Discovery and prospects of new heterocyclic Isatin-hydrazide derivative with a novel role as estrogen receptor α degrader in breast cancer cells.

Introduction: Isatin, a heterocycle scaffold, is the backbone of many anticancer drugs and has previously been reported to engage multiple cellular targets and mechanisms, including angiogenesis, cell cycle, checkpoint pathways and multiple kinases. Here, we report that a novel isatin derivative, 5i, degrades estrogen receptor alpha (ERα) in estrogen-dependent breast cancer cells. This effect of the isatin nucleus has not been previously reported. Tamoxifen and fulvestrant represent standard therapy options in estrogen-mediated disease but have their own limitations. Isatin-based triple angiokinase inhibitor BIBF1120 (Nintedanib) and multikinase inhibitor Sunitinib (Sutent) have been approved by the FDA. Methods: Keeping this in view, we synthesized a series of N'-(1-benzyl-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) hydrazide derivatives and evaluated them in vitro for antiproliferative activities in MCF-7 (ER+) cell line. We further investigated the effect of the most potent compound (5i) on the Erα through Western Blot Analysis. We used in silico pharmacokinetics prediction tools, particularly pkCSM tool, to assess the activity profiles of the compounds. Results and discussion: Compound 5i showed the best antiproliferative activity (IC50 value; 9.29 ± 0.97 µM) in these cells. Furthermore, 5i downregulated ERα protein levels in a dose-dependent manner in MCF-7. A multifaceted analysis of physicochemical properties through Data Warrior software revealed some prominent drug-like features of the synthesized compounds. The docking studies predicted the binding of ligands (compounds) with the target protein (ERα). Finally, molecular dynamics (MD) simulations indicated stable behavior of the protein-ligand complex between ERα and its ligand 5i. Overall, these results suggest that the new isatin derivative 5i holds promise as a new ERα degrader.

Improving Value in Colorectal Cancer Care: An Economic Analysis of Enhanced Recovery Protocols at a Community Hospital.

Background: Enhanced recovery protocols (ERPs) have been shown to improve the outcomes of gastrointestinal cancer care, leading to reduced morbidity of gastrointestinal treatment and reduced delays in systemic therapy. ERP implementation has also previously shown a reduction in length of stay (LOS) without changing the readmission rate; however, the economic cost associated with these measures has not yet been quantified. The aim of this study was to evaluate the economic costs of ERP implementation for colorectal cancer at a community hospital. Methods: The Diagnostic Related Group (DRG) codes were used to assess costs associated with the hospitalizations of cases in the ERP versus non-ERP groups. The American Hospital Association (AHA) Annual Survey from 1999 to 2015 was used to provide the expenses per day for inpatient hospitalization in the United States. Postoperative LOS, average healthcare costs, and postoperative complications between ERP-protocol and non-ERP protocol groups were analyzed using analysis of variance (ANOVA) and independent t-tests. Results: The AHA survey estimated that $2,265 was incurred per day for non-profit hospitals in Florida and $2,346 was incurred per day for the United States. For all DRG codes, the ERP-participating group was associated with a shorter LOS and reduced health care costs. LOS-associated cost was compared between ERP and non-ERP groups: for DRG 329, the total savings was $162,118.8 (n = 12 non-ERP versus n = 8 ERP, P = 4.39 × 10-18); for DRG 330, $314,552.64 (n = 36 non-ERP versus n = 24 ERP, P = 2.72 × 10-22); and for DRG 331, $89,302.73 (n = 11 non-ERP versus n = 23 for ERP, P = 4.19 × 10-20). Conclusions: The implementation of an ERP protocol for colorectal cancer was associated with significantly reduced costs in a community hospital.

Improving Gastrointestinal Cancer Care by Enhanced Recovery Protocol Implementation.

