Synthesis and Analysis of (γ,γ',γ''-Trifluoro)neopentyl (TFNP) Aryl Ethers as a Polar Fluoroaliphatic Motif.

A route is developed to (γ,γ',γ'''-trifluoro)neopentyl (TFNP) aryl ethers to extend the methods for the introduction of the tert-butyl group, carrying a fluorine on each of the methyl substituents. The route combines neopentyltosylate 3 with phenols and thiophenols to give efficient substitution reactions to the corresponding TFNP aryl ethers. The three C-F bonds adopt a helical propeller conformation as revealed by computation and single crystal X-ray structure analysis. The LogPs of TFNP ethers are lower (more hydrophilic) than their neopentyl analogues. The metabolism of selected TFNP ethers was explored in the fungus Cunninghamella elegans.

Radiation recall dermatitis induced by pazopanib.

BACKGROUND: Pazopanib is a multi-targeted tyrosine kinase inhibitor that has recently been approved for treatment of advanced clear cell renal cell carcinoma (RCC). There are no previous reports of pazopanib triggering radiation recall dermatitis (RRD). CASE REPORT: A 60-year-old male patient was commenced on pazopanib for metastatic RCC 2 weeks prior to receiving radiotherapy (10×30 Gy) to bone metastases at the T9 and L4 vertebrae and right mid-shaft of humerus. Although there were no immediate complications from radiotherapy, 2 weeks after finishing radiation he developed a pruritic, erythematous, maculo-papular rash localized to the T9 and right humeral radiotherapy fields. The patient was diagnosed with RRD induced by pazopanib and commenced on a course of oral prednisolone, which resulted in resolution of his rash. He has now completed 5 months of pazopanib with no recurrence of RRD. CONCLUSION: We report the first case of RRD triggered by pazopanib. With increasing use of pazopanib for advanced RCC, clinicians must be aware of the possibility that RRD can occur in patients treated with this agent following radiotherapy.

Impact of Dysphagia Rehabilitation in Adults on Swallowing Physiology Measured With Videofluoroscopy: A Mapping Review.

PURPOSE: The research aims of this review were to (a) map swallowing rehabilitation approaches to specific swallowing impairments using the Modified Barium Swallow Impairment Profile (MBSImP) to develop evidence maps, (b) match desired rehabilitation treatment targets to treatment approaches, and (c) identify gaps in the literature and highlight which rehabilitation approaches require further investigation to support accurate mapping of interventions to physiologic change. METHOD: A mapping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review extension framework. The databases searched were CINAHL, Ovid Medline, and Ovid Embase. Data extracted included swallowing rehabilitation approach details via the Rehabilitation Treatment Specification System framework, study characteristics, and resulting change in swallowing physiology. The resulting change in swallowing physiology was mapped onto MBSImP components, where applicable, and effect sizes were reported where data were available. Extracted data were summarized in the form of evidence maps. RESULTS: Forty-three unique articles met the inclusion criteria for this review and were divided into single-approach and multi-approach exercise studies. Within single-approach studies, 13 different exercise approaches were investigated, and 117 outcome measures could be mapped to MBSImP components. Within multi-approach studies, 13 different combinations of exercise approaches were investigated and 60 outcome measures could be mapped to MBSImP components. CONCLUSIONS: This review supports speech-language pathologists in incorporating current best evidence into their practice, as it found there is potential for improvement in many MBSImP components by using rehabilitative exercises. In the future, more intervention studies are needed to ensure that recommended rehabilitation approaches are beneficial for improving the targeted swallowing physiology.

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function.

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed ß,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.

A case study of trastuzumab treatment for metastatic breast cancer in pregnancy: fetal risks and management of cerebral metastases.

Trastuzumab increases survival amongst women with human epidermal growth factor receptor (HER)-2 receptor positive metastatic breast cancer, but maternal and fetal risks are associated with advanced disease and its treatment in pregnancy. We present a case of a primigravid with HER-2 positive metastatic breast cancer who received trastuzumab throughout pregnancy. She presented with cerebral metastases, requiring surgical decompression and resection. Reversible oligohydramnios developed during pregnancy. Fetal safety data on trastuzumab in pregnancy is limited, but case reports suggest a recurring pattern of (mostly reversible) oligohydramnios.

