Providing family updates: a primer for the medical trainee.

Providing family updates is a common clinical task for medical trainees and practitioners working in hospital settings. Good clinical communication skills are essential in clinical care as it is associated with improved patient satisfaction, understanding of condition, treatment adherence, and better overall clinical outcomes. Moreover, poor communications are often the source of medical complaints. However, while patient-centred communication skills training has generally been incorporated into clinical education, there hitherto remains inadequate training on clinical communications with patients' families, which carry different nuances. In recent years, it is increasingly recognized that familial involvement in the care of hospitalized patients leads to better clinical and psychological outcomes. In fact, in Asian populations with more collectivistic cultures, families are generally highly involved in patient care and decision-making. Therefore, effective clinical communications and regular provision of family updates are essential to build therapeutic rapport, facilitate familial involvement in patient care, and also provide a more holistic understanding of the patient's background and psychosocial set-up. In this article, we herein describe a seven-step understand the clinical context, gather perspectives, deliver medical information, address questions, concerns and expectations, provide tentative plans, demonstrate empathy, postcommunication reflections model as a practical guide for medical trainees and practitioners in provision of structured and effective family updates in their clinical practice.

A review of strategies to overcome immune resistance in the treatment of advanced prostate cancer.

Immunotherapy has become integral in cancer therapeutics over the past two decades and is now part of standard-of-care treatment in multiple cancer types. While various biomarkers and pathway alterations such as dMMR, CDK12, and AR-V7 have been identified in advanced prostate cancer to predict immunotherapy responsiveness, the vast majority of prostate cancer remain intrinsically immune-resistant, as evidenced by low response rates to anti-PD(L)1 monotherapy. Since regulatory approval of the vaccine therapy sipuleucel-T in the biomarker-unselected population, there has not been much success with immunotherapy treatment in advanced prostate cancer. Researchers have looked at various strategies to overcome immune resistance, including the identification of more biomarkers and the combination of immunotherapy with existing effective prostate cancer treatments. On the horizon, novel drugs using bispecific T-cell engager (BiTE) and chimeric antigen receptors (CAR) technology are being explored and have shown promising early efficacy in this disease. Here we discuss the features of the tumour microenvironment that predispose to immune resistance and rational strategies to enhance antitumour responsiveness in advanced prostate cancer.

Deep learning assessment compared to radiologist reporting for metastatic spinal cord compression on CT.

Introduction: Metastatic spinal cord compression (MSCC) is a disastrous complication of advanced malignancy. A deep learning (DL) algorithm for MSCC classification on CT could expedite timely diagnosis. In this study, we externally test a DL algorithm for MSCC classification on CT and compare with radiologist assessment. Methods: Retrospective collection of CT and corresponding MRI from patients with suspected MSCC was conducted from September 2007 to September 2020. Exclusion criteria were scans with instrumentation, no intravenous contrast, motion artefacts and non-thoracic coverage. Internal CT dataset split was 84% for training/validation and 16% for testing. An external test set was also utilised. Internal training/validation sets were labelled by radiologists with spine imaging specialization (6 and 11-years post-board certification) and were used to further develop a DL algorithm for MSCC classification. The spine imaging specialist (11-years expertise) labelled the test sets (reference standard). For evaluation of DL algorithm performance, internal and external test data were independently reviewed by four radiologists: two spine specialists (Rad1 and Rad2, 7 and 5-years post-board certification, respectively) and two oncological imaging specialists (Rad3 and Rad4, 3 and 5-years post-board certification, respectively). DL model performance was also compared against the CT report issued by the radiologist in a real clinical setting. Inter-rater agreement (Gwet's kappa) and sensitivity/specificity/AUCs were calculated. Results: Overall, 420 CT scans were evaluated (225 patients, mean age=60 ± 11.9[SD]); 354(84%) CTs for training/validation and 66(16%) CTs for internal testing. The DL algorithm showed high inter-rater agreement for three-class MSCC grading with kappas of 0.872 (p<0.001) and 0.844 (p<0.001) on internal and external testing, respectively. On internal testing DL algorithm inter-rater agreement (κ=0.872) was superior to Rad 2 (κ=0.795) and Rad 3 (κ=0.724) (both p<0.001). DL algorithm kappa of 0.844 on external testing was superior to Rad 3 (κ=0.721) (p<0.001). CT report classification of high-grade MSCC disease was poor with only slight inter-rater agreement (κ=0.027) and low sensitivity (44.0), relative to the DL algorithm with almost-perfect inter-rater agreement (κ=0.813) and high sensitivity (94.0) (p<0.001). Conclusion: Deep learning algorithm for metastatic spinal cord compression on CT showed superior performance to the CT report issued by experienced radiologists and could aid earlier diagnosis.

