Expanded Access Study of Palbociclib Plus Letrozole for Postmenopausal Women with HR+/HER2- Advanced Breast Cancer in Latin America for Whom Letrozole Therapy is Deemed Appropriate.

BACKGROUND AND OBJECTIVES: Palbociclib is a cyclin-dependent kinase 4/6 inhibitor that is approved in the United States for the treatment of hormone receptor‒positive (HR+)/human epidermal growth factor receptor‒2 negative (HER2-) advanced breast cancer (ABC). The objectives of this expanded access trial were to provide palbociclib in combination with letrozole to patients with HR+/HER2- ABC in Argentina, Brazil, Colombia, and Mexico who were candidates for letrozole therapy before commercial availability of palbociclib, and to evaluate the safety and tolerability of palbociclib plus letrozole. PATIENTS AND METHODS: Postmenopausal women aged ≥ 18 years with HR+/HER2- ABC were eligible to participate in this study. Patients received palbociclib 125 mg once daily (3/1 schedule) and letrozole 2.5 mg once daily (continuous schedule). Safety, objective response rate (ORR), and duration of treatment were evaluated. RESULTS: A total of 130 patients were treated with palbociclib plus letrozole (Argentina, n = 33; Brazil, n = 35; Colombia, n = 28; Mexico, n = 34). The most common treatment-emergent adverse events (TEAEs) of any grade were neutropenia (70.0%), leukopenia (34.6%), anemia (33.8%), decreased neutrophil count (27.7%), and thrombocytopenia (24.6%); 22.3% of patients required a palbociclib dose reduction due to adverse events (AEs). Serious AEs were reported in 32 patients (24.6%). The ORR was 24.8% (95% confidence interval 17.6‒33.2), and the median duration of treatment was 10.6 months (range 0.1‒29.3). CONCLUSION: Palbociclib in combination with letrozole was generally well tolerated with a clinically manageable safety profile; the observed ORR supported treatment benefit in Latin American women with HR+/HER2- ABC. TRIAL REGISTRY: ClinicalTrials.gov, NCT02600923.

This study was done to learn more about the safety of 2 medicines together for women with advanced breast cancer after menopause. All 130 women in the study had the most common kind of breast cancer and were from Argentina, Brazil, Colombia, and Mexico. Everyone took 2 oral medicines called palbociclib and letrozole during the study. The researchers looked for any side effects experienced by the women while taking these medicines together. Another goal of the study was to see how well the treatment worked. Blood tests showed 70.0% of women had a side effect where they had a lower number of a type of white blood cell called a neutrophil. In total, 34.6% of women had low levels of another white blood cell called a leukocyte. These blood test results can mean a person is more likely to get infections. Serious side effects were experienced by 24.6% of the women, which meant these were life-threatening, caused lasting problems, or they needed hospital care. To cope with their side effects, 22.3% of the women switched to a lower palbociclib dose; 24.8% of the women had an overall response, which meant they either had a decrease in their tumor size or all cancer signs disappeared from their body. The most common length of time in the study was 10.6 months and the longest time was 29.3 months. The results of this study support using palbociclib plus letrozole to treat women who live in Latin America with advanced breast cancer after menopause.

The Landscape of Videofluoroscopy in the UK: A Web-Based Survey.

Videofluoroscopy (VFS) is considered one of the gold-standard assessments of swallowing. Whilst guidelines for the application and conduct of VFS exist, their translation into clinical practice remain challenging. To build a greater understanding on how VFS clinics operate in the UK. A web-based survey was shared with speech and language therapists (SLTs) working in VFS clinics via professional networks and social media from October 2018 to January 2019. 101 responses were received. Two thirds of clinics were SLT-led, with the majority of clinics being run by two SLTs (73.6%) and a radiographer (95.5%) also known as radiologic technologists, diagnostic radiographers and medical radiation technologists. Less than 50% of radiographers had received specialist training. Around half of the clinics used a standard assessment or analysis protocol and 88.1% a rating scale. Set recipes for a range of textures were used in 53.4% of VFS clinics. Barium and water soluble contrasts were used, but only 15.8% knew the concentration of contrast used. The most commonly reported VFS pulse and frame rate was 15 per second. There was evidence of a lack of SLT knowledge regarding technical operation of VFS. Screening times varied from 0.7-10 min (median 3 min, IQR 2.5-3.5). Around 50% of respondents reported quality issues affecting analysis. In a survey of UK SLTs, translation of VFS guidance into practice was found to be limited which may impact on the quality of assessment and analysis. Collaboration with radiology, strengthening of guidelines and greater uptake of specialist training is deemed essential.

Current videofluoroscopy practice in the United Kingdom: A survey of imaging professionals.

