Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial.

BACKGROUND: Primary analyses of the phase III BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates with manageable acute toxicity in patients with triple-negative breast cancer (TNBC). Here, we report 4.5-year follow-up data from the trial. PATIENTS AND METHODS: Women with untreated stage II-III TNBC were randomized (2 : 1 : 1) to paclitaxel (weekly for 12 doses) plus: (i) carboplatin (every 3 weeks for four cycles) plus veliparib (twice daily); (ii) carboplatin plus veliparib placebo; or (iii) carboplatin placebo plus veliparib placebo. All patients then received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. The primary endpoint was pCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), and safety. Since the co-primary endpoint of increased pCR with carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel was not met, secondary analyses are descriptive. RESULTS: Of 634 patients, 316 were randomized to carboplatin plus veliparib with paclitaxel, 160 to carboplatin with paclitaxel, and 158 to paclitaxel. With median follow-up of 4.5 years, the hazard ratio for EFS for carboplatin plus veliparib with paclitaxel versus paclitaxel was 0.63 [95% confidence interval (CI) 0.43-0.92, P = 0.02], but 1.12 (95% CI 0.72-1.72, P = 0.62) for carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel. In post hoc analysis, the hazard ratio for EFS was 0.57 (95% CI 0.36-0.91, P = 0.02) for carboplatin with paclitaxel versus paclitaxel. OS did not differ significantly between treatment arms, nor did rates of myelodysplastic syndromes, acute myeloid leukemia, or other secondary malignancies. CONCLUSIONS: Improvement in pCR with the addition of carboplatin was associated with long-term EFS benefit with a manageable safety profile, and without increasing the risk of second malignancies, whereas adding veliparib did not impact EFS. These findings support the addition of carboplatin to weekly paclitaxel followed by doxorubicin and cyclophosphamide neoadjuvant chemotherapy for early-stage TNBC.

Importance of miR-UL-148D Expression Pattern in Cytomegalovirus Infected Transplant Patients.

Background: MicroRNAs (miRNAs) are endogenous, 18-22 nucleotide non-coding RNA molecules. Human cytomegalovirus (HCMV) is a ubiquitous and particular herpes virus that encodes miRNAs, which increases gradually in the presence of infection. One of the important viral miRNAs is HCMV-miRUL-148D, which plays a role in establishing and maintaining viral latency. Objective: The current study aimed to evaluate the expression levels of HCMV-miRUL-148D in active and inactive HCMV infected transplant patient groups compared to healthy individuals. Methods: Total RNA was extracted from blood samples of 60 solid organ transplant patients and 30healthy controls. In-house SYBR Green Real-Time PCR evaluated the expression levels of studied miRNAand gene. Results: The expression level of the UL-148D gene was significantly higher in the active HCMV infectedpatients (p=0.001) compared to other groups. While the miRUL-148D expression level significantly increased in the inactive HCMV-infected patients (p<0.001) compared to other groups. Conclusion: Increased miRUL-148D expression level in the inactive HCMV-infected transplant patients indicates the potential role of this miRUL-148D as a biomarker of the HCMV latent stage.

Breast conservation following neoadjuvant therapy for breast cancer in the modern era: Are we losing the opportunity?

The main rationale for neoadjuvant therapy for breast cancer is to provide effective systemic treatment while surgically down-staging the cancer. This down-staging was initially to convert inoperable patients to operable and later to increase rates of breast conservation in patients initially deemed mastectomy only candidates. Unexpectedly, in recent neoadjuvant trials lower rates of breast conservation have been observed than in past decades, despite remarkable advances in systemic therapies, which have increased pathologic complete response rates. These results point to factors aside from response and eligibility for breast conservation that may lead surgeons and/or patients to recommend and choose mastectomy. Here, we aim to examine the surgical benefits offered by the modern era neoadjuvant therapy and explore factors that have contributed to this decrease in breast conservation rates. If the main benefit of neoadjuvant therapy is to increase the opportunity for breast conservation, then our review suggests that to optimize less invasive surgical approaches, we will need to address both surgeon and patient-level variables and biases that may be limiting our ability to identify patients appropriate for less aggressive options. As an oncology community, we must be aware of the surgical overtreatment of breast cancer, especially in a time where systemic therapies have remarkably improved outcomes and responses.

