Effect of fezolinetant on sleep disturbance and impairment during treatment of vasomotor symptoms due to menopause.

OBJECTIVES: To analyse the effect of fezolinetant on patient-reported sleep disturbance and impairment in individuals with vasomotor symptoms (VMS) using pooled data from the SKYLIGHT 1 and 2 studies. STUDY DESIGN: The SKYLIGHT studies were phase-3, double-blind investigations. Individuals (≥40-≤65 years) who were assigned female at birth and seeking treatment of/relief from moderate-to-severe VMS were enrolled. Participants were randomised to receive placebo, fezolinetant 30 mg, or fezolinetant 45 mg during a 12-week treatment period. MAIN OUTCOME MEASURES: Sleep assessments: Patient-Reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b), PROMIS Sleep-Related Impairment - Short Form 8a (PROMIS SRI SF 8a), and Patient Global Impression of Change/Severity in SD (PGI-C SD and PGI-S SD). Assessments were completed at baseline (except PGI-C SD), weeks 4 and 12. RESULTS: Overall, 1022 individuals were randomised and took ≥1 dose of study drug. PROMIS SD SF 8b results showed that improvements in sleep disturbance were observed for fezolinetant 30 and 45 mg versus placebo (week 12, least squares [LS] mean differences: -0.6 [95 % confidence interval [CI]: -1.7, 0.4] for 30 mg and -1.5 [-2.5, -0.5] for 45 mg). Similar improvements in sleep impairment were reported using the PROMIS SRI SF 8a (week 12, LS mean differences: -1.1 [95 % CI: -2.1, -0.1] for 30 mg and -1.3 [-2.3, -0.3] for 45 mg). For PGI-C SD at week 12, 33.6 % (98/292 participants) of the placebo group felt much/moderately better versus 40.1 % (110/274) and 51.0 % (154/302) of the fezolinetant 30 mg and 45 mg groups, respectively. For PGI-S SD at week 12, 44.0 % (129/293) of the placebo group had severe/moderate problems versus 41.1 % (113/275) and 36.6 % (111/303) of the fezolinetant 30 mg and 45 mg groups, respectively. The 12-week timeframe for this analysis was limited by the length of the placebo-controlled period. CONCLUSIONS: Fezolinetant had a beneficial effect on four measures of sleep disturbance and impairment following treatment for VMS.

A retrospective observational study of osteoporosis management after a fragility fracture in primary care.

In many countries, osteoporosis is predominantly managed by primary care physicians; however, management after a fragility fracture has not been widely investigated. We describe osteoporosis care gaps in a real-world patient cohort. Our findings help inform initiatives to identify and overcome obstacles to effective management of patients after fragility fracture. PURPOSE: A fragility fracture is a major risk factor for subsequent fracture in adults aged ≥ 50 years. This retrospective observational study aimed to characterize post-fracture management in Canadian primary care. METHODS: A total of 778 patients with an index fragility fracture (low-trauma, excluding small bones) occurring between 2014 and 2016 were identified from medical records at 76 primary care centers in Canada, with follow-up until January 2018. RESULTS: Of 778 patients (80.5% female, median age [IQR] 73 [64-80]), 215 were on osteoporosis treatment and 269 had osteoporosis diagnosis recorded prior to their index fracture. The median follow-up was 363 (IQR 91-808) days. Of patients not on osteoporosis treatment at their index fracture, 60.2% (n = 339/563) remained untreated after their index fracture and 62.2% (n = 23/37) continued untreated after their subsequent fracture. After their index fracture, fracture risk assessment (FRAX or CAROC) was not performed in 83.2% (n = 647/778) of patients, and 59.9% (n = 466/778) of patients did not receive bone mineral density testing. Of patients without osteoporosis diagnosis recorded prior to their index date, 61.3% (n = 300/489) remained undiagnosed after their index fracture. At least one subsequent fracture occurred in 11.5% (n = 86/778) of patients. CONCLUSION: In the primary care setting, fragility fracture infrequently resulted in osteoporosis treatment or fracture risk assessment, even after multiple fragility fractures. These results suggest a fragility fracture is not recognized as a major risk factor for subsequent fracture and its occurrence does not prompt primary care physicians to intervene. These data urge initiatives to identify and overcome obstacles to primary care physicians' effective management of patients after fragility fractures.