Diagnostic Accuracy of CT for Metastatic Epidural Spinal Cord Compression.

BACKGROUND: Early diagnosis of metastatic epidural spinal cord compression (MESCC) is vital to expedite therapy and prevent paralysis. Staging CT is performed routinely in cancer patients and presents an opportunity for earlier diagnosis. METHODS: This retrospective study included 123 CT scans from 101 patients who underwent spine MRI within 30 days, excluding 549 CT scans from 216 patients due to CT performed post-MRI, non-contrast CT, or a gap greater than 30 days between modalities. Reference standard MESCC gradings on CT were provided in consensus via two spine radiologists (11 and 7 years of experience) analyzing the MRI scans. CT scans were labeled using the original reports and by three radiologists (3, 13, and 14 years of experience) using dedicated CT windowing. RESULTS: For normal/none versus low/high-grade MESCC per CT scan, all radiologists demonstrated almost perfect agreement with kappa values ranging from 0.866 (95% CI 0.787-0.945) to 0.947 (95% CI 0.899-0.995), compared to slight agreement for the reports (kappa = 0.095, 95%CI -0.098-0.287). Radiologists also showed high sensitivities ranging from 91.51 (95% CI 84.49-96.04) to 98.11 (95% CI 93.35-99.77), compared to 44.34 (95% CI 34.69-54.31) for the reports. CONCLUSION: Dedicated radiologist review for MESCC on CT showed high interobserver agreement and sensitivity compared to the current standard of care.

Deep Learning Model for Grading Metastatic Epidural Spinal Cord Compression on Staging CT.

Background: Metastatic epidural spinal cord compression (MESCC) is a disastrous complication of advanced malignancy. Deep learning (DL) models for automatic MESCC classification on staging CT were developed to aid earlier diagnosis. Methods: This retrospective study included 444 CT staging studies from 185 patients with suspected MESCC who underwent MRI spine studies within 60 days of the CT studies. The DL model training/validation dataset consisted of 316/358 (88%) and the test set of 42/358 (12%) CT studies. Training/validation and test datasets were labeled in consensus by two subspecialized radiologists (6 and 11-years-experience) using the MRI studies as the reference standard. Test sets were labeled by the developed DL models and four radiologists (2−7 years of experience) for comparison. Results: DL models showed almost-perfect interobserver agreement for classification of CT spine images into normal, low, and high-grade MESCC, with kappas ranging from 0.873−0.911 (p < 0.001). The DL models (lowest κ = 0.873, 95% CI 0.858−0.887) also showed superior interobserver agreement compared to two of the four radiologists for three-class classification, including a specialist (κ = 0.820, 95% CI 0.803−0.837) and general radiologist (κ = 0.726, 95% CI 0.706−0.747), both p < 0.001. Conclusion: DL models for the MESCC classification on a CT showed comparable to superior interobserver agreement to radiologists and could be used to aid earlier diagnosis.

Deep Learning Model for Classifying Metastatic Epidural Spinal Cord Compression on MRI.

Background: Metastatic epidural spinal cord compression (MESCC) is a devastating complication of advanced cancer. A deep learning (DL) model for automated MESCC classification on MRI could aid earlier diagnosis and referral. Purpose: To develop a DL model for automated classification of MESCC on MRI. Materials and Methods: Patients with known MESCC diagnosed on MRI between September 2007 and September 2017 were eligible. MRI studies with instrumentation, suboptimal image quality, and non-thoracic regions were excluded. Axial T2-weighted images were utilized. The internal dataset split was 82% and 18% for training/validation and test sets, respectively. External testing was also performed. Internal training/validation data were labeled using the Bilsky MESCC classification by a musculoskeletal radiologist (10-year experience) and a neuroradiologist (5-year experience). These labels were used to train a DL model utilizing a prototypical convolutional neural network. Internal and external test sets were labeled by the musculoskeletal radiologist as the reference standard. For assessment of DL model performance and interobserver variability, test sets were labeled independently by the neuroradiologist (5-year experience), a spine surgeon (5-year experience), and a radiation oncologist (11-year experience). Inter-rater agreement (Gwet's kappa) and sensitivity/specificity were calculated. Results: Overall, 215 MRI spine studies were analyzed [164 patients, mean age = 62 ± 12(SD)] with 177 (82%) for training/validation and 38 (18%) for internal testing. For internal testing, the DL model and specialists all showed almost perfect agreement (kappas = 0.92-0.98, p < 0.001) for dichotomous Bilsky classification (low versus high grade) compared to the reference standard. Similar performance was seen for external testing on a set of 32 MRI spines with the DL model and specialists all showing almost perfect agreement (kappas = 0.94-0.95, p < 0.001) compared to the reference standard. Conclusion: A DL model showed comparable agreement to a subspecialist radiologist and clinical specialists for the classification of malignant epidural spinal cord compression and could optimize earlier diagnosis and surgical referral.

Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial.

OBJECTIVE: To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery. DESIGN: The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort. RESULTS: From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022). CONCLUSION: Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial).

Atypical Response Patterns in Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors-Navigating the Radiologic Potpourri.

BACKGROUND: Atypical response patterns have been a topic of increasing relevance since the advent of immune checkpoint inhibitors (ICIs), challenging the traditional RECIST (Response Evaluation Criteria in Solid Tumors) method of tumor response assessment. Newer immune-related response criteria can allow for the evolution of radiologic pseudoprogression, but still fail to capture the full range of atypical response patterns encountered in clinical reporting. METHODS: We did a detailed lesion-by-lesion analysis of the serial imaging of 46 renal cell carcinoma (RCC) patients treated with ICIs with the aim of capturing the full range of radiologic behaviour. RESULTS: Atypical response patterns observed included pseudoprogression (n = 15; 32.6%), serial pseudoprogression (n = 4; 8.7%), dissociated response (n = 22; 47.8%), abscopal response (n = 9; 19.6%), late response (n = 5; 10.9%), and durable response after cessation of immunotherapy (n = 2; 4.3%). Twenty-four of 46 patients (52.2%) had at least one atypical response pattern and 18 patients (39.1%) had multiple atypical response patterns. CONCLUSIONS: There is a high incidence of atypical response patterns in RCC patients receiving ICIs and the study contributes to the growing literature on the abscopal effect. The recognition of these interesting and overlapping radiologic patterns challenges the oncologist to tweak treatment options such that the clinical benefits of ICIs are potentially maximized.

Discordance Between Advanced Cancer Patients' Perceived and Preferred Roles in Decision Making and its Association with Psychological Distress and Perceived Quality of Care.

OBJECTIVE: We investigated patient-reported roles of families, physicians, and patients themselves in treatment decision making and whether discordance between perceived and preferred roles is associated with psychological distress and perceived quality of care among patients with cancer. METHODS: We analyzed cross-sectional survey data from 599 adults with stage IV solid malignancy in Singapore. Stuart-Maxwell tests were used to compare patients' perceived and preferred roles in decision making. Types of discordance were categorized as follows: involvement at a lesser level than preferred, involvement at a greater level than preferred, and no change in patient involvement. Ordinary least squares regressions examined the associations between types of discordance and patient outcomes, controlling for patient characteristics. RESULTS: Discordance between perceived and preferred roles was observed in 16% of patients. Amongst patients with discordance, 33% reported being involved at a lesser level than they preferred, 47% reported being involved at a greater level than they preferred, and 19% reported discordance where level of patient involvement did not change. Multivariable analyses showed that lesser involvement than preferred and discordance with no change in patient involvement were associated with poorer quality of physician communication (ß = - 9.478 [95% confidence interval {CI} - 16.303 to - 2.653] and ß = - 9.184 [95% CI - 18.066 to - 0.301]) and poorer care coordination (ß = - 11.658 [95% CI - 17.718 to - 5.597] and ß = - 8.856 [95% CI - 16.744 to - 0.968]) compared with concordance. CONCLUSIONS: Most patients reported participating at their desired level. Despite this finding, our results suggest that involving patients at a lesser level than they prefer can lead to poorer perceived quality of physician communication and care coordination and that encouraging patient participation is a safe approach to minimizing poor outcomes.

Low-Dose Nivolumab in Renal Cell Carcinoma: A Real-World Experience.

