Feasibility of a Geriatric Oncology Longitudinal End to End (GOLDEN) Program in a Tertiary Cancer Center in Singapore.

INTRODUCTION: In the National University Cancer Institute, Singapore (NCIS), 2 pilot programs providing (i) surgical prehabilitation before cancer surgery and (ii) geriatric oncology support for older adults planned for chemotherapy and/or radiotherapy were merged to form the Geriatric Oncology Longitudinal End to eNd (GOLDEN) program in 2019 to support patients from the time of their cancer diagnosis, through their treatment process, to cancer survivorship. METHODS AND MATERIALS: Older adults aged ≥65 years were enrolled in either surgical prehabilitation, the geriatric medical oncology (GO) arm, or both. All patients undergo a geriatric assessment. We assessed if patients had a change in treatment plans based on GOLDEN recommendations, and the impact on patient related outcomes. RESULTS: There were 777 patients enrolled in the GOLDEN program over 2 years; 569 (73%) were enrolled in surgical prehabilitation, 308 (40%) were enrolled in the GO arm, with 100 (12.8%) enrolled in both. 56.9% were females. Median age was 73. Lower gastrointestinal (51.2%) and hepatobiliary cancers (24.1%) were the most common cancer types. 43.4% were pre-frail and 11.7% were frail. Of the 308 patients in the GO arm, 86.0% had geriatric syndromes, while 60.7% had a change in their treatment plans based on GOLDEN recommendations. 31.5% reported an improved global health status, while 38.3% maintained their global health status. 226 (73%) responded that they had benefited from the GOLDEN. CONCLUSION: More than half of the population was either pre-frail or frail. Amongst those in the GO arm, the majority had geriatric syndromes and had a change in their treatment plans based on GOLDEN recommendations. Majority reported either improvement or maintenance in global health status, with most feeling they have benefited from the program. Further evaluation of the longitudinal geriatric hematology-oncology program for cancer-related outcomes and sustainability should be carried out.

Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma.

Large numbers of neutrophils infiltrate tumors and comprise a notable component of the inflammatory tumor microenvironment. While it is established that tumor cells exhibit the Warburg effect for energy production, the contribution of the neutrophil metabolic state to tumorigenesis is unknown. Here, we investigated whether neutrophil infiltration and metabolic status promotes tumor progression in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC). We observed a large increase in the proportion of neutrophils in the blood and tumor upon orthotopic transplantation. Intriguingly, these tumor-infiltrating neutrophils up-regulated glycolytic factors and hypoxia-inducible factor 1-alpha (HIF-1α) expression compared to neutrophils from the bone marrow and blood of the same mouse. This enhanced glycolytic signature was also observed in human PDAC tissue samples. Strikingly, neutrophil-specific deletion of HIF-1α (HIF-1αΔNφ) significantly reduced tumor burden and improved overall survival in orthotopic transplanted mice, by converting the pro-tumorigenic neutrophil phenotype to an anti-tumorigenic phenotype. This outcome was associated with elevated reactive oxygen species production and activated natural killer cells and CD8+ cytotoxic T cells compared to littermate control mice. These data suggest a role for HIF-1α in neutrophil metabolism, which could be exploited as a target for metabolic modulation in cancer.

Use of the Cancer and Aging Research Group Predictive Model for Chemotherapy-Related Toxic Effects in a Multiethnic, Older Adult Asian Population.