Pathophysiology and Imaging Findings of COVID-19 Infection: An Organ-system Based Review.

BACKGROUND: COVID-19 commonly presents with upper respiratory symptoms; however, studies have shown that SARS-CoV-2 infection affects multiple organ systems. Here, we review the pathophysiology and imaging characteristics of SARS-CoV-2 infection in organ systems throughout the body and explore commonalities. OBJECTIVE: Familiarity with the underlying pathophysiology and imaging characteristics is essential for the radiologist to recognize these findings in patients with COVID-19 infection. Though pulmonary findings are the most prevalent presentation, COVID-19 may have multiple manifestations and recognition of the extrapulmonary manifestations is especially important because of the potential serious and long-term effects of COVID-19 on multiple organ systems.

Subdural extravasation of crystalloids and blood products through a scalp peripheral intravenous catheter into the subdural space of a neonate on veno-arterial extracorporeal membrane oxygenation.

We describe a rare and devastating complication of a malpositioned scalp peripheral intravenous catheter (PIV) that resulted in subdural extravasation of infused fluids and midline shift in a critically ill neonate who required extracorporeal membrane oxygenation (ECMO). Recognition of increased intracranial pressure was hindered by the hemodynamic changes of being on ECMO and only identified by routine surveillance ultrasonography. Awareness of this complication may lead providers to seek alternate sites for vascular access in such patients, and encourage closer monitoring for this complication when an alternate site is unavailable.

Nonrestorative sleep scale: a reliable and valid short form of the traditional Chinese version.

PURPOSE: Previous research has suggested the essential unidimensionality of the 12-item traditional Chinese version of the Nonrestorative Sleep Scale (NRSS). This study aimed to develop a short form of the traditional Chinese version of the NRSS without compromising its reliability and validity. METHODS: Data were collected from 2 cross-sectional studies with identical target groups of adults residing in Hong Kong. An iterative Wald test was used to assess differential item functioning by gender. Based on the generalized partial credit model, we first obtained a shortened version such that further shortening would result in substantial sacrifice of test information and standard error of measurement. Another shortened version was obtained by the optimal test assembly (OTA). The two shortened versions were compared for test information, Cronbach's alpha, and convergent validity. RESULTS: Data from a total of 404 Chinese adults (60.0% female) who had completed the Chinese NRSS were gathered. All items were invariant by gender. A 6-item version was obtained beyond which the test performance substantially deteriorated, and a 9-item version was obtained by OTA. The 9-item version performed better than the 6-item version in test information and convergent validity. It had discrimination and difficulty indices ranging from 0.44 to 2.23 and - 7.58 to 2.13, respectively, and retained 92% of the test information of the original 12-item version. CONCLUSION: The 9-item Chinese NRSS is a reliable and valid tool to measure nonrestorative sleep for epidemiological studies.

Psoriatic and psoriatic arthritis patients with and without jet-lag: does it matter for disease severity scores? Insights and implications from a pilot, prospective study.

Background: Jet-lag may affect air-travelers crossing at least two time-zones and has several health-care implications. It occurs when the human biological rhythms are out of synch with respect to the day-night cycle at the country destination. Its effect in psoriasis is missing. We aimed to evaluate the effect of Jet-lag in psoriatic patients' management. Methods: This is a prospective observational study that enrolled psoriatic patients that underwent a flight: patients who experienced jet-lag were compared to patients who did not experience jet-lag. Before the flight, a dermatologist recorded clinical and demographical data with particular attention to Psoriasis Area Severity Index (PASI) and Disease Activity in Psoriatic Arthritis (DAPSA). Patients performed Self-Administered Psoriasis Area Severity Index (SAPASI), the Dermatology Life Quality Index (DLQI) and the pruritus Visual Analog Scale (VAS) scores. After the flight, patients completed the SAPASI, DLQI and pruritus-VAS scores. Results: The sample recruited comprised of 70 psoriatic patients aged 42.4 ± 9.7 years (median 42.5 years). Thirty (42.9%) were males, mean BMI was 25.5 ± 2.2 kg/m2. Average disease duration was 15.2 ± 7.1 years, and 20 (28.6%) subjects had developed PsA. Average hours of flight were 5.4 ± 3.5 (median 3.5 h), with 34 (48.6%) subjects reporting jet-lag. At the multivariate regression analysis, the change in the SAPASI score resulted correlated with jet-lag (regression coefficient 1.63, p = .0092), as well the change in the DLQI score (regression coefficient = 1.73, p = .0009), but no change on the pruritus VAS scale was found. Conclusions: The present study suggests that jet-lag may influence disease severity and DLQI scores, but not itch in psoriatic patients.