Surgery of the primary tumor in de novo metastatic breast cancer: To do or not to do?

Approximately five percent of all breast cancer patients in developed countries present with distant metastases at initial diagnosis. Due to its incurability, metastatic breast cancer is generally treated with systemic therapies to achieve disease control and reduce tumor-related symptoms. Primary treatments for metastatic breast cancer are chemotherapy, endocrine- and biologic therapy, whereas surgery with or without radiotherapy is usually performed to treat impending wound issues. Since 2002, several retrospective non-randomized clinical studies have shown that extirpation of the primary tumor correlates with a significantly improved survival in patients with primary metastatic breast cancer. Others have argued that this survival benefit associated with surgery may be due to selection biases. Therefore, in the absence of published results from randomized controlled trials carried out in India and Turkey and completion of a trial in the United States, there is no clear conclusion on whether surgical excision of the primary breast cancer translates into a survival benefit for patients with de novo metastatic disease. Furthermore, timing and type of surgical procedure, as well as selection of patients who could benefit the most from this approach, represent additional points of uncertainty. Despite the epidemiological burden of this condition, there are no guidelines on how to manage breast cancer patients presenting with de novo metastatic breast cancer; and decisions are often left to provider and patient preferences. Here, we present a critical overview of the literature focusing on the rationale and potential role of primary tumour excision in patients with de novo metastatic breast cancer.

Does neoadjuvant bevacizumab increase surgical complications in breast surgery?

BACKGROUND: Neoadjuvant chemotherapy is being increasingly used in operable breast cancer. There are limited data on the safety of bevacizumab (bev) in the neoadjuvant setting. We sought to explore the safety of neoadjuvant cisplatin/bev in a protocol for triple negative breast cancer (TNBC). MATERIALS AND METHODS: A total of 51 patients with confirmed TNBC were enrolled in a single-arm trial of neoadjuvant cisplatin plus bev. Of the 51 patients, 28 with confirmed TNBC were enrolled in our trial of single-agent neoadjuvant cisplatin. Two-sided Fisher exact test were used for comparing the 2 trials. RESULTS: The 51 patients received neoadjuvant protocol therapy with cisplatin/bev and underwent definitive local therapy. Breast conserving therapy (BCT) was performed in 29 (57%) and mastectomy with or without reconstruction in 22 (43%). Postoperative complications were reported in 22 patients (43%); 4 (8%) required explanation of expanders. Also, 28 patients completed neoadjuvant cisplatin therapy. BCT was performed in 13 (46%) and mastectomy with or without reconstruction in 15 (54%). Postoperative complications were reported in 11 patients (39%). None of the 5 reconstructions were lost. We compared all toxicities between the two trials (P = .81 NS), and wound healing related complications between the two trials (P = .10 NS). CONCLUSIONS: Cisplatin/bevacizumab and cisplatin alone neoadjuvant therapy resulted in a significant number of postoperative complications. Specifically, use of expanders/implants may be problematic for patients treated with bev. However, this was a single-arm trial; randomized controlled studies will be needed to determine the optimal use of bevacizumab in the timing of breast cancer surgery.

Can axillary lymph node dissection be omitted in patients with breast cancer and positive sentinel nodes?

Sentinel lymph node biopsy has evolved as the surgical procedure of choice for women with clinically negative axillae, as part of an effort to move toward the less invasive surgical management of breast cancer. Axillary lymph node dissection remains the standard of care for patients with a positive axillary node and was previously performed on all patients with breast cancer prior to the implementation of the sentinel lymph node biopsy. There is, however, controversy regarding whether or not all patients with a positive sentinel lymph node need to undergo completion axillary dissection for either prognostic or therapeutic purposes. This article reviews the literature related to this controversial and evolving topic.