Importance: The Cancer and Aging Research Group (CARG) prediction model for chemotherapy-related toxic effects has been developed but not yet validated in older Asian adults. In view of differences in drug metabolism and toxic effect reporting in the Asian population, the ability of this tool to guide the cancer treatment decision-making process in older Asian adults needs to be assessed. Objective: To examine the validity of the CARG predictive model in a multiethnic Asian cohort of older adults. Design, Setting, and Participants: In this prognostic study, patients of various Asian ethnicities 70 years or older with a solid tumor diagnosis receiving chemotherapy at the National University Cancer Institute, Singapore, were accrued from June 1, 2017, to January 1, 2019. Their risks of chemotherapy-related toxic effects were calculated using the CARG tool. A geriatric assessment was performed, and the treating oncologist (blinded to the CARG scores) was asked to give an estimated likelihood of toxic effects (low, medium, or high). Chemotherapy-related toxic effects were recorded during each clinic visit. Validation of the prediction model was performed by calculating the area under the receiver operating characteristic curve. Multivariate analyses were performed to identify variables in other domains in the geriatric assessment predicting for severe toxic effects. Main Outcomes and Measures: Grade 3 to 5 toxic effects and hospitalization. Results: The study included 200 patients (median age, 74 years [range, 70-89 years]; 110 [55.0%] male; 177 [88.5%] Chinese, 17 [8.5%] Malay, 4 [2.0%] Indian, and 2 [1.0%] other ethnicities [according to Singapore's national system of race classification]). A total of 137 patients (68.5%) experienced grade 3 to 5 toxic effects, and 131 (65.5%) required hospitalization. The area under the receiver operating characteristic curve for the CARG chemotoxicity prediction model was 0.74 (95% CI, 0.67-0.82), retaining good discrimination in the study population. Conclusions and Relevance: This prognostic study conducted in a multiethnic Asian cohort of older adults supports the validity of the CARG predictive model in this population, predicting which older adults are at risk of chemotherapy-related toxic effects.

Outcomes of a Phase II Study of Intraperitoneal Paclitaxel plus Systemic Capecitabine and Oxaliplatin (XELOX) for Gastric Cancer with Peritoneal Metastases.

BACKGROUND: Adding intraperitoneal paclitaxel (IP-PTX) to paclitaxel/5-fluoropyrimidine has shown promising results in patients with gastric cancer peritoneal metastases (GCPM) but has not been studied with standard-of-care platinum/fluoropyrimidine combinations. Our goal to was evaluate IP-PTX with capecitabine/oxaliplatin (XELOX) in GCPM. METHODS: Forty-four patients with GCPM received IP PTX (40 mg/m2, Days 1, 8), oral capecitabine (1000 mg/m2 twice daily, Days 1-14) and intravenous oxaliplatin (100 mg/m2, Day 1) in 21-day cycles. Patients with synchronous GCPM underwent conversion surgery if they had good response after chemotherapy, conversion to negative cytology, no extraperitoneal metastasis, and no peritoneal disease during surgery. The primary endpoint was overall survival and secondary endpoints were progression-free survival and safety. Outcomes from the trial were compared against a matched cohort of 39 GCPM patients who received systemic chemotherapy (SC) comprising platinum/fluoropyrimidine. RESULTS: The median OS for the IP and SC groups was 14.6 and 10.6 months (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.26-0.74; p = 0.002). The median PFS for the IP and SC group was 9.5 and 4.4 months respectively (HR 0.39; 95% CI 0.25-0.66; p < 0.001). Patients in the SC group were younger (IP vs. SC, 61 vs. 56 years, p = 0.021) and had better performance status (ECOG 0, IP vs. SC, 47.7% vs. 76.9%, p = 0.007) compared with the IP cohort. In IP group, conversion surgery was performed in 36.1% (13/36) of patients, with a median OS of 24.2 (95% CI 13.1-35.3) months and 1-year OS of 84.6%. CONCLUSIONS: IP PTX with XELOX is a promising treatment option for GCPM patients. In patients with good response, conversion surgery was feasible with favourable outcomes.

Remaining Agile in the COVID-19 pandemic healthcare landscape - How we adopted a hybrid telemedicine Geriatric Oncology care model in an academic tertiary cancer center.