BACKGROUND: The approved doses of the single agent nivolumab - an anti-programmed cell death protein 1 (PD-1) monoclonal antibody - for renal cell carcinoma (RCC) are 3 mg/kg and a 240-mg flat dose, despite efficacy shown at lower doses in earlier CheckMate trials. In view of financial constraints, the minimum dose of nivolumab required for efficacy remains a critical area of inquiry. METHODS: A retrospective review of RCC patients receiving single-agent anti-PD-1 treatment was conducted. Using the median cutoff of the maximum dose per body weight received, we investigated the effect of lower dosages on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse event-free survival (irAE-FS). Survival analysis was made by Kaplan-Meier, by uni- and multivariable Cox models, and by modeling the statistical interaction between dosages and survival. RESULTS: 32 patients were recruited: 8 patients (25%) receiving first-line treatment and 24 (75%) receiving second-line treatment and beyond. A median split at 2.15 mg/kg yielded 16 patients in both the lower-dose (LD) and the higher-dose (HD) cohort. Hazard ratios (HRs) demonstrated no difference in OS after adjustment for gender (HR = 0.22, 95% CI 0.05-1.05, p = 0.054; favoring LD), as well as in PFS after adjustment for gender and concurrent radiation therapy (HR = 0.58, 95% CI 0.25-1.34, p = 0.210; favoring LD). No differences in ORR were observed (50.0 vs. 43.8%, p = 1.00, in the LD and the HD cohort, respectively). Immune-related phenomena were observed in the LD group, including pseudoprogression and increased all-grade immune-related toxicities (irAE-FS: HR = 1.72, 95% CI 0.48-6.14, p = 0.293; favoring HD). Iterative dichotomization of dosages showed no dose-OS or dose-irAE-FS relationship. CONCLUSION: Our study suggests no apparent reduction in efficacy when using a low-dosage nivolumab regimen.

Phase 1 Study of Low-Dose Fractionated Whole Abdominal Radiation Therapy in Combination With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer (GCGS-01).

PURPOSE: Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC). METHODS AND MATERIALS: Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m2, concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m2) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity. RESULTS: A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP. CONCLUSIONS: The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m2. Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered.

Development, internal validation and calibration of a risk score to predict survival in patients with EGFR-mutant non-small cell lung cancer.

AIMS: EGFR tyrosine kinase inhibitors (TKIs) are first-line molecularly targeted therapies in patients with advanced non-small cell lung cancer (NSCLC) who carry sensitising EGFR mutations, due to its superior survival outcomes compared with conventional chemotherapy regimens. In this study, we sought to identify clinical, immune and biochemical variables with prognostic significance in this patient subgroup and incorporate them into a nomogram-based risk score. METHODS: A total of 199 patients with EGFR mutation-positive, advanced NSCLC (defined as stage IV at initial diagnosis or incurable disease recurrence) treated with first-line EGFR TKI therapy were retrospectively profiled. Univariable and multivariable survival analyses were conducted, with variables from the multivariable model with the highest Harrell's Concordance (C) Index selected for inclusion in the subsequent survival nomogram. Internal validation and internal calibration of our prognostic nomogram were also performed. RESULTS: Serum lactate dehydrogenase (LDH) and lung/pleural metastasis were independent predictors of unfavourable overall survival in all three multivariable models. A survival nomogram was generated based on the multivariable model with the highest Harrell's C Index, incorporating the following 11 variables: white cell count, haemoglobin, LDH, neutrophil/lymphocyte ratio, ethnicity (Chinese vs non-Chinese), Karnofsky-Performance Status (score of '90-100' or '70-80' vs '0-60'), Charlson Comorbidity Index (≥3, or 2, or 1 vs 0), neurological symptoms, brain, lung/pleural and adrenal metastases. CONCLUSION: We identified serum LDH as an independent predictor of unfavourable clinical outcomes in patients with advanced, EGFR mutation-positive NSCLC. We further developed a robust nomogram-based risk score that incorporates clinical, biochemical and immune variables that can provide more targeted prognostication and management in this patient subgroup.

Integration of Antiangiogenic Therapy with Cisplatin and Gemcitabine Chemotherapy in Patients with Nasopharyngeal Carcinoma.