INTRODUCTION: Videofluoroscopy (VFSS) is a frequently used radiological investigation for dysphagia and is conducted within a radiology setting by speech and language therapists (SLTs) working alongside imaging personnel (radiologists and/or radiographers). Previous surveys of SLT practice have reported variability in VFSS protocols and procedures. The aim of this study was to explore current clinical practice for VFSS from the perspective of imaging personnel engaged in VFSS within the United Kingdom. METHODS: A comprehensive online survey enabled exploration of current practices of imaging professionals. Target participants were diagnostic imaging personnel (radiographers and radiologists) with experience of working in VFSS clinics. Descriptive statistics describe and summarise the data alongside inferential statistics where appropriate. RESULTS: 54 survey participants represented 40 unique acute healthcare organisations in the UK, in addition to two respondents from the Republic of Ireland. The survey demonstrated high variance in clinical practice across all stages of the VFSS procedure. Clinicians were not always compliant with current UK guidelines and the roles and responsibilities of different professionals working within the clinics were often not clearly defined. CONCLUSION: Further research is required to develop new international, interprofessional VFSS guidelines to standardise service delivery for VFSS, improving diagnostic accuracy, efficiency and patient experience. IMPLICATIONS FOR PRACTICE: In the absence of VFSS guidelines for imaging personnel, practitioners should familiarise themselves with the UK Royal College of Speech and Language Therapists VFSS Position paper; IR (ME)R guidelines and DRLs for the client groups with which they work to guide clinics and improve practice. Clinicians should revisit protocols and clinical governance regarding safe practice in order to improve the quality of care within the VFSS clinic.

Thymectomy in the treatment of ocular myasthenia gravis.

BACKGROUND: Thymectomy is an effective and accepted treatment for myasthenia gravis, but thymectomy for ocular myasthenia gravis (Osserman stage I) is controversial. OBJECTIVE: To assess the efficacy and propriety of thymectomy for the treatment of ocular myasthenia gravis. METHODS: We conducted a review and follow-up of all patients who had thymectomy for the treatment of ocular myasthenia gravis between 1970 and 1998 at the University of California, Davis, Medical Center, and the University of Rome, "La Sapienza," Rome, Italy. Patient response to thymectomy was categorized as follows: cured, patients who became symptom-free and required no further medication; improved, patients who required less medication and whose symptoms were less severe; unchanged, patients whose symptoms and medications were the same; worse, patients who had more severe symptoms, needed more medication, or died. RESULTS: Sixty-one patients (mean age 37 years; range 14-73 years) were followed up for a mean duration of 9 years (range 0.5-29 years). Ocular myasthenia gravis with mixed and cortical thymomas, stages I to IV, occurred in 12 patients, and ocular myasthenia without thymomas occurred in 49 patients. Transsternal thymectomy (n = 55) and transcervical thymectomy (n = 6) resulted in cure in 31 (51%) patients, improvement in 12 (20%) patients, no change in 16 (26%) patients, and worsening of symptoms (including 1 postoperative death) in 2 patients. Patient outcomes were statistically independent of the duration of preoperative symptoms (mean 9.5 months), patient age, or the presence or absence of thymoma. In patients with ocular myasthenia, 70% were cured or improved after thymectomy; in the subgroup of patients with ocular myasthenia and thymoma, 67% were cured or improved. CONCLUSION: Thymectomy is an effective and safe treatment for patients with ocular myasthenia gravis.

The history of lung transplantation.

Experimental lung transplantation began in the former Soviet Union in 1946. Experiments in the 1950s sought to understand the physiology and to master the technique of reimplantation. Study of the immunology of allografting in the 1960s lead to the first lung transplantation in a human in 1963 in the United States. Palliative lung transplantation was first reported from Canada in 1986 after the advent of effective and tolerable immunosuppressive regimens. Lung transplantation in centers of excellence is now an effective palliative method for more than 80% of carefully selected recipients. Widespread transplantation to treat end stage pulmonary dysfunction is impossible because of too few organ donors and imperfect management of rejection and infection.

Role of bronchial artery embolization in the management of hemoptysis.

OBJECTIVE: To assess the modern morbidity of hemoptysis and the contribution of therapeutic bronchial artery embolization to its management. METHODS: Medical record review of patients admitted for the treatment of hemoptysis from January 1991 to November 1995 and of patients who had therapeutic bronchial artery embolization from June 1986 to August 1995. Hemoptysis was labeled major or minor. RESULTS: A total of 138 patients were admitted with hemoptysis, 31 with major and 107 with minor hemoptysis. No emergency pulmonary resections were required. Mean follow-up was 13.5 months. Mortality was 29.7% (41/138) but was caused by bronchial bleeding in only 4.3% (6/138). Twenty-six patients underwent therapeutic bronchial artery embolization (mean follow-up [range], 14 months [0.3-69.0 months]). The initial success rate (no further bleeding during the initial admission) was 85% (22/26). The long-term success rate (no further bleeding during follow-up) was 58% (15/26). Only 2 patients with therapeutic bronchial artery embolization died of further hemoptysis. CONCLUSIONS: Hemoptysis signals life-threatening diseases. Therapeutic bronchial artery embolization is a good treatment adjunct to control bronchial bleeding and reduces the need for high-risk emergency lung resections.