INTRODUCTION: The COVID-19 pandemic has impacted healthcare on an unprecedented scale, with healthcare resources being channeled into managing the devastating effects of the outbreak. Healthcare provision for vulnerable older adults has also been affected by lockdowns and suspension of selected medical services worldwide. In our tertiary cancer center, the National University Cancer Institute, Singapore (NCIS), our Geriatric Oncology (GO) service for older adults with cancer was halted for five months. In this paper, we describe the adoption of a hybrid telemedicine model by our GO service to continue care provision for older adults in the midst of the pandemic. MATERIALS AND METHODS: Comprehensive geriatric assessments (CGA) were done via telemedicine and virtual multidisciplinary discussions were held prior to the patients' clinic visits. A hybrid telemedicine consultation allowed geriatricians and oncologists, segregated in different sites during the pandemic, to provide a hybrid physical and video geriatric oncology consultation. Scheduled phone follow ups by GO nurses helped to monitor patients for treatment-related toxicities and geriatric syndromes. RESULTS: Two hundred fifty patients were enrolled in the program from July 2020 to August 2021. All were assessed with a CGA, with 240 receiving interventions in the one-stop clinic. The average amount of time spent per visit was shortened from four hours to two and a half hours with an average of three interventions on the same day, versus one previously. Of the patients who received interventions, 84.8% were satisfied with the hybrid telemedicine model and 80.8% of them had reported a maintained or improved quality of life after being enrolled in the program. DISCUSSION: Telemedicine has been widely adopted during the pandemic, but older adults with limited digital literacy may find it a challenge. Our hybrid telemedicine model has allowed us to continue to provide cancer care, identify issues brought about by social isolation, and render timely assistance. It has become imperative to adapt, prepare and plan for the challenges we may face amid the ongoing COVID-19 pandemic and similar future outbreaks. Only by doing so can we remain agile and resilient, to continue providing quality care to our older patients with cancer.

Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations in CTNNB1 or APC: A Multi-institutional Retrospective Study.

PURPOSE: Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments. EXPERIMENTAL DESIGN: We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or next-generation sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), and overall survival (OS). Kaplan-Meier analysis and Cox proportional hazards regression were performed to identify differences in cPFS, rPFS, TTNT, and OS by mutation subtype, desmoid tumor location, and treatment regimen. RESULTS: A total of 259 evaluable patients were analyzed for at least one of the survival outcomes, with 177 patients having mutation data. First- and second-line cPFS, rPFS, and TTNT were not significantly affected by mutation subtype; however, APC-mutant desmoid tumors demonstrated nonstatistically significant inferior outcomes. Extremity/trunk desmoid tumor location and treatment with doxorubicin-based, methotrexate/vinca alkaloids and sorafenib regimens were associated with better clinical outcomes compared with surgery or "other" therapies, including estrogen-receptor blockade and imatinib. OS was significantly worse with APC or CTNNB1 negative/other mutations. CONCLUSIONS: Mutation subtype did not affect responses to specific systemic therapies. APC mutations and nonextremity desmoid tumor locations remain prognostic for worse outcomes, and earlier initiation of systemic therapy for these higher-risk desmoid tumors should be prospectively evaluated. See related commentary by Greene and Van Tine, p. 3911.

Stereotactic radiosurgery in alveolar soft part sarcoma brain metastases: Case series and literature review.

Alveolar soft part sarcoma (ASPS) has the highest incidence of brain metastasis amongst sarcomas. There is a paucity of literature published focusing on radiation therapy for this condition. This is a single centre retrospective review of the treatment of three patients with 12 ASPS brain metastasis using single dose stereotactic radiosurgery (SRS). Five lesions were treated with low (<25 Gy) and seven with high (≥25 Gy) dose. Four lesions had a volume of >1.5 cm3 and were defined as large, while seven had a volume of ≤0.5 cm3 and were defined as small. The local tumor control as well as the clinical complication rates were studied. There was a statistically significant relation between treatment dose and tumor control rate. All large tumors treated with low dose recurred and required surgical removal within two months following SRS, while the large lesion treated with high dose recurred after 11 months. Five of the six small tumors treated with high doses were controlled, while the sixth required retreatment and was stable thereafter. No patient suffered from undue symptomatic radiation effects. The success rate following SRS for small ASPS metastases treated with high doses seems to be sufficient to justify the treatment. The short time for large tumor to recur, significant increase in tumor size requiring surgical removal of the tumors, makes low dose SRS unattractive. Based on this limited patient population, it seems that high dose SRS should be used for all ASPS brain metastases except for large tumors deemed surgically accessible.

Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma.

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1ß inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.

MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma.

Soft tissue sarcoma (STS) is a heterogeneous disease that arises from connective tissues. Clinical outcome of patients with advanced tumors especially de-differentiated liposarcoma and uterine leiomyosarcoma remains unsatisfactory, despite intensive treatment regimens including maximal surgical resection, radiation, and chemotherapy. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) have been shown to contribute to oncogenic translation via phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). However, little is known about the role of MNK1/2 and their downstream targets in STS. In this study, we show that depletion of either MNK1 or MNK2 suppresses cell viability, anchorage-independent growth, and tumorigenicity of STS cells. We also identify a compelling antiproliferative efficacy of a novel, selective MNK inhibitor ETC-168. Cellular responsiveness of STS cells to ETC-168 correlates positively with that of phosphorylated ribosomal protein S6 (RPS6). Mirroring MNK1/2 silencing, ETC-168 treatment strongly blocks eIF4E phosphorylation and represses expression of sarcoma-driving onco-proteins including E2F1, FOXM1, and WEE1. Moreover, combination of ETC-168 and MCL1 inhibitor S63845 exerts a synergistic antiproliferative activity against STS cells. In summary, our study reveals crucial roles of MNK1/2 and their downstream targets in STS tumorigenesis. Our data encourage further clinical translation of MNK inhibitors for STS treatment.

The treatment landscape of advanced angiosarcoma in Asia-A multi-national collaboration from the Asian Sarcoma Consortium.

Angiosarcoma (AS) is a rare disease with a dismal prognosis. The treatment landscape and prognostic factors for advanced AS, including locally advanced, unresectable, and metastatic disease remain elusive. The Asian Sarcoma Consortium is an international collaborative effort to understand the sarcoma treatment landscape in Asia. We undertook a retrospective chart review of AS patients seen in 8 sarcoma academic centers across Asia. Patients with complete clinical, treatment, and follow-up data were enrolled. Overall, 276 advanced AS patients were included into this study; 84 (30%) of the patients had metachronous metastatic AS. The median age was 67 y; primary sites of AS was cutaneous in 55% and visceral in 45% of patients. In total, 143 (52%) patients received at least 1 line of systemic chemotherapy. The most common first-line chemotherapy regimen used was paclitaxel (47.6%) followed by liposomal doxorubicin (19.6%). The median overall survival (OS) was 7.8 mo. Significant prognostic factors for OS included age > 65 (hazard ratio (HR) 1.54, P = .006), male gender (HR 1.39, P = .02), and a cutaneous primary AS site (HR 0.63, P = .004). The median progression-free survival (PFS) for first-line chemotherapy was 3.4 mo. PFS for single vs combination or paclitaxel vs liposomal doxorubicin chemotherapy regimens were comparable. This study provides an insight into the treatment patterns and prognostic factors of advanced AS patients in Asia. Prognosis of advanced AS remains poor. Data from this study serve as a benchmark for future clinical study design.

Impaired Bidirectional Synaptic Plasticity in Juvenile Offspring Following Prenatal Ethanol Exposure.