Risk of febrile neutropenia and early treatment cessation in men receiving standard and dose-reduced 3-weekly docetaxel for metastatic castration-resistant prostate cancer.

BACKGROUND: Docetaxel is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC); however, many patients experience febrile neutropenia (FN) and cease treatment early due to toxicity. It is not known whether lower dose (LD) q3-weekly docetaxel impacts toxicity or efficacy. METHODS: Multicenter retrospective study included 166 patients with mCRPC who received q3-weekly docetaxel between 2010 and 2015. Demographic, disease, chemotherapy (standard dose, SD > 60 mg/m2 vs LD ≤ 60 mg/m2 ) and toxicity data were collected. Univariable and multivariable logistic and competing risk regression models evaluated docetaxel-dose association with FN and early treatment cessation (ETC) due to toxicity. Associations between dose and efficacy end points were also evaluated. Analyses were repeated employing inverse propensity score weights. RESULTS: Patients who received LD docetaxel (28.9%) were older with poorer Eastern Cooperative Oncology Group (ECOG) status. Fifteen percent of patients experienced FN, with a nonsignificant trend to lower incidence in the LD group (multiple adjusted odds ratio [OR] = 0.42; P = 0.21). Neither baseline patient nor prior treatment factors were predictive of FN. ETC due to toxicity occurred in 35%, with risk associated with increasing age, comorbidity count and poorer ECOG. There was no difference between LD and SD with respect to ETC due to toxicity, in unweighted and weighted analyses (LD vs SD, multivariable weighted hazard ratio [HR] = 1.47; P = 0.08). LD was associated with reduced prostate-specific antigen (PSA) response (50% vs 66.1%, multivariable weighted HR = 0.54; P = 0.03) and overall survival (median 7.9 vs 13.8 months, multivariable weighted HR = 2.19; P < 0.0001). CONCLUSIONS: LD docetaxel for mCRPC did not mitigate the risk of FN or ETC due to toxicity. Dose reduction may result in poorer PSA response and survival.

Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials.

Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.

Excellent disease control and survival in patients with advanced nasopharyngeal cancer treated with chemoradiation.

PURPOSE: To determine the efficacy and safety of epirubicin, cisplatin, and infusional fluorouracil (5-FU) chemotherapy followed by radiation with concurrent cisplatin in patients with locally and/or regionally advanced nasopharyngeal cancer. PATIENTS AND METHODS: Thirty-five patients were treated with three cycles of induction chemotherapy with epirubicin 50 mg/m(2) and cisplatin 75 mg/m(2) combined with continuous-infusion 5-FU 200 mg/m(2) daily for 9 weeks, followed by concurrent chemoradiation of 60 Gy in 2-Gy fractions with cisplatin 20 mg/m(2) daily for 5 days in weeks 1 and 6. RESULTS: Median age was 43 years, 74% had World Health Organization type III histology, and 91% had stage IV disease (International Union Against Cancer, ed 4). All patients received three cycles of induction chemotherapy, and 97% completed chemoradiation. The estimated 4-year progression-free survival rate was 81% (95% CI, 59% to 93%), and the estimated 4-year overall survival rate was 90% (95% CI, 74% to 97%). Only two patients have had a locoregional relapse by the close-out date despite the use of only 60 Gy. Induction chemotherapy was well tolerated, with 11% grade 3 or 4 stomatitis, 26% grade 3 vomiting, and no episodes of febrile neutropenia. Acute toxicities of chemoradiation were as follows: 23% grade 3 or 4 vomiting, 6% febrile neutropenia, 31% grade 3 mucositis, and 23% grade 3 skin toxicity. The most prevalent grade 3 late effects were xerostomia and hearing loss. CONCLUSION: This regimen was well tolerated, can be delivered as planned, and has resulted in excellent locoregional disease control and survival in patients with locally advanced nasopharyngeal cancer.