Changes in the FEV1/FVC ratio during childhood and adolescence: an intercontinental study.

In children, the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) is reportedly constant or falls linearly with age, whereas the ratio of residual volume (RV) to total lung capacity (TLC) remains constant. This seems counter-intuitive given the changes in airway properties, body proportions, thoracic shape and respiratory muscle function that occur during growth. The age dependence of lung volumes, FEV1/FVC and RV/TLC were studied in children worldwide. Spirometric data were available for 22,412 healthy youths (51.4% male) aged 4-20 yrs from 15 centres, and RV and TLC data for 2,253 youths (56.7% male) from four centres; three sets included sitting height (SH). Data were fitted as a function of age, height and SH. In childhood, FVC outgrows TLC and FEV1, leading to falls in FEV1/FVC and RV/TLC; these trends are reversed in adolescence. Taking into account SH materially reduces differences in pulmonary function within and between ethnic groups. The highest FEV1/FVC ratios occur in those shortest for their age. When interpreting lung function test results, the changing pattern in FEV1/FVC and RV/TLC should be considered. Prediction equations for children and adolescents should take into account sex, height, age, ethnic group, and, ideally, also SH.

Matched pair analyses of stage IV breast cancer with or without resection of primary breast site.

BACKGROUND: Reports demonstrate improved survival of stage IV breast cancer patients with primary cancer resection. This may result from selection for surgery, rather than biological processes. METHODS: We performed matched-pair analysis that minimized potential bias in selecting surgery for primary cancer. Chart review was also performed of 5-year survivors to assess selection bias affecting breast surgery. RESULTS: 19,464 breast cancer patients were identified; 808 (4.2%) were stage IV: 622 were analyzed after eliminating wrong diagnoses or staging, and limiting patients to Massachusetts residents. Matched-pair analysis narrowed or eliminated apparent survival benefit associated with primary site surgery in several comparisons. When the impact of the sequence of systemic and surgical treatments was studied in stage IV patients, 90% 2-year survival occurred in patients receiving chemotherapy first, in contrast to receiving chemotherapy simultaneously with or after surgery, suggesting selection for delayed surgery after excellent response to initial chemotherapy. In bone metastases, the 2-year survival advantage occurred with chemotherapy before surgery; no difference in survival with or without surgery occurred when these treatments were simultaneous. Among 5-year survivors, frequency of primary site surgery after excellent response to systemic therapy, breast surgery in stage III patients incorrectly classified as stage IV, and frequency of oligo metastases all indicated selection bias. CONCLUSIONS: Case selection bias in primary breast cancer resection in state IV patients may explain most, if not all, the apparent survival advantage of such surgery.

Prediction of breast cancer size by ultrasound, mammography and core biopsy.

Neoadjuvant chemotherapy and non-surgical tumor ablation rely upon imaging studies to determine tumor size. In this study the accuracy of ultrasound (US) mammography and core biopsy in determining tumor size was examined in 202 patients with Stages I and II breast cancer. The most accurate single modality for determining tumor size was mammography with a correlation coefficient of 0.66, followed by US (r = 0.48) and core biopsy (r = 0.28). Size measurements were less accurate in lobular than ductal cancers. The combination of the three modalities understaged 25% of the tumors > 1cm in size, and overstaged 10% of those < 1cm. The inability to accurately determine tumor size has important implications for the use of non-surgical ablation.

Observation of divergent-beam X-ray diffraction from a crystal of diamond using synchrotron radiation.

In 1947 Kathleen Lonsdale conducted a series of experiments on X-ray diffraction using a divergent beam external to a crystal sample. Unlike the Kossel technique, where divergent X-rays are excited by the presence of fluorescing atoms within the crystal, the use of an external divergent source made it possible to study non-fluorescing crystals. The resulting photographs not only illustrated the complexity of X-ray diffraction from crystals in a truly beautiful way, but also demonstrated unprecedented experimental precision. This long-forgotten work is repeated here using a synchrotron radiation source and, once again, considerable merit is found in Lonsdale's technique. The results of this experiment suggest that, through the use of modern 'third-generation' synchrotron sources, divergent-beam diffraction could soon enjoy a renaissance for high-precision lattice-parameter determination and the study of crystal perfection.