Clonal origin of multiple lung cancers: K-ras and p53 mutations determined by nonradioisotopic single-strand conformation polymorphism analysis.

Disease stage is the most important factor in determining prognosis and treatment of lung cancer. Staging of lung cancer is complicated by presentation of multiple pulmonary malignant lesions with a similar histology. It is a dilemma to decide if these lesions are synchronous primaries arising from different malignant clones or metastases from a single clone. Lung cancer is associated with multiple genetic abnormalities including mutations of K-ras and p53, which are believed to occur prior to onset of metastasis. To determine the clonal origin of multiple pulmonary malginant nodules, we analyzed point-mutations of K-ras and p53 by microdissection, polymerase chain reactions (PCR), nonradioisotopic single-strand conformation polymorphism (SSCP) analysis, and DNA sequencing. Each pulmonary lesion was microdissected from paraffin slides. Genomic DNA was amplified by two sequential PCRs followed by electrophoresis in a minigel and silver staining. Deoxyribonucleic acid sequencing was performed if necessary to confirm a mutation found upon SSCP analysis. Applying this molecular approach, we were able to differentiate the clonal origins of multiple malignant nodules of the lung as exemplified by the two cases presented.

The alveolar type II cell is a pluripotential stem cell in the genesis of human adenocarcinomas and squamous cell carcinomas.

Studies in a canine bronchogenic carcinoma model indicate that alveolar type II cells may differentiate from carcinogen-exposed epithelium of larger bronchi and generate adenocarcinomas with bronchioloalveolar and other growth patterns. In this study, we investigated whether type II cells are one of the major proliferating cells (= stem cells) in the genesis of two major subsets of bronchogenic carcinoma in humans. Adenocarcinomas (17 bronchioloalveolar; 3 papillary; and 10 other) and squamous cell carcinomas (n = 27) as well as (pre)neoplastic lesions in adjacent bronchi and bronchioles were examined for the presence of type II cell markers and cellular proliferation markers (PCNA; Ki-67) using light and electron microscopy and immunohistochemistry. Distinctive features of type II cells, which do not depend upon the degree of cell maturity, are the approximately cuboid shape, large and roundish nucleus, cytoplasmic staining for surfactant protein A (SP-A), and presence of multilamellar bodies or their precursory forms. Cells with this phenotype were found in early progressive (i.e., dysplastic, in situ, microinvasive) lesions in conducting airways and in all the carcinomas investigated, although with a much greater abundance among glandular lesions compared to squamous lesions. The most consistent sites of type II cells were the basal and adjacent epithelial layers. Nuclear PCNA (Ki-67) expression usually predominated in the same region. None of the lesions displayed specific Clara cell features. Our findings strongly suggest that the type II cell is a pluripotential stem cell in human lung carcinogenesis. Based on our findings in humans and dogs, we postulate that type II tumor stem cells may originate from one of two sources: (1) normal bronchial epithelium (by an oncofetal mechanism of differentiation); and (2) normal alveolar type II cells.

The effect of patient characteristics on response to focal laser treatment for diabetic macular edema.

PURPOSE: The purpose of the study was to determine which patient characteristics influence response to focal photocoagulation for clinically significant diabetic macular edema (CSME). METHODS: A retrospective chart review was performed of 547 eyes from 361 patients who were observed for at least 1 year (mean, 2.6 +/- standard deviation 1.7 years) after surgery. Preoperative patient characteristics were tested for their significance in predicting outcome using multiple regression analysis. RESULTS: Increasing patient age has a negative effect on visual outcome (P = 0.0179). Patients with diet-controlled diabetes show improvement in mean vision, whereas patients whose diabetes is controlled with insulin, oral agents, or both show declines, and these differences are significant (P < 0.0001). Neither cataract surgery before or after focal photocoagulation nor simultaneous panretinal photocoagulation for patients having concomitant high-risk proliferative retinopathy had a significant effect on outcome. CONCLUSIONS: Younger patients with CSME and those with diet-controlled diabetes can be given more favorable prognoses. Patients with CSME and high-risk proliferative disease can have cost-effective simultaneous focal and panretinal photocoagulation without adversely affecting visual outcome.