The utility of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography in the investigation of patients with disseminated carcinoma of unknown primary origin.

PURPOSE: A retrospective analysis of the use of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) positron emission tomography (PET) was performed in patients with histologically proven disseminated carcinoma of unknown primary tumor (CUP). PROCEDURES: The records of 31 patients with CUP, excluding patients with isolated neck metastases, were reviewed to identify the ability of PET to detect the putative primary site (PPS) and/or to change therapeutic management. RESULTS: In eight out of 31 cases (26%), a PPS was confirmed, either definitively (one pathologically, one radiologically) (true positive) or clinically (six cases). For three cases (10%), histological evidence of a primary tumor distant from the PPS was found (false positive). In a further seven cases (23%), the PPS remained unconfirmed, whereas for 13 cases (42%) no PPS was identified. In five out of seven patients in whom the PET suggested a high probability of having identified the primary site, the PPS was confirmed definitively or clinically. PET altered clinical management in at least 12 cases (38%). CONCLUSIONS: PET contributed to the management of previously extensively investigated patients with CUP. Identification of a PPS and/or change in management was documented in 38% of cases, the majority of which were lung or pancreatic cancer. These findings are worthy of evaluation in a prospective study.

Syndrome of inappropriate anti-diuretic hormone secretion secondary to carboplatin after docetaxel-carboplatin-trastuzumab combination for early stage HER-2 positive breast cancer.

Carboplatin is a platinum analogue, widely used in the treatment of numerous cancer types including lung, genitourinary and ovarian cancers. It is also used in the adjuvant treatment of human epidermal growth factor receptor 2 positive breast cancer, where a non-anthracycline regimen is preferred. It is considered generally to be less toxic though potentially less efficacious than cisplatin, another platinum compound. Cisplatin is well recognized as causing hyponatremia, through the mechanism of renal salt wasting. Conversely, carboplatin has only rarely been associated with hyponatremia. We report here a case of severe hyponatremia occurring 6 days after adjuvant treatment with a carboplatin-containing chemotherapy regimen for early stage breast cancer. The mechanism of hyponatremia was consistent with the syndrome of inappropriate anti-diuretic hormone secretion based on biochemical and clinical findings, and response to fluid restriction. With no previously reported cases of docetaxel-associated or trastuzumab-associated hyponatremia, the causative agent was considered to be carboplatin. Additionally there was no recurrence of hyponatremia on recommencement of docetaxel and trastuzumab therapy. Hyponatremia secondary to carboplatin has been rarely reported in the literature, with only three previously reported cases. Although it is rare, oncologists should be aware of the potential for carboplatin to cause hyponatremia and the need to monitor electrolytes throughout therapy.

The usefulness of fluorine 18-labelled deoxyglucose positron emission tomography in the investigation of patients with cervical lymphadenopathy from an unknown primary tumor.

BACKGROUND: The usefulness of fluorine 18-labelled deoxyglucose positron emission tomography (PET) in the detection of unknown primary tumor in patients seen with malignant cervical lymphadenopathy thought to arise from a head and neck primary differs in the published reports to date. To assess the role of PET in this scenario in our institution, an audit was performed. METHODS: The records of 21 patients who met the clinical indication were reviewed. End points were the ability of PET to detect an unknown primary tumor and/or distant metastatic disease. RESULTS: In 8 of the 21 patients, PET detected a potential primary site, although none was unequivocally PET positive. One case was pathologically confirmed. In five patients the potential primary site identified on PET could not be confirmed: two had negative biopsies, and three had no clinical evolution in the PET-suspect area for at least 24 months after the initial study. In the remaining two patients, the potential primary site detected by PET was treated without biopsy. PET detected additional regional and/or distant disease that had not been previously documented in nine cases. CONCLUSIONS: PET did not add significantly to the detection of an occult primary tumor in patients who had already been comprehensively evaluated by clinical and radiologic investigations. It was of substantial benefit, however, in detecting unsuspected distant disease in patients with undifferentiated nodal histologic findings and helped in delineating regional disease in patients with N2 disease.