmonary arterial hypertension (PAH). Its functions are mediated in part by the serotonin transporter protein (SERT) whose gene can have two allelic forms, both long (L) and short (S). The first was associated with greater function.ObjectivesTo determine whether the prevalence of the L allelic form of SERT is higher in patients with PAH than in the general population. To observe whether there are any clinical differences in patients with PAH based on the SERT allele.MethodsWe included patients diagnosed with PAH with catheterization based on the established criteria. Peripheral blood samples were taken and the DNA was extracted from the peripheral leukocytes. We amplified the promoter region of SERT by polymerase chain reaction and separated the products by electrophoresis. The patient samples were compared with samples from 50 healthy controls and among the most common types of PAH (idiopathic, thromboembolic and associated with connective tissue disorders). Several clinical variables were assessed according to the SERT gene alleles.ResultsThe study included 50 patients, and adequate samples were obtained in 49 patients (30 women). Mean age at diagnosis was 56±16 years. No differences were seen in the distribution of alleles between patients and controls (P=.54). There were no differences among the three most common types of PAH (P=.3). The most frequent allelic form was LS (54% patients, 56% controls). There were no differences in either age of diagnosis or response to treatment according to the SERT alleles. There was a trend toward higher mean pulmonary pressure levels in the LL forms (49±5 mmHg vs 42±9 mmHg, P=.07).ConclusionsThe distribution of SERT gene alleles does not appear to be different in patients with PAH than in the normal population. Different types of PAH have a similar distribution of alleles. The LL forms do not appear to confer either clinical differences or differences in response to treatment.     

Limited Surgery and Tamoxifen in the Treatment of Elderly Breast Cancer Patients

Abstract A conservative approach to treating breast cancer patients was adopted for those more than 70 years of age with T1-3 and small localized T4b N0-1 lesions. It consists of tumor excision or simple mastectomy with adjuvant tamoxifen. From the prospective breast cancer database, patients 70 years or older at the time of diagnosis were identified for the period January 1990 to December 1996. Demographic, clinical, pathological, and oncologic data were retrieved. A total of 236 patients were identified. Ninety-seven patients (41%) were treated according to the conservative protocol. Of these, 74 had a tumor excision and 23 had a simple mastectomy. Their mean age was 79 years. TNM staging was stage I in 18 patients, stage II in 66 patients, and stage III in 13 patients. There was no 30-day mortality. Eleven patients were not compliant with tamoxifen use. Two patients were lost to follow-up. The mean follow-up is 51 months (range 4 to 109 months). The cumulative incidence of local and regional recurrence at 8 years is 5% and 7%, respectively. Locoregional recurrences were controlled with excision, mastectomy, or axillary dissection. The cumulative disease-specific, overall, and disease-free survival at 5 years is 86%, 64% and 46%, respectively. Tumor excision or simple mastectomy with tamoxifen offers sufficient tumor control for elderly patients. Axillary dissection and breast or chest wall radiotherapy can safely be omitted, thereby greatly reducing health care resource utilization.     

Analysis of the Lymphatic Stream to Predict Sentinel Nodes in Gastric Cancer Patients

Purpose

To investigate the pattern of lymphatic drainage in gastric cancer patients to predict sentinel node placement according to tumor location.

Methods

A total of 462 pT1 or T2 gastric adenocarcinoma patients with metastasis to 1–3 lymph nodes (LNs) who had undergone lymphadenectomy greater than D1+β were included in the study. The distribution of metastatic LNs was evaluated according to tumor longitudinal and circumferential location. The incidence rate of atypical metastasis (skip or transversal metastasis) and related clinicopathologic factors were analyzed.

Results

The rates of skip and transversal metastasis were 15.8 % (73 of 462) and 10.3 % (23 of 224), respectively. Atypical metastasis was observed regardless of tumor location. Tumors that showed the most frequent atypical metastasis were located in the lower third and lesser curvature (LC) of the stomach (29.0 % for skip metastasis and 18.0 % for transversal metastasis). In uni- and multivariate analyses, an LC tumor was a risk factor for skip metastasis, and tumor located circumferentially in the LC or longitudinally in the lower third of the stomach was an independent risk factor for transversal metastasis. There was no correlation between tumor aggressiveness and atypical metastasis.

Conclusions

Tumors at any location had a chance of atypical metastasis; however, those located longitudinally in the lower or circumferentially at the LC had a significantly higher chance of atypical metastasis compared to other locations. When sentinel node navigation surgery is applied, special care should be taken with tumors at these locations to prevent false-negative results.     

Breast Cancer Detection by Preoperative Imaging in Reduction Mammaplasty Patients: A Single Center Study of 918 Patients

Background

The role of preoperative imaging and the usability of different imaging modalities is highly variable and controversial in reduction mammaplasty patients. Our study describes the imaging process in a single center in regard to modality selection, age and timing, and of the association between imaging and histopathological findings in reduction mammaplasty specimens.

Methods

Nine hundred eighteen women, who underwent reduction mammaplasty during 1.1.2007–31.12.2011, were retrospectively reviewed for demographics, preoperative imaging, further preoperative examinations, and pathology reports.

Results

Preoperative imaging had been conducted for 89.2% (n = 819) of the patients. In 49 (6.0%) patients, suspicious preoperative imaging led to further examinations revealing 2 high-risk lesions (atypical ductal hyperplasia (ADH), lobular carcinoma in situ (LCIS)), and 2 cancers preoperatively. Postoperatively abnormal histopathology specimens were revealed in 88 (10.4%) patients. The incidence of high-risk lesions was 5.5% (n = 47), and the incidence of cancer was 1.2% (n = 10). Preoperative imaging was normal (BI-RADS 1 and BI-RADS 2) in 80.8% of these patients. The sensitivity of the preoperative imaging for cancer detection was 20.0%, and the specificity was 100.0%.

Conclusions

Preoperative imaging and further examinations do not sufficiently detect malignant or cancer risk-increasing findings. Therefore, histopathological analysis of reduction mammaplasty specimens seems mandatory.

     

腋下副乳腺癌4例诊治分析

目的探讨腋下副乳腺癌的临床特点、诊断及治疗方法。方法对我院1986～2000年期间收治的4例副乳腺癌患者的临床资料进行回顾性分析。结果4例均行乳腺癌改良根治术或根治术，术后辅以放、化疗。随访资料表明，1例Ⅱ期患者术后3年死于肿瘤广泛转移，1例Ⅲ期患者术后8个月肿瘤局部复发，另2例Ⅲ期患者分别存活4年及10年。结论手术为腋下副乳腺癌的首选治疗手段，术后应辅以放、化疗及内分泌治疗。为改善预后．应提高对此病的重视并及时行手术活检以明确副乳腺包块性质。     

Outcomes of Abbreviated MRI (Ab-MRI) for Women of any Breast Cancer Risk and Breast Density in a Community Academic Setting

Annals of Surgical Oncology - Abbreviated magnetic resonance imaging (Ab-MRI) has been evaluated for elevated breast cancer risk or dense breasts but has not been evaluated across all risk...