BACKGROUND: The hippocampus is particularly vulnerable to the teratogenic effects of prenatal ethanol exposure (PNEE), and hippocampal structural and functional deficits are thought to contribute to the learning and memory deficits that are a hallmark feature of fetal alcohol spectrum disorders. METHODS: Sprague Dawley dams were exposed to a liquid diet that contained EtOH (35.5% EtOH-derived calories) throughout gestation, and then, PNEE juvenile (P21-28) male and female offspring were used for in vitro electrophysiological recordings. We examined long-term potentiation (LTP), long-term depression (LTD), and depotentiation in the medial perforant path input to the dentate gyrus (DG) to determine the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in both sexes. RESULTS: PNEE reduced the responsiveness of the DGs of male but not in female offspring, and this effect was no longer apparent when GABAergic signaling was inhibited. There was also a sex-specific LTD impairment in males, but increasing the duration of the conditioning stimulus could overcome this deficit. The magnitude of LTP was also reduced, but in both sexes following PNEE. This appears to be an increase in the threshold for induction, not in capacity, as the level of LTP induced in PNEE animals was increased to control levels when additional conditioning stimuli were administered. CONCLUSIONS: These data are the first to describe, in a single study, the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in the juvenile DG in both males and in females. The data suggest that PNEE increases the threshold for LTP in the DG in both sexes, but produces a sex-specific increase in the threshold for LTD in males These alterations reduce the dynamic range for synaptic plasticity in both sexes.

Two Transcutaneous Stimulation Techniques in Shoulder Pain: Transcutaneous Pulsed Radiofrequency (TPRF) versus Transcutaneous Electrical Nerve Stimulation (TENS): A Comparative Pilot Study.

Objective: To compare the safety and efficacy of 2 transcutaneous stimulation techniques, transcutaneous pulsed radiofrequency (TPRF) versus transcutaneous electrical nerve stimulation (TENS), in chronic shoulder tendonitis. Design: A prospective, randomized, and double-blind clinical trial. Setting: Academic pain service of a city hospital. Subjects: Fifty patients with sonography-confirmed shoulder tendonitis. Methods: Fifty patients were randomly allocated into two groups for electrical stimulation treatment with 3-month follow-ups: Group 1 (n=25), TENS and Group 2 (n=25), TPRF. Both groups underwent either treatment for 15 minutes every other day, three times total. Our primary goals were to find any treatment comfort level, adverse event, and changes in Constant-Murley shoulder (CMS) scores. The secondary goals were finding the changes in pain, enjoyment of life, and general activity (PEG) scores. Results: For primary goals, no adverse events were noted throughout this study. No differences were found between groups for treatment tolerability (3.20 + 0.87 vs. 2.16 + 0.75). Statistically significant lower PEG scores were noticeable with the TPRF group after the course (12.73 + 5.79 vs. 24.53 + 10.21, p=0.013). Their statistical significance lasted for 3 months although the difference gap diminished after 1 month. CMS scores were significantly higher in the TPRF group (70.84 + 6.74 vs. 59.56 + 9.49, p=0.007) right after treatment course but the significance did not last. Conclusions: In treating chronic shoulder tendinitis using two transcutaneous stimulation techniques, both TPRF and TENS are safe and effective. TPRF is superior to TENS.

Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma.

Liposarcomas (LPSs) are a group of malignant mesenchymal tumors showing adipocytic differentiation. Here, to gain insight into the enhancer dysregulation and transcriptional addiction in this disease, we chart super-enhancer structures in both LPS tissues and cell lines. We identify a bromodomain and extraterminal (BET) protein-cooperated FUS-DDIT3 function in myxoid LPS and a BET protein-dependent core transcriptional regulatory circuitry consisting of FOSL2, MYC, and RUNX1 in de-differentiated LPS. Additionally, SNAI2 is identified as a crucial downstream target that enforces both proliferative and metastatic potentials to de-differentiated LPS cells. Genetic depletion of BET genes, core transcriptional factors, or SNAI2 mitigates consistently LPS malignancy. We also reveal a compelling susceptibility of LPS cells to BET protein degrader ARV-825. BET protein depletion confers additional advantages to circumvent acquired resistance to Trabectedin, a chemotherapy drug for LPS. Moreover, this study provides a framework for discovering and targeting of core oncogenic transcriptional programs in human cancers.