Background: Enhanced recovery protocols (ERPs) have become the standard of care for patients undergoing elective small bowel surgeries but have not yet been adequately studied in community hospitals. In this study, a multidisciplinary ERP was developed and implemented at a community hospital to include minimal anesthesia, early ambulation and enteral alimentation, and multimodal analgesia. The aim of this study was to determine the effects of the ERP on postoperative length of stay (LOS), readmission (RA) rates following bowel surgery, and postoperative outcomes. Methods: The study design was a retrospective review of patients undergoing major bowel resection at Holy Cross Hospital (HCH) from January 1, 2017 to December 31, 2017. Patient charts for diagnostic-related group (DRG) 329, 330, and 331 were retrospectively reviewed at HCH in 2017 to compare outcomes in ERP versus non-ERP cases. The Medicare claims database (CMS) was also retrospectively reviewed to compare HCH data to the national average LOS and RA for the same DRG codes. Mean values for LOS and RA were statistically compared to determine significant differences between ERP versus non-ERP patients at HCH and national CMS data versus HCH patients. Results: LOS was analyzed for each DRG at HCH. At HCH, for DRG 329, the mean LOS for non-ERP was 13.0833 days (n = 12) versus 3.375 days (n = 8) (P ≤ 0.001) for ERP. For DRG 330, the mean LOS for non-ERP was 10.861 days (n = 36) versus 4.583 days (n = 24) (P ≤ 0.001) for ERP. For DRG 331, the mean LOS for non-ERP was 7.272 days (n = 11) versus 3.348 days (n = 23) (P = 0.004) for ERP. LOS was also compared to national CMS data. The LOS at HCH for DRG 329 improved from the 10th to 90th percentile (n = 238,907); DRG 330 improved from the 10th to the 72nd percentile (n = 285,423); DRG 331 improved from 10th to 54th percentile (n = 126,941) (P < 0.001). The RA at HCH in ERP and non-ERP cases was 3% at 30 and 90 days. CMS RA for DRG 329 was 25.1% at 90 days and 9.9% at 30 days; DRG 330 RA was 18.3% at 90 days and 6.6% at 30 days; DRG 331 RA was 11% at 90 days and 3.9% at 30 days. Conclusion: Implementation of ERP following bowel surgery at HCH significantly improved outcomes, in comparison to non-ERP cases, national CMS data, and Humana data. Further research on ERP for other fields and its impact on outcomes in other community settings is recommended.

Stereotactic body radiotherapy of adrenal metastases-A dose-finding study.

Optimal doses for the treatment of adrenal metastases with stereotactic radiotherapy (SBRT) are unknown. We aimed to identify dose-volume cut-points associated with decreased local recurrence rates (LRR). A multicenter database of patients with adrenal metastases of any histology treated with SBRT (biologically effective dose, BED10 ≥50 Gy, ≤12 fractions) was analyzed. Details on dose-volume parameters were required (planning target volume: PTV-D98%, PTV-D50%, PTV-D2%; gross tumor volume: GTV-D50%, GTV-mean). Cut-points for LRR were optimized using the R maxstat package. One hundred and ninety-six patients with 218 lesions were included, the largest histopathological subgroup was adenocarcinoma (n = 101). Cut-point optimization resulted in significant cut-points for PTV-D50% (BED10: 73.2 Gy; P = .003), GTV-D50% (BED10: 74.2 Gy; P = .006), GTV-mean (BED10: 73.0 Gy; P = .007), and PTV-D2% (BED10: 78.0 Gy; P = .02) but not for the PTV-D98% (P = .06). Differences in LRR were clinically relevant (LRR ≥ doubled for cut-points that were not achieved). Further dose-escalation was not associated with further improved LRR. PTV-D50%, GTV-D50%, and GTV-mean cut-points were also associated with significantly improved LRR in the adenocarcinoma subgroup. Separate dose optimizations indicated a lower cut-point for the PTV-D50% (BED10: 69.1 Gy) in adenocarcinoma lesions, other values were similar (<2% difference). Associations of cut-points with overall survival (OS) and progression-free survival were not significant but durable freedom from local recurrence was associated with OS in a landmark model (P < .001). To achieve a significant improvement of LRR for adrenal SBRT, a moderate escalation of PTV-D50% BED10 >73.2 Gy (adenocarcinoma: 69.1 Gy) should be considered.

Assessment of hand function in women with lymphadenopathy after radical mastectomy.

BACKGROUND: Breast cancer related upper limb lymphedema (BCRL) is a common complication in post-mastectomy patients. It is known to cause upper limb disability, which subsequently may affect the grip strength and hand function. There is little evidence on the objective assessment of functional activities particularly hand function in women with BCRL. Therefore, this study objectively assesses the handgrip strength and hand functions in women with BCRL. METHOD: A cross-sectional study design was conducted on a sample of women with (n = 31) and without (n = 31) BCRL. The Handgrip strength and hand functions were measured using a dynamometer and Jebsen-Taylor hand function test, respectively. RESULTS: The results showed a significantly reduced handgrip strength in women with BCRL as compared to age-matched healthy adult women for both right and left hands (p < 0.05). Similarly, hand functions were significantly impaired in women with BCRL as compared to healthy adult women (p < 0.05). Reduction in handgrip strength and hand function in women with BCRL were clinically meaningful as indicated by moderate to large effect sizes (Cohen's d = 0.61 to 0.99 and 0.54 to 3.02, respectively) in all outcomes except power handgrip strength in left hand (Cohen's d = 0.38). CONCLUSION: The results of this study indicate a significant reduction of hand grip strength and hand function in women with BCRL. Our findings suggest that objective measures of grip strength and function be included in the assessment of women with BCRL to better guide clinical decision making and patient care, which may include management of impairment associated with hand strength and function. Future studies that evaluate hand grip strength and function in a larger sample which includes a more diverse age group of women with BCRL are warranted to confirm the current findings.

