Severe combined hyperlipidaemia and retinal lipid infiltration in a patient with Type 2 diabetes mellitus

Severe combined hyperlipidaemia has occasionally been associated with infiltration of tissues in addition to arteries and the skin. We report a woman with Type 2 diabetes mellitus (DM) and severe combined hyperlipidaemia who developed retinal lipid infiltration, resulting in blindness. A 61-year-old woman with a 15-year history of Type 2 DM was admitted following a two-week history of progressive visual loss. Examination identified lipid infiltration into the retina. Phenotypically she had severe combined hyperlipidaemia with elevated IDL cholesterol and a broad beta band on lipoprotein electrophoresis, raising the possibility of familial dysbetalipoproteinaemia. However, gene sequencing analysis indicated that the patient was homozygous for the E3/E3 allele of the ApoE gene with no mutations detected in either the coding region or intron-exon boundaries. Her lipid profile improved following dietary therapy and gemfibrozil treatment, but this had little effect on either her fundal appearances or her visual acuity. Type 2 DM plays a vital role both in allowing expression of severe combined hyperlipoproteinaemia, in addition to serving as a risk factor for complications such as tissue infiltration

The cost effectiveness of bevacizumab when added to capecitabine, with or without mitomycin-C, in first line treatment of metastatic colorectal cancer: results from the Australasian phase III MAX study

Background: Based on the clinical data, bevacizumab has been approved in Australia and globally for the treatment of advanced colorectal cancer. However, limited evidence exists for its cost-effectiveness. The purpose of this study was to evaluate the cost effectiveness of adding bevacizumab to capecitabine monotherapy in patients with metastatic colorectal cancer, using data from the prospective economic evaluation conducted alongside the MAX trial. Methods: Individual patient level data on resource use and progression free survival were prospectively collected in the phase III MAX trial. Resource use data were collected for the period between randomisation and disease progression, and unit costs were assigned from the perspective of the Australian health care funder. Effectiveness was measured in quality adjusted progression free survival years, with utility scores obtained from both the community valued EQ-5D questionnaire and the patient valued UBQ-C questionnaire. Progression free survival was used as a secondary effectiveness measure. Results: The addition of bevacizumab to capecitabine monotherapy cost approximately $192,156 (95$135,619 to $326,894) per quality adjusted progression free survival year gained when using publicly listed pharmaceutical prices and utility values from the EQ-5D questionnaire. This decreased to$149,455 (95% CI, $100,356 to$245,910) when values from the UBQ-C questionnaire were applied. The incremental cost per progression free survival year was $145,059 (95$106,703 to $233,225). Conclusions: Bevacizumab was not found to be cost effective at its listed price, based on results from the MAX trial.Roche Products Pty Lt

The cost effectiveness of bevacizumab when added to capecitabine, with or without mitomycin-C, in first line treatment of metastatic colorectal cancer: results from the Australasian phase III MAX study

Background: Based on the clinical data, bevacizumab has been approved in Australia and globally for the treatment of advanced colorectal cancer. However, limited evidence exists for its cost-effectiveness. The purpose of this study was to evaluate the cost effectiveness of adding bevacizumab to capecitabine monotherapy in patients with metastatic colorectal cancer, using data from the prospective economic evaluation conducted alongside the MAX trial. Methods: Individual patient level data on resource use and progression free survival were prospectively collected in the phase III MAX trial. Resource use data were collected for the period between randomisation and disease progression, and unit costs were assigned from the perspective of the Australian health care funder. Effectiveness was measured in quality adjusted progression free survival years, with utility scores obtained from both the community valued EQ-5D questionnaire and the patient valued UBQ-C questionnaire. Progression free survival was used as a secondary effectiveness measure. Results: The addition of bevacizumab to capecitabine monotherapy cost approximately $192,156 (95$135,619 to $326,894) per quality adjusted progression free survival year gained when using publicly listed pharmaceutical prices and utility values from the EQ-5D questionnaire. This decreased to$149,455 (95% CI, $100,356 to$245,910) when values from the UBQ-C questionnaire were applied. The incremental cost per progression free survival year was $145,059 (95$106,703 to $233,225). Conclusions: Bevacizumab was not found to be cost effective at its listed price, based on results from the MAX trial.Roche Products Pty Lt