Nonrestorative sleep scale: reliable and valid for the Chinese population.

PURPOSE: To conduct a linguistic and psychometric evaluation of a Chinese version of the Nonrestorative Sleep Scale (NRSS). METHODS: The Chinese NRSS was created from a standard forward-backward translation and trialed on 10 Chinese adults. Telephone interviews were then conducted with 100 adults, who completed the Chinese NRSS, the Pittsburgh Sleep Quality Index (PSQI), the Athens Insomnia Scale (AIS), the Center for Epidemiological Studies Depression Scale (CES-D), and the Toronto Hospital Alertness Test (THAT). A household survey was conducted with 20 subjects, followed by a confirmatory factor analysis (CFA), and a bifactor model was developed to evaluate the reliability and validity of the NRSS. RESULTS: The bifactor model had the root mean square error of approximation (RMSEA), standardized root mean square residual (SRMR), and comparative fit index (CFI) of 0.06, 0.06, and 0.97, respectively. Convergent validity was shown from the moderate associations with PSQI (r = - 0.66, P < 0.01), AIS (r = - 0.65, P < 0.01), CES-D (r = - 0.54, P < 0.01), and THAT (r = 0.68, P < 0.01). The coefficient omega (0.92), omega hierarchical (0.81), factor determinacy (0.93), H value (0.91), explained common variance (0.63), and percentage of uncontaminated correlations (0.80) derived from the bifactor CFA supported the essential unidimensionality of NRSS. CONCLUSIONS: The Chinese NRSS is a valid and reliable essential unidimensional tool for the assessment of nonrestorative sleep in the Chinese population.

Predictors of duloxetine response in patients with oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN): a secondary analysis of randomised controlled trial - CALGB/alliance 170601.

Duloxetine is an effective treatment for oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN). However, predictors of duloxetine response have not been adequately explored. The objective of this secondary and exploratory analysis was to identify predictors of duloxetine response in patients with painful oxaliplatin-induced CIPN. Patients (N = 106) with oxaliplatin-induced painful CIPN were randomised to receive duloxetine or placebo. Eligible patients had chronic CIPN pain and an average neuropathic pain score ≥4/10. Duloxetine/placebo dose was 30 mg/day for 7 days, then 60 mg/day for 4 weeks. The Brief Pain Inventory-Short Form and the EORTC QLQ-C30 were used to assess pain and quality of life, respectively. Univariate and multiple logistic regression analyses were performed to identify demographic, physiologic and psychological predictors of duloxetine response. Higher baseline emotional functioning predicted duloxetine response (≥30% reduction in pain; OR 4.036; 95% CI 0.999-16.308; p = 0.050). Based on the results from a multiple logistic regression using patient data from both the duloxetine and placebo treatment arms, duloxetine-treated patients with high emotional functioning are more likely to experience pain reduction (p = 0.026). In patients with painful, oxaliplatin-induced CIPN, emotional functioning may also predict duloxetine response. ClinicalTrials.gov, Identifier NCT00489411.

CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth.

Metastasis of solid tumors is associated with poor prognosis and bleak survival rates. Tumor-infiltrating myeloid cells (TIMs) are known to promote metastasis, but the mechanisms underlying their collaboration with tumor cells remain unknown. Here, we report an oncogenic role for microRNA (miR) in driving M2 reprogramming in TIMs, characterized by the acquisition of pro-tumor and pro-angiogenic properties. The expression of miR-21, miR-29a, miR-142-3p and miR-223 increased in myeloid cells during tumor progression in mouse models of breast cancer and melanoma metastasis. Further, we show that these miRs are regulated by the CSF1-ETS2 pathway in macrophages. A loss-of-function approach utilizing selective depletion of the miR-processing enzyme Dicer in mature myeloid cells blocks angiogenesis and metastatic tumor growth. Ectopic expression of miR-21 and miR-29a promotes angiogenesis and tumor cell proliferation through the downregulation of anti-angiogenic genes such as Col4a2, Spry1 and Timp3, whereas knockdown of the miRs impedes these processes. miR-21 and miR-29a are expressed in Csf1r+ myeloid cells associated with human metastatic breast cancer, and levels of these miRs in CD115+ non-classical monocytes correlates with metastatic tumor burden in patients. Taken together, our results suggest that miR-21 and miR-29a are essential for the pro-tumor functions of myeloid cells and the CSF1-ETS2 pathway upstream of the miRs serves as an attractive therapeutic target for the inhibition of M2 remodeling of macrophages during malignancy. In addition, miR-21 and miR-29a in circulating myeloid cells may potentially serve as biomarkers to measure therapeutic efficacy of targeted therapies for CSF1 signaling.

Early radiologic evidence of severe respiratory distress syndrome as a predictor of nasal continuous positive airway pressure failure in extremely low birth weight newborns.

OBJECTIVE: To determine whether early radiologic evidence of severe respiratory distress syndrome (RDS) is predictive of nasal continuous positive airway pressure (CPAP) failure in extremely low birth weight (ELBW) infants during the first 72 h of age. STUDY DESIGN: Retrospective analysis of 235 consecutively inborn ELBW infants who received initial support with CPAP. CPAP success (n=151) and CPAP failure (n=84) groups were designated according to outcome within the first 72 h of age. We assessed the ability of radiologic evidence of severe RDS in the initial chest radiograph, alone and in combination with other variables available in the first hours of life, to predict CPAP failure. RESULT: Severe RDS had a positive predictive value (PPV) of 0.81 (95% confidence interval (CI) 0.64, 0.92) for CPAP failure. The combination of severe RDS and gestational age (GA) ⩽ 26 weeks had a PPV of 0.92 (95% CI 0.68, 0.96). CONCLUSION: Early radiologic evidence of severe RDS is predictive of CPAP failure, especially in infants with GA ⩽ 26 weeks.

Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis.

Previous studies have demonstrated that cyclin D1, an upstream regulator of the Rb/E2F pathway, is an essential component of the ErbB2/Ras (but not the Wnt/Myc) oncogenic pathway in the mammary epithelium. However, the role of specific E2fs for ErbB2/Ras-mediated mammary tumorigenesis remains unknown. Here, we show that in the majority of mouse and human primary mammary carcinomas with ErbB2/HER2 overexpression, E2f3a is up-regulated, raising the possibility that E2F3a is a critical effector of the ErbB2 oncogenic signaling pathway in the mammary gland. We examined the consequence of ablating individual E2fs in mice on ErbB2-triggered mammary tumorigenesis in comparison to a comparable Myc-driven mammary tumor model. We found that loss of E2f1 or E2f3 led to a significant delay in tumor onset in both oncogenic models, whereas loss of E2f2 accelerated mammary tumorigenesis driven by Myc-overexpression. Furthermore, southern blot analysis of final tumors derived from conditionally deleted E2f3(-/loxP) mammary glands revealed that there is a selection against E2f3(-/-) cells from developing mammary carcinomas, and that such selection pressure is higher in the presence of ErbB2 activation than in the presence of Myc activation. Taken together, our data suggest oncogenic activities of E2F1 and E2F3 in ErbB2- or Myc-triggered mammary tumorigenesis, and a tumor suppressor role of E2F2 in Myc-mediated mammary tumorigenesis.

The inception, achievements, and implications of the China GAVI Alliance Project on Hepatitis B Immunization.