Bronchial carcinogenesis in syngeneic hamsters.

Endobronchial sustained release implants of carcinogen were placed in males (m) and females (f) of four varieties of syngeneic hamsters: BIOF1D; BIO87.20; BIO1.5; BIO15.16. The sequential progression of carcinogenesis that occurred was faster for 1.5m than for 1.5f (P = 0.01) and less rapid for 15.16m than for 87.20m and F1Dm (P < 0.05). Fewer invasive cancers occurred in 15.16m than in the other male varieties (P < 0.01), in 1.5m than in 87.20m (P < 0.05), and in 87.20f than in 87.20m (P < 0.05). Adenocarcinoma occurred with greater frequency in the 1.5 variety than in the F1D variety (P < 0.05). Significant variability in susceptibility, incidence, and types of invasive cancers formed exists, providing new opportunities for further study of bronchial carcinogenesis.

Surgical management and treatment of esophageal fistula.

Esophageal fistula may involve the respiratory or cardiovascular system. Fistulas involving the respiratory system which originate from esophageal cancers are the most common. Diagnosis is best made with barium esophagogram. ERF of any cause usually leads to repetitive contamination of the respiratory tract, resulting in sepsis and death of the patient if untreated. In the case of MERF, whether from esophageal or lung cancer, only palliative treatment is usually possible. Better results, including cure, may be expected when a MERF is caused by lymphoma. Curative operation with closure of the fistula is usually possible for BERF if the fistula is identified and treated before irreversible damage has been done by infection, sepsis, and malnutrition. Esophagocardiovascular fistulas occur infrequently in comparison with ERF. These may involve the aorta, usually as a result of a thoracic aneurysm. Rarely one may encounter esophageal fistula to the pericardium or heart. Few survivors have been reported, but successful management is possible if early diagnosis is made and prompt surgical management is undertaken.

Comparison of DNA topoisomerase II alpha expression in small cell and nonsmall cell carcinoma of the lung. In search of a mechanism of chemotherapeutic response.

BACKGROUND: Small cell carcinoma of the lung (SCLC) is distinguished from nonsmall cell carcinoma (NSCLC) by its exquisite initial sensitivity to chemotherapy. Antineoplastic drugs effective against SCLC include doxorubicin, etoposide, and others. Recently, the molecular target of these drugs has been identified as the alpha form of DNA topoisomerase II, which is important in DNA replication and in the separation of chromosomes during normal cellular division. In this study we compared DNA topoisomerase II alpha expression in SCLC and NSCLC by immunohistochemistry. We hypothesized that the sensitivity of SCLC and relative insensitivity of NSCLC to these chemotherapeutic agents stem from different frequencies of DNA topoisomerase II alpha expression. METHODS: DNA topoisomerase II alpha expression was analyzed in 17 cases of SCLC and 24 cases of NSCLC by immunohistochemistry utilizing a monoclonal antibody recognizing the alpha isoform of DNA topoisomerase II. A topo II index was determined by dividing the number of tumor nuclei expressing DNA topoisomerase II by the total number of tumor nuclei counted. RESULTS: A significantly higher frequency of DNA topoisomerase II alpha expression was identified in SCLC (P < 0.001). The average topo II index for SCLC was 0.60 (range: 0.45-0.76) compared with NSCLC, 0.31 (range: 0.05-0.75). CONCLUSIONS: We conclude that DNA topoisomerase II alpha is expressed at a higher frequency in SCLC than in NSCLC, and that this expression is possibly involved in the response of SCLC to chemotherapeutic agents.

Multimodality therapy in stage III non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer commonly presents as locally advanced disease. This category of tumors is heterogeneous. Although some patients clearly benefit from operative management alone, the vast majority (more than 90%) will succumb to their disease within 5 years. In the past decade a large clinical research effort has been undertaken in an attempt to improve on this outcome using a combination of chemotherapy, radiotherapy, and operation. METHODS: The English-language literature was reviewed using the headings for lung neoplasms and text words combined modality therapy and multimodality therapy. In addition, the bibliographies of relevant articles were reviewed. Emphasis was placed on prospective randomized trials and large phase II studies. We review the rationale, design, and outcome of these trials, including both operative and nonoperative approaches. RESULTS: Several prospective, randomized trials now demonstrate an advantage to combined modality management over radiotherapy or operation alone when a cisplatin-based chemotherapy regimen is incorporated into the treatment plan. This advantage was seen using both operative and nonoperative approaches. CONCLUSIONS: Combined modality therapy offers an improved outcome for patients with stage III non-small cell lung cancer. Whether both operation and radiotherapy are needed for local control, the best sequence of treatment and the optimal chemotherapy regimen remain to be defined.