PURPOSE: Induction cisplatin and gemcitabine chemotherapy is a standard treatment for locally advanced nasopharyngeal carcinoma (NPC). Inhibition of VEGF axis has been shown to promote maturation of microvasculature and improve perfusion. We conducted a four-arm study to assess the effect of two doses of either sunitinib or bevacizumab with chemotherapy in NPC. PATIENTS AND METHODS: Patients with treatment-naïve locally advanced NPC were treated with three cycles of 3-weekly cisplatin and gemcitabine preceded by 1 week of anti-VEGF therapy for each cycle, followed by standard concurrent chemoradiation: arm A patients received 7 days of 12.5 mg/day sunitinib; arm B 7 days of 25 mg/day sunitinib; arm C bevacizumab 7.5 mg/kg infusion; arm D bevacizumab 2.5 mg/kg infusion. Patients with metastatic NPC were treated with up to six cycles of similar treatment without concurrent chemoradiation. RESULTS: Complete metabolic response (mCR) by whole body 18FDG PET was highest in arm C (significant difference in four groups Fisher exact test P = 0.001; type 1 error = 0.05), with 42% mCR (95% confidence interval, 18-67) and 3-year relapse-free survival of 88% in patients with locally advanced NPC. Significant increase in pericyte coverage signifying microvascular maturation and increased immune cell infiltration was observed in posttreatment tumor biopsies in Arm C. Myelosuppression was more profound in sunitinib containing arms, and tolerability was established in arm C where hypertension was the most significant toxicity. CONCLUSIONS: Bevacizumab 7.5 mg/kg with cisplatin and gemcitabine was well tolerated. Promising tumor response was observed and supported mechanistically by positive effects on tumor perfusion and immune cell trafficking into the tumor.

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers.

PURPOSE: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies. PATIENTS AND METHODS: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy. RESULTS: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n = 9) included multiple cycles of NK cells (1 × 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment. CONCLUSIONS: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.

Safety and tolerability of cryocompression as a method of enhanced limb hypothermia to reduce taxane-induced peripheral neuropathy.

PURPOSE: Severe peripheral neuropathy is a common dose-limiting toxicity of taxane chemotherapy, with no effective treatment. Frozen gloves have shown to reduce the severity of neuropathy in several studies but comes with the incidence of undesired side effects such as cold intolerance and frostbite in extreme cases. A device with thermoregulatory features which can safely deliver tolerable amounts of cooling while ensuring efficacy is required to overcome the deficiencies of frozen gloves. The role of continuous-flow cooling in prevention of neurotoxicity caused by paclitaxel has been previously described. This study hypothesized that cryocompression (addition of dynamic pressure to cooling) may allow for delivery of lower temperatures with similar tolerance and potentially improve efficacy. METHOD: A proof-of-concept study was conducted in cancer patients receiving taxane chemotherapy. Each subject underwent four-limb cryocompression with each chemotherapy infusion (three hours) for a maximum of 12 cycles. Cryocompression was administered at 16 °C and cyclic pressure (5-15 mmHg). Skin surface temperature and tolerance scores were recorded. Neuropathy was assessed using clinician-graded peripheral sensory neuropathy scores, total neuropathy score (TNS) and nerve conduction studies (NCS) conducted before (NCSpre), after completion (NCSpost) and 3 months post-chemotherapy (NCS3m). Results were retrospectively compared with patients who underwent paclitaxel chemotherapy along with continuous-flow cooling and controls with no hypothermia. RESULTS: In total, 13 patients underwent 142 cycles of cryocompression concomitant with chemotherapy. Limb hypothermia was well tolerated, and only 1 out of 13 patients required an intra-cycle temperature increase, with no early termination of cryocompression in any subject. Mean skin temperature reduction of 3.8 ± 1.7 °C was achieved. Cryocompression demonstrated significantly greater skin temperature reductions compared to continuous-flow cooling and control (p < 0.0001). None of the patients experienced severe neuropathy (clinician-assessed neuropathy scores of grade 2 or higher). NCS analysis showed preservation of motor amplitudes at NCS3m in subjects who underwent cryocompression, compared to the controls who showed significant deterioration (NCS3m cryocompression vs. NCS3m control: ankle stimulation: 8.1 ± 21.4%, p = 0.004; below fibula head stimulation: 12.7 ± 25.6%, p = 0.0008; above fibula head stimulation: 9.4 ± 24.3%, p = 0.002). Cryocompression did not significantly affect taxane-induced changes in sensory nerve amplitudes. CONCLUSION: When compared to continuous-flow cooling, cryocompression permitted delivery of lower temperatures with similar tolerability. The lower skin surface temperatures achieved potentially lead to improved efficacy in neurotoxicity amelioration. Larger studies investigating cryocompression are required to validate these findings.

Family caregivers of advanced cancer patients: self-perceived competency and meaning-making.