Interstitial single fraction brachytherapy for malignant pulmonary tumours.

PURPOSE: Interstitial brachytherapy for pulmonary tumours is an alternative to stereotactic radiotherapy, allowing high conformity despite it being an invasive technique. The aim of the study was the analysis of dose distribution, toxicity and tumour response rates. METHODS: In the years 2014-2019, 27 patients with pulmonary tumours received 36 interstitial brachytherapies with Ir-192: 11 patients with non-small cell lung cancer, 16 patients with pulmonary metastases of other entities. RESULTS: Patients were treated with a median (interquartile range) prescription dose of 20 (20-26) Gy in a single fraction. Mean lung dose to the ipsilateral lung was 2.8 (1.6-4.7) Gy. Maximum doses to the heart, oesophagus, thoracic wall and spinal cord were 2.4 (1.8-4.6) Gy, 2.0 (1.2-6.2) Gy, 12.6 (8.0-18.2) Gy and 1.5 (0.6-3.9) Gy. Median survival after treatment was 15 months, with a 1- and 2­year local control of 84% and 60%. Median overall survival after initial cancer diagnosis was 94 months; 2 years following brachytherapy, 75% of patients with colorectal cancer vs. 37% with other histologies were alive; p = 0.14. In 69% (n = 25), brachytherapy could be performed without acute complications. A self-limiting bleeding occurred in 8% (n = 3), fever in 3% (n = 1), pneumothorax in 17% (n = 6), and pulmonary failure in 3% (n = 1). Patients with > 20 Gy in 95% of planning target volume had higher pneumothorax rates needing intervention (31% vs. 5%, p = 0.04). CONCLUSIONS: Interstitial brachytherapy for pulmonary tumours is a highly conformal therapy with minimal doses to the organs at risk. For the majority of patients, treatment can be performed without relevant complications in a single fraction with a satisfactory local control.

Stereotactic or conformal radiotherapy for adrenal metastases: Patient characteristics and outcomes in a multicenter analysis.

To report outcome (freedom from local progression [FFLP], overall survival [OS] and toxicity) after stereotactic, palliative or highly conformal fractionated (>12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤12 fractions, biologically effective dose [BED10] ≥ 50 Gy), 3DCRT/IMRT (>12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 < 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). Three hundred twenty-six patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT and Pall-RT in 260, 27 and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%) and melanoma (6.7%). Unadjusted FFLP was higher after SBRT vs Pall-RT (P = .026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4% and 27.7%). OS was longer after SBRT vs other groups (P < .05) and increased in patients with locally controlled metastases in a landmark analysis (P < .0001). Toxicity was mostly mild; notably, four cases of adrenal insufficiency occurred, two of which were likely caused by immunotherapy or tumor progression. Radiotherapy for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. One-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway.

Mechanochemical reaction of Al and melamine: a potential approach towards the in situ synthesis of aluminum nitride-carbon nanotube nanocomposites.

In the current study, an inexpensive solid-state mechanochemical technique is proposed for the in situ synthesis of nanostructured aluminum nitride (AlN) and carbon nanotubes (CNTs). The CNTs and nitrogen-doped CNTs are synthesized through a novel bottom-up milling approach in which melamine as the solid source of both carbon and nitrogen is milled with aluminum. However, the efficiency of CNT formation remarkably enhances when the milled powder is exposed to a subsequent heat treatment. The effect of various parameters such as milling media, aluminum-to-melamine molar ratio (Al/M), milling time and subsequent heating temperature on the yield and formation mechanism of the produced CNTs are assessed. A detailed characterization of the final products reveals that small amorphous carbon nitride domains resulting from polymerization of melamine molecules at the intermediate stages of milling are responsible for the synthesis of CNTs either during the milling or subsequent heat treatment processes.

LINAC stereotactic radiosurgery for trigeminal neuralgia -retrospective two-institutional examination of treatment outcomes.