Longitudinal monitoring reveals dynamic changes in circulating tumor cells (CTCs) and CTC-associated miRNAs in response to chemotherapy in metastatic colorectal cancer patients.

We evaluated the changes in CTC count and CTC-associated miRNAs during the course of chemotherapy in patients with metastatic colorectal cancer. Blood samples were collected from 9 metastatic colorectal cancer patients prior to chemotherapy and at every other chemotherapy session during the course of treatment. CTCs were isolated and enumerated using a size-exclusion method (CellSievo, Singapore). CTC-associated miRNAs were isolated using a paper-based, partitioning method, and analyzed using reverse transcription quantitative real-time PCR (MiRXES, Singapore). CTC count trends generally correlated with disease progression defined by radiological measurements and trends in carcinoembryonic antigen (CEA) levels; hence CTC counts may be useful in cases where CEA is not elevated. CTC-associated miRNAs identified were miR-15b, miR-16, miR-19a, miR-21, miR-25, miR-30d, miR-126, miR-185, miR-221, miR-222, and miR-324-5p. The expression of CTC-associated miRNAs did not appear to correlate with CTC count and exhibited inter-individual heterogeneity. This pilot study suggests that analysis of CTC changes during the course of treatment may be useful in monitoring response to therapy in metastatic colorectal cancer.

Carcinosarcomas and Related Cancers: Tumors Caught in the Act of Epithelial-Mesenchymal Transition.

In this review, we outline the biology and management of patients with carcinosarcomas and related malignancies, which are often included under the broader concept of sarcomatoid carcinomas. Carcinosarcomas are unusual tumors that are commonly gynecologic in origin, where they are referred to as malignant mixed Müllerian tumors, but may appear in any anatomic site. Although a variety of hypotheses have been presented as to the biphasic nature of these tumors, carcinosarcomas seem to represent the best example in human cancers of the concept of epithelial-mesenchymal transition (EMT), in which the two parts of the tumor are genomically related to one another, as opposed to the mesenchymal component that represents a second neoplasm or (benign) reactive process. In general, patients with carcinosarcomas fare worse than patients with carcinomas of the same anatomic site. Treatment paradigms for carcinosarcomas generally follow those of carcinomas of the same organ site, except where clinical trials provide more specific options. Agents that block or reverse EMT are worth examination in patients with carcinosarcoma and arguably may be even more effective in carcinomas, given evidence of dependence on EMT to generate successful metastases. Information about EMT may also inform other phase transitions in cancer, such as those between prostate or lung carcinoma and more aggressive tumors with neuroendocrine differentiation.

Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer.

BACKGROUND: Prolonged anti-angiogenic therapy destroys tumor vasculature, whereas vascular-normalizing doses may enhance intra-tumoral drug delivery. We hypothesize that low-dose, short-course sunitinib normalizes vasculature, enhancing chemotherapy efficacy. PATIENTS AND METHODS: In phase Ib, treatment-naïve breast cancer patients received four cycles of pre-operative doxorubicin/cyclophosphamide, with sunitinib before each cycle. The optimal dose of sunitinib leading to tumor vessel normalization on immunohistochemistry was identified. In phase II, subjects were randomized to chemotherapy alone or chemotherapy plus sunitinib at the recommended phase II dose (RP2D). Primary endpoint was pathological complete response (pCR) rate. Tumor and functional imaging biomarkers were evaluated serially. RESULTS: In phase Ib (n=9), sunitinib 12.5 mg daily for 7 days before each chemotherapy was established as RP2D. In phase II, patients receiving chemotherapy plus sunitinib (n=24) had similar pCR rates (5.0% versus 4.3%, p=1.00), but a higher incidence of chemotherapy dose delays (33.3% versus 8.7%, p=0.04), compared to those receiving chemotherapy alone (n=25). The addition of sunitinib to chemotherapy significantly increased vascular normalization index (VNI) and decreased lymphatic vessel density (D2-40) on immunohistochemistry [VNI:25.50±27.94% versus 49.29±31.84%, p=0.034; D2-40:3.29±2.70 versus 1.29±1.54, p=0.014, baseline versus post-cycle 1], and improved perfusion on DCE-MRI (Ktrans:12.6±9.6 mL/100 g/min versus 16.3±10.7 mL/100 g/min, baseline versus post-cycle 1, p=0.015). Conversely, immunohistochemical and DCE-MRI parameters were not significantly altered by chemotherapy alone. CONCLUSION: Low-dose, short-course sunitinib prior to anthracycline-based chemotherapy in breast cancer patients did not improve pCR and increased chemotherapy dose delays. However, the addition of sunitinib induced compelling pharmacodynamic evidence of vascular normalization. Further studies with alternative cytotoxic regimens should be explored.