BACKGROUND: Family caregivers of patients with advanced cancer have been reported to provide long hours of care and be at risk for poor psychological outcomes. Although research has focused on the nature of caregiving burden, little attention has been paid to identifying protective factors that improve caregiver psychological outcomes. AIM: We examined the relationship between caregivers' time spent caregiving and the following psychological outcomes: anxiety, depression and caregiving esteem. Subsequently, we explored the main and moderating effects of caregiver-perceived self-competency and sense of meaning on caregiver psychological outcomes. DESIGN/PARTICIPANTS: Cross-sectional analysis was conducted using the baseline data from an ongoing cohort study. Family caregivers of advanced cancer patients (n=287) were recruited from two tertiary hospitals in Singapore. RESULTS: Time spent caregiving was not significantly associated with caregiver anxiety, depression or caregiving esteem. However, significant main effects of self-competency on anxiety and caregiving esteem; and sense of meaning on anxiety, depression and caregiving esteem were observed. Moderator analyses further indicated that self-competency attenuated the positive relationship between time spent caregiving and anxiety, while sense of meaning attenuated the negative relationship between time spent caregiving and caregiving esteem. CONCLUSION: Greater perceived self-competency and sense of meaning are related to better caregiver psychological outcomes, and protect caregivers from worsening outcomes as caregiving hours increase. Our findings suggest that screening caregivers for distress is an important part of care, and that supportive interventions for caregivers should aim to enhance their perceived caregiving competencies and the ability to make meaning of their caregiving role.

Oncologist-patient-caregiver decision-making discussions in the context of advanced cancer in an Asian setting.

OBJECTIVE: Patient involvement in treatment decisions is recommended in clinician-patient encounters. Little is known about how oncologists engage patients in shared decision making in non-Western countries. We assessed the prevalence of shared decision making among Singaporean oncologists and analysed how they discussed prognosis. METHODS: We audio-recorded 100 consultations between advanced cancer patients and their oncologists. We developed a coding system to assess oncologist encouragement of patient participation in decision making and disclosure of an explicit prognosis. We assessed patient and oncologist characteristics that predicted these behaviours. RESULTS: Forty-one consultations involved treatment discussions. Oncologists almost always listed more than one treatment option (90%). They also checked patient understanding (34%), discussed pros and cons (34%) and addressed uncertainty (29%). Oncologists discussed prognosis mostly qualitatively (34%) rather than explicitly (17%). They were more likely to give an explicit prognosis when patients/caregivers asked questions related to prognosis. CONCLUSION: Oncologists in our sample engaged their patients in decision making. They have areas in which they can improve to involve patients at a deeper level to ensure shared decision making. Findings will be used to develop an intervention targeting oncologists and patients to promote patient involvement in decision making.

Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies.

RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance.

Cost of Medical Care of Patients with Advanced Serious Illness in Singapore (COMPASS): prospective cohort study protocol.

BACKGROUND: Advanced cancer significantly impacts quality of life of patients and families as they cope with symptom burden, treatment decision-making, uncertainty and costs of treatment. In Singapore, information about the experiences of advanced cancer patients and families and the financial cost they incur for end-of-life care is lacking. Understanding of this information is needed to inform practice and policy to ensure continuity and affordability of care at the end of life. The primary objectives of the Cost of Medical Care of Patients with Advanced Serious Illness in Singapore (COMPASS) cohort study are to describe changes in quality of life and to quantify healthcare utilization and costs of patients with advanced cancer at the end of life. Secondary objectives are to investigate patient and caregiver preferences for diagnostic and prognostic information, preferences for end-of-life care, caregiver burden and perceived quality of care and to explore how these change as illness progresses and finally to measure bereavement adjustment. The purpose of this paper is to present the COMPASS protocol in order to promote scientific transparency. METHODS: This cohort study recruits advanced cancer patients (n = 600) from outpatient medical oncology clinics at two public tertiary healthcare institutions in Singapore. Patients and their primary informal caregiver are surveyed every 3 months until patients' death; caregivers are followed until 6 months post patient death. Patient medical and billing records are obtained and merged with patient survey data. The treating medical oncologists of participating patients are surveyed to obtain their beliefs regarding care delivery for the patient. DISCUSSION: The study will allow combination of self-report, medical, and cost data from various sources to present a comprehensive picture of the end-of-life experience of advanced cancer patients in a unique Asian setting. This study is responsive to Singapore's National Strategy for Palliative Care which aims to identify opportunities to meet the growing need for high quality care for Singapore's aging population. Results will also be of interest to policy makers and researchers beyond Singapore who are interested to understand and improve the end-of-life experience of cancer patients. TRIAL REGISTRATION: NCT02850640 (Prospectively registered on June 9, 2016).

Third generation EGFR TKIs: current data and future directions.

Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care.