BACKGROUND: In this pooled 2-center series LINAC radiosurgery (SRS) has been applied as a treatment option for a subset of refractory trigeminal neuralgia (TN) patients. This study approached to retrospectively assess the efficacy and safety of LINAC SRS and to provide a brief overview addressed to the technical development from frame-based towards frameless robotic SRS. METHODS: From 2001 to 2017 n = 55 patients (pts) were treated, n = 28 were female (51%), mean age: 66 years (range 36-93 years); TN etiology: 37 classic TN, 15 multiple sclerosis (MS)-related TN, 2 symptomatic TN, and 1 atypical TN. Previous treatment was present in n = 35 (63.6%) pts. (some multiple or combined) with n = 23 microsurgical vascular decompression and n = 17 percutaneous retrogasserian rhizotomy. A 6 MV LINAC (4-5 mm collimators) was applied in all pts. (n = 26 framebased - n = 29 frameless robotic). The dorsal root entry zone (DREZ) was targeted in n = 35 cases and the retrogasserian target in n = 20 pts. with a homogeneous dose for the entire study cohort (90 Gy). SRS outcome was measured using the Barrow Neurological Institute (BNI) score for pain and hypaesthesia and statistically evaluated by univariate and multivariate analyzes. RESULTS: Mean follow-up (FU) was 30 months (2 lost FU); the total rate of post SRS BNI pain I-IIIa (=painfree w or w/o medication) was 69% (88% for the classic TN pts), 29% (38.8% classic TN) were classified as BNI pain I-II (=painfree w/o medication). A BNI hypaesthesia II-III was present in 9.4% (n = 5) and BNI hypaesthesia IV in n = 2. Between groups analysis demonstrated no correlation of SRS responsiveness with age, gender, MS- or not MS-associated TN, previous surgery, framebased/frameless robotic SRS. DREZ targeting significantly better suppressed TN compared to RG targeting (p = 0.01). Additionally, a statistical trend for a better BNI pain outcome (p = 0.07) along with a significant increase in BNI hypaesthesia (p = 0.01) was found when using a larger partial trigeminal 70 Gy volume. CONCLUSION: Our retrospective analysis support LINAC SRS as an effective and safe treatment option in TN. Frameless robotic SRS of TN is safe when using a dedicated LINAC system. A target definition closer to the brainstem and tendencially a larger target volume were associated with a better outcome for pain.

Aggressive versus symptom-guided drainage of malignant pleural effusion via indwelling pleural catheters (AMPLE-2): an open-label randomised trial.

BACKGROUND: Indwelling pleural catheters are an established management option for malignant pleural effusion and have advantages over talc slurry pleurodesis. The optimal regimen of drainage after indwelling pleural catheter insertion is debated and ranges from aggressive (daily) drainage to drainage only when symptomatic. METHODS: AMPLE-2 was an open-label randomised trial involving 11 centres in Australia, New Zealand, Hong Kong, and Malaysia. Patients with symptomatic malignant pleural effusions were randomly assigned (1:1) to the aggressive (daily) or symptom-guided drainage groups for 60 days and minimised by cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group [ECOG] score 0-1 vs ≥2), presence of trapped lung, and prior pleurodesis. Patients were followed up for 6 months. The primary outcome was mean daily breathlessness score, measured by use of a 100 mm visual analogue scale during the first 60 days. Secondary outcomes included rates of spontaneous pleurodesis and self-reported quality-of-life measures. Results were analysed by an intention-to-treat approach. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000963527. FINDINGS: Between July 20, 2015, and Jan 26, 2017, 87 patients were recruited and randomly assigned to the aggressive (n=43) or symptom-guided (n=44) drainage groups. The mean daily breathlessness scores did not differ significantly between the aggressive and symptom-guided drainage groups (geometric means 13·1 mm [95% CI 9·8-17·4] vs 17·3 mm [13·0-22·0]; ratio of geometric means 1·32 [95% CI 0·88-1·97]; p=0·18). More patients in the aggressive group developed spontaneous pleurodesis than in the symptom-guided group in the first 60 days (16 [37·2%] of 43 vs five [11·4%] of 44, p=0·0049) and at 6 months (19 [44·2%] vs seven [15·9%], p=0·004; hazard ratio 3·287 [95% CI 1·396-7·740]; p=0·0065). Patient-reported quality-of-life measures, assessed with EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L), were better in the aggressive group than in the symptom-guided group (estimated means 0·713 [95% CI 0·647-0·779] vs 0·601 [0·536-0·667]). The estimated difference in means was 0·112 (95% CI 0·0198-0·204; p=0·0174). Pain scores, total days spent in hospital, and mortality did not differ significantly between groups. Serious adverse events occurred in 11 (25·6%) of 43 patients in the aggressive drainage group and in 12 (27·3%) of 44 patients in the symptom-guided drainage group, including 11 episodes of pleural infection in nine patients (five in the aggressive group and six in the symptom-guided drainage group). INTERPRETATION: We found no differences between the aggressive (daily) and the symptom-guided drainage regimens for indwelling pleural catheters in providing breathlessness control. These data indicate that daily indwelling pleural catheter drainage is more effective in promoting spontaneous pleurodesis and might improve quality of life. FUNDING: Cancer Council of Western Australia and the Sir Charles Gairdner Research Advisory Group.