Spirometric reference values in a large Middle Eastern population.

Ethnic differences in pulmonary function have been frequently reported. The purposes of this study were to derive equations for the prediction of normative spirometry values for a large population of Persians in Isfahan and compare them to reference values from a White Euro-USA population. Spirometry measurements were obtained from 4,341 randomly selected healthy nonsmoker subjects in Isfahan, Iran, utilising American Thoracic Society guidelines and a vigorous quality assurance program. Measured data from 3,213 subjects were analysed using multiple regression techniques to derive prediction equations for spirometric variables; the remaining 1,128 subjects were used as a control group to test the validity of the derived equations. In addition, predicted values were compared with values derived from recently published equations for the USA. Derived prediction equations showed good performance for most spirometric parameters. Compared with USA Whites, adult Persians have minimally lower forced vital capacities, while the values for children are close to USA Whites. In comparison with reference equations based on European or USA populations, local reference values are more biologically and technically suitable for the interpretation of spirometric data from Iranian populations.

Is arm span an accurate measure of height to predict pulmonary function parameters?

UNLABELLED: Interpretation of pulmonary function tests basically depends on prediction of normal values derived from equations using non-deformed body height. In many patients body height can not be accurately measured. The arm-span method has been used for estimating body height, but the normal relationship between body height and arm span is not exact and differs in various ethnic groups and even between two genders of the same race. In order to minimise the error of estimation of non-deformed body height, the normal relationship between body height and arm span was determined for 754 Persian males and 708 females aged 7 to 82 years, all having normal body stature. In accordance with earlier reports, two sets of spirometric parameters derived once from height, sex, age; and again from arm-span, sex, age were statistically different, and overestimated when the measured arm-span was used. The body-height/arm-span relationship is described using linear regression equations; in subgroups aging 20 years or less and those older than 20 in different genders. The results indicate significant sex and age differences in the arm-span/height ratio. Two sets of spirometric parameters predicted by real height, sex, age/and predicted height, sex, age were not statistically different for most of the parameters especially vital capacity. IN CONCLUSION: height estimated from arm span, performs much better than arm span to predict pulmonary function parameters.

Prevalence of asthma and related symptoms in junior high school children in Isfahan, Iran.

Asthma is the most common chronic disease in children. There are scattered epidemiological data concerning the prevalence of this disorder in developing countries. From October 1998 to May 1999 we studied 4069 randomly selected, junior high-school children in urban areas of Isfahan for asthma and related symptoms. The ages were expected to be 12-15 years. The children completed a questionnaire, and 3924 completed questionnaires were returned (response rate = 96.4%). Pupils with chronic respiratory symptoms were interviewed, physically examined at hospital and 1710 of them also underwent post exercise spirometry. The overall prevalence of asthma ever in life was 9.5%, with a male to female ratio of 2/1. The frequencies of current asthma, wheezing ever in life and exercise induced wheezy breathing were 7.3%, 19.1% and 14.2% respectively. Wheeze was heard on chest auscultation in 4.1% of the children. Pulmonary function tests revealed forced expiratory volume in 1 sec (FEV1) < 80% in 5.9%, forced mid-expiratory flow (FEF25-75) < 70%, in 9.7% and FEF75 < 70% in 20.6% of the tested children. All of the later findings strongly correlate with history of asthma. Parental smoking, similar illness in parents and/or siblings, lower levels of parental education and presence of cats, cockroaches and chicken in the household were significant risk factors. The prevalence of asthma in the students of the junior high schools of Isfahan is not far less than the average rates reported in many parts of the world, and it seems necessary to pay more attention to poorly controlled air pollution in Isfahan as an industrial city.