The China GAVI Hepatitis B Immunization Project was initiated in 2002 with the signing of a Memorandum of Understanding between GAVI and the Government of China. The Project was one of the three (China, India, and Indonesia) GAVI-initiated special projects done to support countries too large to receive full GAVI support for hepatitis B vaccine and safe injections. The Project in China was designed by the Chinese Government and partners to deliver free hepatitis B vaccine and safe injections to all newborns in the 12 Western Provinces and Poverty Counties in 10 Provinces of Central China (1301 Counties with approximately 5.6 million births per year), eliminating the gap in immunization coverage between wealthier and poorer regions of China. The project budget (USD 76 million) was equally shared by GAVI and the Chinese Government. Initially planned for 5 years, two no cost extensions extended the project to 2011. Although China produced hepatitis B vaccine, before the project the vaccine was sold to parents who were also charged a "user fee" for the syringe and vaccine administration. Basic Expanded Program on Immunization (EPI) vaccines such as BCG, DTP, Polio, and measles vaccines were provided free to parents, although they were charged a user fee. Vaccines were sold by China CDC Offices at provincial, prefecture, county level and township hospitals, and village doctors received a substantial portion of their income from the sale of hepatitis B and other vaccines. The result of charging for hepatitis B vaccine was that coverage was relatively high in Eastern and wealthier counties in Central China (~80-90%), but was much lower (~40%) in Western China and Poverty Counties where parents could not afford the vaccine. The Project was administered by the China MOH and China CDC EPI program, and two Project Co-managers, one from the Chinese Government and the other an international assignee, were chosen. The project had an oversight Operational Advisory Group composed of the Chinese Government, WHO, UNICEF, and GAVI. The initial targets of the project as delineated in the initial MOU for the Project areas (HepB3 coverage will reach 85% at the county level, >75% of newborns at the county level will receive the first dose of hepatitis B within 24h of birth, and all immunization injections will be with auto disable [AD] syringes) were substantially exceeded. The differential in vaccine coverage between wealthier and poorer parts of China was eliminated contributing to a great improvement in equity. With additional contributions of the Chinese Government the Project was accomplished substantially under budget allowing for additional catch up immunization of children under 15 years of age. More than 5 million health workers were trained in how to deliver hepatitis B vaccine, timely birth dose (TBD), and safe injections, and public awareness of hepatitis B and its prevention rose significantly. TBD coverage was expedited by concurrent efforts to have women deliver in township clinics and district hospitals instead of at home. The effective management of the Project, with a Project office sitting within the China EPI and an Operational Advisory Group for oversight, could serve as a model for other GAVI projects worldwide. Most importantly, the carrier rate in Chinese children less than 5 years of age has fallen to 1%, from a level of 10% before the inception of the Project. Liver cancer, one of the major cancer killers in China (250,000-300,000 annual estimated deaths), will dramatically decline as immunized cohorts of Chinese children age. While hepatitis C and non-alcoholic liver disease also exist in China and can lead to liver cancer and cirrhosis, the majority of liver disease in China is hepatitis B related and therefore preventable. The authors believe that China's success in preventing hepatitis B is one of the greatest public health achievements of the 21st century. Work remains to be done in several key areas. There are still pockets of home births in rural provinces where a TBD is difficult to deliver, and China is strengthening its policy of screening pregnant women for HBsAg and delivering HBIG plus vaccine to newborns of HBV carrier mothers. Approximately 10% of the adult population of China remain chronic carriers of hepatitis B virus and cannot be helped by the vaccine, so prevention of liver cancer and cirrhosis in those groups remains a future challenge for China.

Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab.

BACKGROUND: Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. METHODS: Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. RESULTS: A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02-1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. CONCLUSIONS: Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.

