ARTIFICIAL INTELLIGENCE: CREATING NEW PARADIGMS IN THE MANAGEMENT OF NON-COMMUNICABLE DISEASES.

The role of Artificial Intelligence (AI) in medical science is growing immensely. Since AI contains features that can address both preventive and therapeutic aspects of non-communicable diseases (NCDs), it can potentially lessen the massive burden of morbidity and mortality associated with NCDs. AI can help in various ways in NCDs including predicting disease occurrence, monitoring, ensuring treatment and follow-up of patients. Low- and middle-income countries can harness the benefit of AI for the management of chronic diseases and effectively address challenges like manpower shortage, accessibility to health care, etc. However, AI needs to be used responsibly and rationally in NCDs for its maximum benefit.

Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial.

Background: Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59-0.98; two-sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial. Patients and methods: Patients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Results: Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases. Conclusions: In S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Clinical trial registration: ClinicalTrials.gov, NCT00375674.

Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: patient-reported outcomes from the ABRAZO phase 2 trial.

BACKGROUND: Talazoparib (1 mg/day) exhibited promising efficacy and safety in patients with advanced breast cancer during ABRAZO (NCT02034916); this study evaluated patient-reported outcomes (PROs). PATIENTS AND METHODS: ABRAZO is a two-cohort, two-stage, phase 2 study of talazoparib in patients with advanced breast cancer after a response to prior platinum-based therapy (cohort 1 [C1], n = 49) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2], n = 35). PROs were assessed on day 1 (baseline), every 6 weeks for an initial 24 weeks, and every 12 weeks thereafter until progression, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and its breast cancer module, QLQ-BR23. RESULTS: Global health status/quality of life (GHS/QoL) was maintained from baseline across all time points for both C1 and C2. For C1 and C2, median time to deterioration (TTD) of GHS/QoL (95% confidence interval [CI]) was 2.8 (2.1, 3.0) and 5.5 (4.2, 5.7) months, respectively. Median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1-3.1 months and 4.2-5.6 months, respectively; median TTD for all QLQ-BR23 symptom scales ranged 2.6-4.0 months and 4.2-5.6 months, respectively. There were no statistically significant differences in estimated overall change from baseline in the GHS/QoL scale for both cohorts (C1: -2.6 [95% CI, -7.8, 2.5]; C2: 1.2 [95% CI, -5.5, 8.0]). Significant overall improvements in the breast symptoms and arm symptoms and the future perspective of patients in C1 and C2 were observed, despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2). CONCLUSION: Despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2), patients in both C1 and C2 reported significant overall improvements in their breast symptoms, arm symptoms and future perspective, and their GHS/QoL was maintained from baseline.

Quality of life with talazoparib versus physician's choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial.

Background: In the EMBRACA phase III trial, talazoparib (1 mg daily, orally) demonstrated a statistically significant improvement in PFS versus physician's choice of chemotherapy (PCT; capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with HER2-negative advanced breast cancer carrying a germline BRCA1/2 mutation; we evaluated patient-reported outcomes (PROs). Patients and methods: Patients were randomized 2 : 1 to receive talazoparib or PCT. PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks), and at the end of treatment, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23. Prespecified exploratory analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis carried out in the global health status/quality of life (GHS/QoL), and all functional and symptom scales from the EORTC QLQ-C30 and -BR23 questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and a Cox proportional hazards model. Results: Baseline scores were similar between arms. Statistically significant estimated overall improvement from baseline in GHS/QoL was seen for talazoparib compared with statistically significant deterioration for PCT {3.0 [95% confidence interval (CI) 1.2, 4.8] versus -5.4 [95% CI -8.8, -2.0]; between arms, P < 0.0001}. A statistically significant greater delay was observed in TTD in GHS/QoL, favoring talazoparib over PCT [hazard ratio, 0.38 (95% CI 0.26, 0.55; median, 24.3 versus 6.3 months, respectively; P < 0.0001)]. A statistically significant overall change and a statistically significant delay in TTD, all favoring talazoparib, were also observed in multiple functions and symptoms. Conclusion: Patients who received talazoparib had significant overall improvements and significant delay in TTD in multiple cancer-related and breast cancer-specific symptoms, functions, and GHS/QoL. ClinicalTrials.gov: NCT01945775.

Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial.