Prevalence of chronic bronchitis and chronic respiratory symptoms in adults over the age of 35 years in Isfahan, Iran in 1998.

OBJECTIVE: Chronic obstructive airways disease (COPD) in older patients is reported to be not only common, but also frequently overlooked and untreated by general practitioners. Chronic bronchitis is one of the major components of COPD and can be readily screened. This study investigates the prevalence of chronic bronchitis and related symptoms in Iran with special reference to COPD. METHODOLOGY: A random sample of 4636 participants aged 35 years and over, attended a research clinic for interview and physical examinations. Those reporting classic symptoms of chronic bronchitis were referred to a pulmonary clinic for pulmonary function testing. RESULTS: Two hundred and sixteen patients (4.65%) had chronic bronchitis. Among these, 78 (36.1%) had obstructive airways disease. Decreased forced expiratory volume in 1 s/forced vital capacity to levels of less than 70% were recorded in 45 patients (42.9% of the tested population). Less than 25% of the patients had a previous diagnosis of chronic bronchitis and/or airways disease. CONCLUSION: Obstructive airway diseases are under-diagnosed in developing countries. Physicians practising in such areas of the world should be aware, and try to detect the subclinical illnesses, especially in urban areas.

Pancreatic epithelial cyst in an adult treated by central pancreatectomy.

The infrequent occurrence of benign epithelial cysts of the pancreas is the reason why little is known regarding their clinical relevance and surgical management. We report the case of a 38-year-old woman with a benign epithelial cyst that was resected by the rarely performed central pancreatectomy. The presentation, evaluation, and differences between this and other cystic lesions of the pancreas are discussed. The benefits of central pancreatectomy for this benign lesion are reviewed.

Prevalence of asthma and related symptoms in primary school children of Isfahan, Iran, in 1998.

As developing countries adopt an industrialized style of living, an increase in asthma prevalence can be expected. A cross sectional study was undertaken to evaluate the prevalence rates of asthma and related symptoms and clinical findings in Isfahan, Iran. A randomly selected population of Isfahan primary school children, consisting of 3,982 children aged 6 to 11 was enrolled in the study. Parents completed a Persian questionnaire modified from ISAAC and ECRHS questionnaires. The returned 3,828 (96.1%) questionnaires were reviewed and 686 children suffering from asthma or any of the related symptoms were invited for further evaluations. In this stage 655 children (95.5%) underwent a medical interview and physical examinations, of which 415, underwent post exercise spirometry and body-plethysmography. The prevalence rates for previously diagnosed asthma, dyspnea and wheezing ever, dyspnea and wheezing in the last 12 months and frequently recurring dyspneal attacks were 0.71%, 7.6%, 3.9% and 1.6%, respectively. Wheezing was heard upon auscultation of the chests of 70 children (10.7%). Forced expiratory volume in 1st second (FEV1) < 80% of prediction was recorded in 3.1% of the children, other findings included reduced peak expiratory flow rate (PEF), mean expiratory flow 25 to 75 percent (FEF 25-75), forced expiratory flow at 75% of FVC (FEF 75), and increased residual volume (RV) and air-ways resistance in 4.3%, 10.6%, 21.2%, 30.1% and 63.2% of the pupils, respectively. We conclude that asthma screening programs employing clinical methods should be encouraged, but measurement of airway resistance is not a suitable tool for epidemiologic studies.

Primary sclerosing cholangitis.

Two new cases of primary sclerosing cholangitis with a rapid fatal course, particularly the patient in Case 2, are presented. Primary sclerosing cholangitis is a rare condition of unknown cause presenting with extrahepatic biliary obstruction due to a chronic inflammatory obliterative process with the absence of stones, cancer, or previous biliary surgery. This condition is often associated with ulcerative colitis, retroperitoneal fibrosis, and Riedel's thyroiditis. Surgical treatment for promoting bile drainage and long-term corticosteroid therapy are effective palliative measures.