Proportion of surgical patients with undiagnosed obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) affects ~9-24% of the general population, and 90% remain undiagnosed. Those patients with undiagnosed moderate-to-severe OSA may be associated with an increased risk of perioperative complications. Our objective was to evaluate the proportion of surgical patients with undiagnosed moderate-to-severe OSA. METHODS: After research ethics board approval, patients visiting preoperative clinics were recruited over 4 yr and screened with the STOP-BANG questionnaire. The 1085 patients, who consented, subsequently underwent polysomnography (PSG) (laboratory or portable) before operation. Chart review was conducted in this historical cohort to ascertain the clinical diagnosis of OSA by surgeons and anaesthetists, blinded to the PSG results. The PSG study-identified OSA patients were further classified based on severity using the apnoea-hypopnoea index (AHI) cut-offs. RESULTS: Of 819 patients, 111 patients had pre-existing OSA and 58% (64/111) were not diagnosed by the surgeons and 15% (17/111) were not diagnosed by the anaesthetists. Among the 708 study patients, PSG showed that 233 (31%) had no OSA, 218 (31%) patients had mild OSA (AHI: 5-15); 148 (21%) had moderate OSA (AHI: 15-30), and 119 (17%) had severe OSA (AHI>30). Before operation, of the 267 patients with moderate-to-severe OSA, 92% (n=245) and 60% (n=159) were not diagnosed by the surgeons and the anaesthetists, respectively. CONCLUSIONS: We found that anaesthetists and surgeons failed to identify a significant number of patients with pre-existing OSA and symptomatic undiagnosed OSA, before operation. This study may provide an impetus for more diligent case finding of OSA before operation.

High STOP-Bang score indicates a high probability of obstructive sleep apnoea.

BACKGROUND: The STOP-Bang questionnaire is used to screen patients for obstructive sleep apnoea (OSA). We evaluated the association between STOP-Bang scores and the probability of OSA. METHODS: After Institutional Review Board approval, patients who visited the preoperative clinics for a scheduled inpatient surgery were approached for informed consent. Patients answered STOP questionnaire and underwent either laboratory or portable polysomnography (PSG). PSG recordings were scored manually. The BMI, age, neck circumference, and gender (Bang) were documented. Over 4 yr, 6369 patients were approached and 1312 (20.6%) consented. Of them, 930 completed PSG, and 746 patients with complete data on PSG and STOP-Bang questionnaire were included for data analysis. RESULTS: The median age of 746 patients was 60 yr, 49% males, BMI 30 kg m(-2), and neck circumference 39 cm. OSA was present in 68.4% with 29.9% mild, 20.5% moderate, and 18.0% severe OSA. For a STOP-Bang score of 5, the odds ratio (OR) for moderate/severe and severe OSA was 4.8 and 10.4, respectively. For STOP-Bang 6, the OR for moderate/severe and severe OSA was 6.3 and 11.6, respectively. For STOP-Bang 7 and 8, the OR for moderate/severe and severe OSA was 6.9 and 14.9, respectively. The predicted probabilities for moderate/severe OSA increased from 0.36 to 0.60 as the STOP-Bang score increased from 3 to 7 and 8. CONCLUSIONS: In the surgical population, a STOP-Bang score of 5-8 identified patients with high probability of moderate/severe OSA. The STOP-Bang score can help the healthcare team to stratify patients for unrecognized OSA, practice perioperative precautions, or triage patients for diagnosis and treatment.

Phase I-II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo.

In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin-polymerizing agents and to anti-vascular endothelial growth factor-directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. For this purpose of this study, 54 patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1-3, 8-10, and 15-17, plus paclitaxel (90 mg/m(2)) on days 2, 9, 16, and bevacizumab (10 mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40 to 60% (alpha = 0.10, beta = 0.10). No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals (C.I) 39%, 70%). The adverse event profile was consistent with paclitaxel-bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in seven patients showed increased acetylation of Hsp90 and α-tubulin following vorinostat. Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab.

Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809.