Background: Patient-reported outcomes are integral in benefit-risk assessments of new treatment regimens. The PALOMA-2 study provides the largest body of evidence for patient-reported health-related quality of life (QOL) for patients with metastatic breast cancer (MBC) receiving first-line endocrine-based therapy (palbociclib plus letrozole and letrozole alone). Patients and methods: Treatment-naïve postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) MBC were randomized 2 : 1 to palbociclib plus letrozole (n = 444) or placebo plus letrozole (n = 222). Patient-reported outcomes were assessed at baseline, day 1 of cycles 2 and 3, and day 1 of every other cycle from cycle 5 using the Functional Assessment of Cancer Therapy (FACT)-Breast and EuroQOL 5 dimensions (EQ-5D) questionnaires. Results: As of 26 February 2016, the median duration of follow-up was 23 months. Baseline scores were comparable between the two treatment arms. No significant between-arm differences were observed in change from baseline in FACT-Breast Total, FACT-General Total, or EQ-5D scores. Significantly greater improvement in pain scores was observed in the palbociclib plus letrozole arm (-0.256 versus -0.098; P = 0.0183). In both arms, deterioration of FACT-Breast Total score was significantly delayed in patients without progression versus those with progression and patients with partial or complete response versus those without. No significant difference was observed in FACT-Breast and EQ-5D index scores in patients with and without neutropenia. Conclusions: Overall, women with MBC receiving first-line endocrine therapy have a good QOL. The addition of palbociclib to letrozole maintains health-related QOL and improves pain scores in treatment-naïve postmenopausal patients with ER+/HER2- MBC compared with letrozole alone. Significantly greater delay in deterioration of health-related QOL was observed in patients without progression versus those who progressed and in patients with an objective response versus non-responders. ClinicalTrials.gov: NCT01740427 (https://clinicaltrials.gov/ct2/show/NCT01740427).

Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial.

BACKGROUND: In the PALOMA-3 study, palbociclib plus fulvestrant demonstrated improved progression-free survival compared with fulvestrant plus placebo in hormone receptor-positive, HER2- endocrine-resistant metastatic breast cancer (MBC). This analysis compared patient-reported outcomes (PROs) between the two treatment groups. PATIENTS AND METHODS: Patients were randomized 2 : 1 to receive palbociclib 125 mg/day orally for 3 weeks followed by 1 week off (n = 347) plus fulvestrant (500 mg i.m. per standard of care) or placebo plus fulvestrant (n = 174). PROs were assessed on day 1 of cycles 1-4 and of every other subsequent cycle starting with cycle 6 using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. High scores (range 0-100) could indicate better functioning/quality of life (QoL) or worse symptom severity. Repeated-measures mixed-effect analyses were carried out to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline. Between-group comparisons of time to deterioration in global QoL and pain were made using an unstratified log-rank test and Cox proportional hazards model. RESULTS: Questionnaire completion rates were high at baseline and during treatment (from baseline to cycle 14, ≥95.8% in each group completed ≥1 question on the EORTC QLQ-C30). On treatment, estimated overall global QoL scores significantly favored the palbociclib plus fulvestrant group [66.1, 95% confidence interval (CI) 64.5-67.7 versus 63.0, 95% CI 60.6-65.3; P = 0.0313]. Significantly greater improvement from baseline in pain was also observed in this group (-3.3, 95% CI -5.1 to -1.5 versus 2.0, 95% CI -0.6 to 4.6; P = 0.0011). No significant differences were observed for other QLQ-BR23 functioning domains, breast or arm symptoms. Treatment with palbociclib plus fulvestrant significantly delayed deterioration in global QoL (P < 0.025) and pain (P < 0.001) compared with fulvestrant alone. CONCLUSION: Palbociclib plus fulvestrant allowed patients to maintain good QoL in the endocrine resistance setting while experiencing substantially delayed disease progression. CLINICAL TRIAL REGISTRATION: NCT01942135.

Impact of palbociclib plus letrozole on pain severity and pain interference with daily activities in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer as first-line treatment.

Background Palbociclib is a recently approved drug for use in combination with letrozole as initial endocrine-based therapy for the treatment of postmenopausal women with advanced estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. This report assesses the impact of palbociclib in combination with letrozole versus letrozole alone on patient-reported outcomes of pain. Methods Palbociclib was evaluated in an open-label, randomized, phase II study (PALOMA-1/TRIO-18) among postmenopausal women with advanced ER+/HER2- breast cancer who had not received prior systemic treatment for their advanced disease. Patients received continuous oral letrozole 2.5 mg daily alone or the same letrozole dose and schedule plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over repeated 28-day cycles. The primary study endpoint was investigator-assessed progression-free survival in the intent-to-treat population, and these results have recently been published (Finn et al., Lancet Oncol 2015;16:25-35). One of the key secondary endpoints was the evaluation of pain, as measured using the Brief Pain Inventory (BPI) patient-reported outcome tool. The BPI was administered at baseline and on day 1 of every cycle thereafter until disease progression and/or treatment discontinuation. Clinical trial registration This study is registered with ClinicalTrials.gov (NCT00721409). Results There were no statistically significant differences in Pain Severity or Pain Interference scores of the BPI between the two treatment groups for the overall population or among those with any bone disease at baseline. A limitation of the study is that results were not adjusted for the concomitant use of opioids or other medications used to control pain. Conclusions The addition of palbociclib to letrozole was associated with increased efficacy without negatively impacting pain severity or pain interference with daily activities.

Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma.

BACKGROUND: The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS). RESULTS: The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival. CONCLUSIONS: Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01210495.

Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial.

BACKGROUND: Axitinib demonstrated greater progression-free survival vs sorafenib in a phase III study of previously treated patients with metastatic renal cell carcinoma. Here, we report patient-reported kidney-specific symptoms and health status, measured by the Functional Assessment of Cancer Therapy (FACT) Kidney Cancer Symptom Index (FKSI) and the European Quality of Life self-report questionnaire (EQ-5D). METHODS: In all, 723 patients received axitinib (starting dose 5 mg twice daily (b.i.d.)) or sorafenib (400 mg b.i.d.). The FKSI-15, including the disease-related symptoms (FKSI-DRS) subscale, was administered on day 1 before dosing, every 4 weeks and at end of treatment (EOT)/withdrawal. Statistical methods included a mixed-effects repeated-measures model. RESULTS: At baseline, patients in both arms had relatively high mean FSKI-15 and FKSI-DRS scores, comparable to the general US population. Subsequent on-treatment overall mean scores were similar between axitinib and sorafenib, and there was no substantial decline during treatment. Scores substantially worsened at EOT, mainly due to disease progression. CONCLUSION: Patient-reported outcomes were comparable for second-line axitinib and sorafenib and were maintained at relatively high levels while on treatment, but worsened at EOT. As duration of treatment was longer with axitinib than sorafenib, time to worsening of symptoms can be delayed longer with axitinib.

Minimally invasive surgical tube cystotomy for treating obstructive urolithiasis in small ruminants with an intact urinary bladder.

Ten young, male, entire small ruminants (seven kids and three lambs) with obstructive urolithiasis, which were presented within three days of complete blockage and before rupture of the urinary bladder and urethra, underwent a minimally invasive surgical tube cystotomy through the left paralumbar fossa. The catheter was placed in the bladder lumen through a metallic cannula and fixed to the skin with a stay suture. Surgery was performed with the animal standing (six cases) or in right lateral recumbency (four cases) on the day of presentation. All animals were discharged the same day. Eight animals urinated normally within a mean of seven days (range four to 10 days). One animal had a blockage of urine flow as a result of kinking of the catheter on the third postoperative day, and in another the catheter collapsed on the fourth postoperative day. These were managed by a second, conventional surgical tube cystotomy. No recurrence of the condition was noticed in any of the animals during a six-month follow-up period.

Collection and characterization of semen in Mithun (Bos frontalis) bulls.

The objective of this study was to collect semen from semiwild Mithun (Bos frontalis) bulls using an artificial vagina (AV) and to determine semen characteristics. Collection of semen with an AV was attempted in five Mithun bulls using both anestrous and estrous Mithun females. No Mithun bull mounted an anestrous female Mithun during 60 trials, but satisfactory mounting, including extension of the penis, occurred in 25 trials with estrous Mithun females. In 15 of these trials, semen was successfully collected in an AV with an internal temperature of 42 to 46 degrees C. However, in 10 trials with an AV with an internal temperature of 36 to 40 degrees C, semen was not collected. Mean (+/- SEM) intervals to first mount and to ejaculation in the AV were 27.9+/-3.6 sec and 113.8+/-6.6 sec, respectively. Semen volume and pH were 3.1+/-0.35 mL and 6.59+/-0.04, and mean mass activity (scale, 0 to 4), initial sperm motility, live sperm count, sperm concentration, total number of sperm in the ejaculate, and overall sperm length were 2.2+/-0.3, 78.6+/-2.6%, 80.7+/-2.2%, 710.8+/-66.8 x 10(6)/mL, 2114+/-364.4 sperm, and 67.9+/-0.6 microm, respectively. The proportion of morphologically normal sperm was 80.6+/-0.2%, whereas the proportion with a morphologically abnormal head, midpiece, tail, and acrosome were 4.2+/-0.4%, 1.6+/-0.5%, 6.1+/-1.1%, and 7.1+/-0.9%, respectively. The mean incidence of tail-less heads and proximal and distal protoplasmic droplets were 0.5+/-0.1%, 0.3+/-0.2%, and 2.4+/-0.3%, respectively. In conclusion, we successfully collected semen from semiwild Mithun bulls with an AV maintained at 42 to 46 degrees C, and overall, the semen was within the normal range of that collected from fertile domestic bulls.