Contemporary Therapy for Advanced Soft-Tissue Sarcomas in Adults: A Review.

IMPORTANCE: Immune checkpoint inhibitors have shown promising results in several cancers and are now put to the test in sarcomas. This brief summary presents data regarding the previously approved and newer agents for more common sarcomas and focuses on specific sarcoma histologic subtypes or novel approaches for which there is particular optimism. Approaches involving epigenetic agents, metabolic therapy, and modulators of the tumor microenvironment represent other ways the field of sarcoma medical oncology will progress in 2016 and beyond. OBSERVATIONS: A recent series of successful randomized trials provides new systemic therapy options for patients with metastatic soft-tissue sarcomas in the United States, after a gap of more than 10 years in which no new drugs were approved. The agents with most recent approval include pazopanib, trabectedin, and eribulin. As a sign that progress is not linear, 2 cousins of ifosfamide failed to show benefit in phase 3 trials, despite prior positive results of randomized phase 2 trials. CONCLUSIONS AND RELEVANCE: The biological features of each sarcoma subtype are associated with specific sensitivity patterns to chemotherapy, and despite their rarity, future trials will need to emphasize specific histologic subtypes (many with well-defined genetic alterations) to best fit diagnosis to therapy.

Cancer physicians' attitude towards treatment of the elderly cancer patient in a developed Asian country.

BACKGROUND: With an aging population and an increasing number of elderly patients with cancer, it is essential for us to understand how cancer physicians approach the management and treatment of elderly cancer patients as well as their methods of cancer diagnosis disclosure to older versus younger patients in Singapore, where routine geriatric oncology service is not available. METHODS: 57 cancer physicians who are currently practicing in Singapore participated in a written questionnaire survey on attitudes towards management of the elderly cancer patient, which included 2 hypothetical clinical scenarios on treatment choices for a fit elderly patient versus that for a younger patient. RESULTS: The participants comprised of 68% medical oncologists, 18% radiation oncologists, and 14% haematologists. Most physicians (53%) listed performance status (PS) as the top single factor affecting their treatment decision, followed by cancer type (23%) and patient's decision (11%). The top 5 factors were PS (95%), co-morbidities (75%), cancer stage (75%), cancer type (75%), patient's decision (53%), and age (51%). 72% of physicians were less likely to treat a fit but older patient aggressively; 53% and 79% opted for less intensive treatments for older patients in two clinical scenarios of lymphoma and early breast cancer, respectively. 37% of physicians acknowledged that elderly cancer patients were generally under-treated.Only 9% of physicians chose to disclose cancer diagnosis directly to the older patient compared to 61% of physicians to a younger patient, citing family preference as the main reason. Most participants (61%) have never engaged a geriatrician's help in treatment decisions, although the majority (90%) would welcome the introduction of a geriatric oncology programme. CONCLUSIONS: Advanced patient age has a significant impact on the cancer physician's treatment decision-making process in Singapore. Many physicians still accede to family members' request and practice non-disclosure of cancer diagnosis to geriatric patients, which may pose as a hurdle to making an informed decision regarding management for the geriatric cancer patients. Having a formal geriatric oncology programme in Singapore could potentially help to optimize the management of geriatric oncology patients.