BACKGROUND: Chemotherapy-induced ovarian failure (CIOF) is a frequent side-effect of adjuvant chemotherapy that results in rapid bone loss. We hypothesised that zoledronic acid (ZA), a third-generation amino bisphosphonate, would prevent bone loss in premenopausal women who developed CIOF. METHODS: Women (439) were randomised to intravenous (i.v.) ZA 4 mg every 3 months for 2 years starting within 1-3 months after randomization (arm A) or 1 year after randomization (arm B, controls). CIOF was prospectively defined as ≥ 3 months of amenorrhoea, follicle-stimulating hormone (FSH) ≥ 30 MIU/ml and non-pregnant at 1 year. The primary end-point was the percentage change in bone mineral density (BMD) in the lumbar spine (LS) from baseline to 12 months in the ZA and in control groups in women who developed CIOF; the secondary end-point was BMD in LS at 3 years in all randomised women. FINDINGS: One hundred and fifty (56%) met the definition of CIOF at 1 year. Overall, grade 3 toxicities of ZA were fatigue (1%) arthralgias (21%) and pain (84%). The median percent change (interquartile range, IQR) at 1 year was +1.2% (-0.5% to +2.8%) and -6.7% (-9.7% to -2.9%) p<0.001 and at 3 years was +1.0% (-1.6% to +5.2%) and -0.5% (-3.7% to +3.2%) p=0.019 in arms A and B, respectively. INTERPRETATION: ZA every 3 months is well tolerated and prevents rapid bone loss in premenopausal women that develop CIOF. Giving ZA with rather than 1 year after the start of adjuvant chemotherapy is the preferred sequence to prevent bone loss.

Do cell surface trafficking impairments account for variable cell surface sodium iodide symporter levels in breast cancer?

The Na(+)/I(-) symporter (NIS) is a transmembrane glycoprotein that mediates iodide uptake into thyroid follicular cells and serves as the molecular basis of radioiodine imaging and therapy for thyroid cancer patients. The finding that NIS protein is present in 80-90% of breast tumors suggests that breast cancer patients may also benefit from NIS-mediated radionuclide imaging and targeted therapy. However, only 17-25% of NIS-positive breast tumors have detectable radionuclide uptake activity. The discrepancy between NIS expression and radionuclide uptake activity is most likely contributed by variable cell surface NIS protein levels. Apart from the prevalent view that NIS cell surface trafficking impairments account for the variability, our current study proposes that differential levels of NIS expression may also account for variable cell surface NIS levels among breast tumors. We address the need to confirm the identity of intracellular NIS staining to reveal the mechanisms underlying variable cell surface NIS levels. In addition, we warrant a quantitative correlation between cell surface NIS levels and radionuclide uptake activity in patients such that the cell surface NIS levels required for radionuclide imaging can be defined and the defects impairing NIS activity can be recognized.

Phase I and pharmacokinetic study of mitomycin C and celecoxib as potential modulators of tumor resistance to irinotecan in patients with solid malignancies.

PURPOSE: Based on the preclinical evidence of topoisomerase I (Topo-1) upregulation by mitomycin C(MMC) and decreased NF-kappaB activation by celecoxib, we evaluated combinations of irinotecan/MMC and irinotecan/MMC/celecoxib in patients with advanced solid malignancies. PATIENTS-METHODS: Initially, patients received MMC on day 1 and irinotecan on days 2, 8, 15 and 22, every 6 weeks. MMC dose was fixed at 6 mg/m(2) and cumulative doses of >36 mg/m(2) were not permitted. Irinotecan was escalated in 25 mg/m(2) increments. Due to late-onset diarrhea, the schedule was subsequently shortened to 4 weeks, omitting irinotecan on days 15 and 22. In the second part of the study, celecoxib 400 mg orally twice daily was added to irinotecan/MMC regimen. Potential pharmacokinetic interactions and Topo-1 and DT-diaphorase (NQ01) gene expressions in peripheral-mononuclear cells were evaluated. RESULTS: Forty-five patients were enrolled. Irinotecan 125 mg/m(2) on days 2 and 8 in combination with MMC 6 mg/m(2) on day 1 every 4 weeks is recommended for future studies; myelosuppression and diarrhea are dose-limiting. The addition of celecoxib resulted in unacceptable toxicities despite reductions on irinotecan's dose. No relevant pharmacokinetic interactions occurred between irinotecan and MMC, and mean increases in Topo-1, were observed. Sixteen of 36 patients evaluable for response-assessment had discernable anti-tumor activity, including 1 complete, 4 partial, 10 minor and 1 tumor marker response. Four patients had prolonged (>4 months) disease-stability (stable disease, not included in CR or PR). Patients experiencing complete and partial responses had higher increments in Topo-1 expression. CONCLUSIONS: Modulation of irinotecan by MMC is feasible, devoid of pharmacological interactions and active in solid malignancies. The lack of improvement in therapeutic index does not support the addition of celecoxib.