Protocol of the Australasian Malignant Pleural Effusion-2 (AMPLE-2) trial: a multicentre randomised study of aggressive versus symptom-guided drainage via indwelling pleural catheters.

INTRODUCTION: Malignant pleural effusions (MPEs) can complicate most cancers, causing dyspnoea and impairing quality of life (QoL). Indwelling pleural catheters (IPCs) are a novel management approach allowing ambulatory fluid drainage and are increasingly used as an alternative to pleurodesis. IPC drainage approaches vary greatly between centres. Some advocate aggressive (usually daily) removal of fluid to provide best symptom control and chance of spontaneous pleurodesis. Daily drainages however demand considerably more resources and may increase risks of complications. Others believe that MPE care is palliative and drainage should be performed only when patients become symptomatic (often weekly to monthly). Identifying the best drainage approach will optimise patient care and healthcare resource utilisation. METHODS AND ANALYSIS: A multicentre, open-label randomised trial. Patients with MPE will be randomised 1:1 to daily or symptom-guided drainage regimes after IPC insertion. Patient allocation to groups will be stratified for the cancer type (mesothelioma vs others), performance status (Eastern Cooperative Oncology Group status 0-1 vs ≥2), presence of trapped lung (vs not) and prior pleurodesis (vs not). The primary outcome is the mean daily dyspnoea score, measured by a 100 mm visual analogue scale (VAS) over the first 60 days. Secondary outcomes include benefits on physical activity levels, rate of spontaneous pleurodesis, complications, hospital admission days, healthcare costs and QoL measures. Enrolment of 86 participants will detect a mean difference of VAS score of 14 mm between the treatment arms (5% significance, 90% power) assuming a common between-group SD of 18.9 mm and a 10% lost to follow-up rate. ETHICS AND DISSEMINATION: The Sir Charles Gairdner Group Human Research Ethics Committee has approved the study (number 2015-043). Results will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: ACTRN12615000963527; Pre-results.

Endobronchial glomus tumor.

We report a case of a 52-year-old patient who had undergone a bladder resection and an ileal conduit for a transitional cell carcinoma. He then presented with a short history of hemoptysis 3 months later. Rigid bronchoscopy was performed revealing an endobronchial lesion, which was removed via laser and debulking method without complications. Histopathologic examination confirmed it to be a benign endobronchial glomus tumor. On the basis of our literature search, this is the 34th reported case of glomus tumor arising from the respiratory tract, seventh reported case of an endobronchial glomus tumor treated bronchoscopically, and the first possibly coincidental finding in relation to a patient with primary transitional bladder cell carcinoma.

A Case of Recurrent Respiratory Papillomatosis Successfully Removed Via Endoscopic Argon Plasma Coagulation (APC) With No Evidence of Recurrence.

Recurrent respiratory papillomatosis (RRP) is a benign disease caused by the human papilloma virus (HPV), characterized by the formation of recurrent, epithelial neoplastic lesions in the airways. While benign, they can cause significant airway obstruction in some cases. Difficulties in treatment arise from the recurrent nature of the lesions despite repeated procedures. Other known procedures that result in deep tissue damage also cause unacceptable collateral damage to the underlying airway mucosa. We describe a case of recurrent papillomatosis that was successfully treated with argon plasma coagulation ( APC) when laser and electrocautery ablation had failed in the past. After the papillomatasis was treated with APC, there is no recurrence on repeat scope at 4 months and 9 months after the initial procedure. The procedure was done as a day case and there is no complication from the procedure. The property of the APC that allows it to cause only superficial thermal damage to the tissue makes it a suitable adjunct therapy to the treatment of papillomas, which are usually superficial lesions.

A rare double pathology- coexistent large cell neuroendocrine cell carcinoma of the lung with Basal cell carcinoma of the skin.

No abstract available.