Irinotecan or FOLFIRI for 2nd line colorectal

Background Second-line treatment with irinotecan for advanced or metastatic colorectal cancer prolongs survival. It is uncertain whether irinotecan is better administered with 5- fluorouracil or alone in patients previously treated with a fluoropyrimidine. We compared toxicity (particularly diarrhoea), quality of life, and efficacy of combination chemotherapy and irinotecan in these patients. Methods In DaVINCI, a randomised phase II trial, patients with advanced colorectal cancer were randomly allocated to: combination therapy (FOLFIRI), irinotecan (180 mg/m2 IV over 90 min, day 1), 5-fluorouracil (400 mg/m2 IV bolus and 2400 mg/m2 by 46-hour infusion from day 1) and folinic acid (20 mg/m2 IV bolus, day 1), 2-weekly; or single-agent, irinotecan (350 mg/m2 IV over 90 min), 3-weekly. Toxicity was evaluated every treatment cycle; QOL and response 6 weekly. Analysis was by intention to treat. Results were also combined with those of other trials. Findings We randomised 44 patients to combination and 45 to single-agent. The most common toxicity was complete alopecia (single-agent 37%, combination 14%, P<0.02). Eight patients in the irinotecan arm and 4 in the combination arm had grade 3–4 diarrhoea (P=0.24). The treatment groups did not differ significantly in overall QOL changes, response rate, or progression free or overall survival. In a systematic review of 29 trials of second-line irinotecan-based treatment, single-agent irinotecan was associated with more diarrhoea and alopecia than the combination, but efficacy was similar. Interpretation Combination treatment compared with single-agent irinotecan appears to reduce the rateof complete alopecia and diarrhoea without compromising efficacy on clinical outcomes.Australasian Gastro-Intestinal Trials Grou

Efficacy and safety results from IMblaze370, a randomised Phase III study comparing atezolizumab+cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal cancer

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Outcomes of Older Patients (≥ 70 Years) Treated With Targeted Therapy in Metastatic Chemorefractory Colorectal Cancer: Retrospective Analysis of NCIC CTG CO.17 and CO.20

© 2018 Elsevier Inc. This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/ This author accepted manuscript is made available following 12 month embargo from date of publication (November 2018) in accordance with the publisher’s archiving policyBackground The safety and efficacy of targeted therapy in older patients (≥ 70 years) with metastatic colorectal cancer is not well evaluated. Patients and Methods Outcomes of older patients (including overall survival [OS], progression-free survival [PFS], toxicity, and quality of life [QoL]) were compared to young patients using data from 2 large previously reported clinical trials, CO.17 (cetuximab vs. best supportive care) and CO.20 (cetuximab plus placebo vs. cetuximab plus brivanib). Only patients with wild-type KRAS tumors were included. Results A total of 251 (26.3%) of 955 patients were ≥ 70 years old. No significant differences in OS, PFS, or grade 3/4 adverse events were observed between older and younger patients treated with cetuximab (or cetuximab with placebo) in either trial. Younger patients trended toward superior OS in both CO.17 (hazard ratio = 1.80; P = .16) and CO.20 (hazard ratio = 1.34; P = .07). QoL maintenance favored younger patients in CO.17 (3.6 vs. 5.7 months; P = .046) but no difference of QoL maintenance was observed in the larger CO.20 trial (1.7 vs. 1.8 months; P = .64). Combination therapy of cetuximab and brivanib was significantly more toxic in older adults (87% vs. 77%; P = .03). Conclusion OS, PFS, and toxicities were similar between older and younger patients with wild-type KRAS metastatic colorectal cancer when treated with cetuximab. Both age groups likely experience similar QoL maintenance with cetuximab. Dual targeted therapy was significantly more toxic in older patients

The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors

Extent: 11 p.BACKGROUND: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS: Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary “sludge” in Arms A/B/C was 39%/36%/27%. CONCLUSION: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. Trial registration: ClinicalTrials.gov NCT00448786Lee S. Rosen, Lara Lipton, Timothy J. Price, Neil D. Belman, Ralph V. Boccia, Herbert I. Hurwitz, Joe J. Stephenson Jr., Lori J. Wirth, Sheryl McCoy, Yong-jiang Hei, Cheng-Pang Hsu and Niall C. Tebbut

hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA

SIMPLE SUMMARY: Recent clinical trials suggest that combination therapies that include either gemcitabine or 5-fluorouracil (5-FU) both give significant survival benefits for pancreatic cancer patients. The tumor level of the nucleoside transporter hENT1 is prognostic in patients treated with adjuvant gemcitabine but not adjuvant 5-FU. This work shows for the first time that hENT1 is only predictive of benefit from gemcitabine over 5-FU in patients with low levels of CDA transcript. A choice between adjuvant 5-FU based combination therapies (such as FOLFIRINOX) and gemcitabine-based therapy (e.g., GemCap) could be made based on a combination of hENT1 protein and CDA mRNA measured in a resected tumor. ABSTRACT: Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient