Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics.

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.

Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. RESULTS: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.

Towards precision medicine for anxiety disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs.

Anxiety disorders are increasingly prevalent, affect people's ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed and sub-optimally treated, resulting in adverse life events and/or addictions. We endeavored to discover blood biomarkers for anxiety, using a four-step approach. First, we used a longitudinal within-subject design in individuals with psychiatric disorders to discover blood gene expression changes between self-reported low anxiety and high anxiety states. Second, we prioritized the list of candidate biomarkers with a Convergent Functional Genomics approach using other evidence in the field. Third, we validated our top biomarkers from discovery and prioritization in an independent cohort of psychiatric subjects with clinically severe anxiety. Fourth, we tested these candidate biomarkers for clinical utility, i.e. ability to predict anxiety severity state, and future clinical worsening (hospitalizations with anxiety as a contributory cause), in another independent cohort of psychiatric subjects. We showed increased accuracy of individual biomarkers with a personalized approach, by gender and diagnosis, particularly in women. The biomarkers with the best overall evidence were GAD1, NTRK3, ADRA2A, FZD10, GRK4, and SLC6A4. Finally, we identified which of our biomarkers are targets of existing drugs (such as a valproate, omega-3 fatty acids, fluoxetine, lithium, sertraline, benzodiazepines, and ketamine), and thus can be used to match patients to medications and measure response to treatment. We also used our biomarker gene expression signature to identify drugs that could be repurposed for treating anxiety, such as estradiol, pirenperone, loperamide, and disopyramide. Given the detrimental impact of untreated anxiety, the current lack of objective measures to guide treatment, and the addiction potential of existing benzodiazepines-based anxiety medications, there is a urgent need for more precise and personalized approaches like the one we developed.

Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Surgical vs Non-surgical interventions for distal radius fractures: a quantitative analysis of Patient-Rated Wrist Evaluation measures.

Trials to assess differences in PRWE (Patient Related Wrist Evaluation) over time, for both surgical and non-surgical interventions post DRFs (distal radius fractures) are rare. The DASH (Disabilities of the Arm, Shoulder and Hand) questionnaire has been shown to be improved by a greater margin in the medium term for surgical interventions, than non surgical interventions. However, a study found that PRWE can be considered superior to the DASH questionnaire for DRFs, due to greater specificity to wrist pain and function. Conflicting data makes it difficult to determine surgical vs non-surgical superiority for DRF's over time with PRWE as a recovery metric. PubMed and Cochrane were searched for randomised controlled trials up to 31.8.23, reporting PRWE over 3, and 12 months. Data was extracted by 2 researchers. The differences in PRWE over time post surgical and non-surgical interventions was assessed using unpaired T testing. 1226 records were screened. 4 studies enrolling 817 participants met the eligibility criteria and were analysed. Significantly lower PRWE in surgical intervention has been identified at the 3 month mark (p<0.001). There was greater significant change in non-surgical intervention between months 3 and 12 (p<0.001). Change in PRWE over time may be a good indicator of functional outcomes in DRFs post surgical or non-surgical interventions. This could inform future clinical trial design and surgical decision-making. Further work is required to design even more user-friendly and digital patient- reported outcomes specifically for DRFs.

Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs.

Mood disorders (depression, bipolar disorders) are prevalent and disabling. They are also highly co-morbid with other psychiatric disorders. Currently there are no objective measures, such as blood tests, used in clinical practice, and available treatments do not work in everybody. The development of blood tests, as well as matching of patients with existing and new treatments, in a precise, personalized and preventive fashion, would make a significant difference at an individual and societal level. Early pilot studies by us to discover blood biomarkers for mood state were promising [1], and validated by others [2]. Recent work by us has identified blood gene expression biomarkers that track suicidality, a tragic behavioral outcome of mood disorders, using powerful longitudinal within-subject designs, validated them in suicide completers, and tested them in independent cohorts for ability to assess state (suicidal ideation), and ability to predict trait (future hospitalizations for suicidality) [3-6]. These studies showed good reproducibility with subsequent independent genetic studies [7]. More recently, we have conducted such studies also for pain [8], for stress disorders [9], and for memory/Alzheimer's Disease [10]. We endeavored to use a similar comprehensive approach to identify more definitive biomarkers for mood disorders, that are transdiagnostic, by studying mood in psychiatric disorders patients. First, we used a longitudinal within-subject design and whole-genome gene expression approach to discover biomarkers which track mood state in subjects who had diametric changes in mood state from low to high, from visit to visit, as measured by a simple visual analog scale that we had previously developed (SMS-7). Second, we prioritized these biomarkers using a convergent functional genomics (CFG) approach encompassing in a comprehensive fashion prior published evidence in the field. Third, we validated the biomarkers in an independent cohort of subjects with clinically severe depression (as measured by Hamilton Depression Scale, (HAMD)) and with clinically severe mania (as measured by the Young Mania Rating Scale (YMRS)). Adding the scores from the first three steps into an overall convergent functional evidence (CFE) score, we ended up with 26 top candidate blood gene expression biomarkers that had a CFE score as good as or better than SLC6A4, an empirical finding which we used as a de facto positive control and cutoff. Notably, there was among them an enrichment in genes involved in circadian mechanisms. We further analyzed the biological pathways and networks for the top candidate biomarkers, showing that circadian, neurotrophic, and cell differentiation functions are involved, along with serotonergic and glutamatergic signaling, supporting a view of mood as reflecting energy, activity and growth. Fourth, we tested in independent cohorts of psychiatric patients the ability of each of these 26 top candidate biomarkers to assess state (mood (SMS-7), depression (HAMD), mania (YMRS)), and to predict clinical course (future hospitalizations for depression, future hospitalizations for mania). We conducted our analyses across all patients, as well as personalized by gender and diagnosis, showing increased accuracy with the personalized approach, particularly in women. Again, using SLC6A4 as the cutoff, twelve top biomarkers had the strongest overall evidence for tracking and predicting depression after all four steps: NRG1, DOCK10, GLS, PRPS1, TMEM161B, GLO1, FANCF, HNRNPDL, CD47, OLFM1, SMAD7, and SLC6A4. Of them, six had the strongest overall evidence for tracking and predicting both depression and mania, hence bipolar mood disorders. There were also two biomarkers (RLP3 and SLC6A4) with the strongest overall evidence for mania. These panels of biomarkers have practical implications for distinguishing between depression and bipolar disorder. Next, we evaluated the evidence for our top biomarkers being targets of existing psychiatric drugs, which permits matching patients to medications in a targeted fashion, and the measuring of response to treatment. We also used the biomarker signatures to bioinformatically identify new/repurposed candidate drugs. Top drugs of interest as potential new antidepressants were pindolol, ciprofibrate, pioglitazone and adiphenine, as well as the natural compounds asiaticoside and chlorogenic acid. The last 3 had also been identified by our previous suicidality studies. Finally, we provide an example of how a report to doctors would look for a patient with depression, based on the panel of top biomarkers (12 for depression and bipolar, one for mania), with an objective depression score, risk for future depression, and risk for bipolar switching, as well as personalized lists of targeted prioritized existing psychiatric medications and new potential medications. Overall, our studies provide objective assessments, targeted therapeutics, and monitoring of response to treatment, that enable precision medicine for mood disorders.

What are the similarities and differences in lung cancer symptom appraisal and help-seeking according to smoking status? A qualitative study with lung cancer patients.

OBJECTIVE: Lung cancer in never-smokers represents a growing proportion of patients. The relationship between smoking status, symptom appraisal and help-seeking behaviour is complex. Little is known about cancer symptom-related health behaviours according to smoking status. The aim of the study was to explore lung cancer patients' experiences of a lung cancer diagnosis, identifying differences by smoking history. METHOD: This was a qualitative study involving telephone interviews with 40 lung cancer patients (20 never smokers, 11 former smokers and 9 current smokers). We used framework analysis to analyse the data using the Common Sense Model of Illness Self-Regulation as a theoretical framework, developed after initial analysis. RESULTS: All patients were likely to delay seeking help for symptoms in primary care regardless of smoking history, but for different reasons. Smoking history was instrumental to how individuals perceived and responded to early symptoms of lung cancer. Differences in interpretation and coping responses to new symptoms seemed to be caused by the higher presence of comorbidities due to smoking, and perceptions of the current state of health. Individuals with a smoking history reported acting with urgency in seeking help and follow up, whereas patients who experienced low levels of concern were more easily reassured by clinicians, resulting in delays. CONCLUSIONS: Never and former smokers perceive, interpret, and respond to symptoms of lung cancer differently to smokers. However, few people attribute their lung symptoms to cancer initially, even with a smoking history. Interventions that drive increased urgency and vigilance in never smokers may be effective.

The impact of cultural stress and gender norms on alcohol use severity among Latino immigrant men.

Alcohol misuse affects 15 million people in the United States. Compared to White men, Latino men have disproportionately higher rates of both alcohol misuse and negative alcohol-related consequences (e.g. drunk driving, liver disease, alcohol dependence, HIV/AIDS). This cross sectional study examined how cultural stressors [immigration stress and negative context of reception (NCR)] coupled with traditional Latino male gender norms (machismo and caballerismo) influences alcohol use severity (AUS) among adult Latino immigrant men. Data for the present study was collected between 2017 and 2018 from 279 Cuban, Central American, and South American adult Latino men who immigrated to the US approximately 10 years prior. Results from hierarchical multiple regression analysis revealed higher levels of perceived NCR (ß = 0.15, p = .01), and machismo (ß = 0.16, p = .02) were associated with greater AUS. Significant interaction effects were found between both cultural stressors and machismo [immigration stress x machismo (ß = 0.22, p < .001); NCR x machismo (ß = 0.22, p < .001)] whereby higher levels of machismo strengthened the association between cultural stress and AUS. Findings from the present study can inform culturally appropriate interventions aimed at mitigating alcohol use among Latino immigrant men.

Challenges and opportunities in productivity and sustainability of rice cultivation system: a critical review in Indian perspective.

Abstract: Rice-wheat cropping system, intensively followed in Indo-Gangetic plains (IGP), played a prominent role in fulfilling the food grains demand of the increasing population of South Asia. In northern Indian plains, some practices such as intensive rice cultivation with traditional method for long-term have been associated with severe deterioration of natural resources, declining factor productivity, multiple nutrients deficiencies, depleting groundwater, labour scarcity and higher cost of cultivation, putting the agricultural sustainability in question. Varietal development, soil and water management, and adoption of resource conservation technologies in rice cultivation are the key interventions areas to address these challenges. The cultivation of lesser water requiring crops, replacing rice in light-textured soil and rainfed condition, should be encouraged through policy interventions. Direct seeding of short duration, high-yielding and stress tolerant rice varieties with water conservation technologies can be a successful approach to improve the input use efficiency in rice cultivation under medium-heavy-textured soils. Moreover, integrated approach of suitable cultivars for conservation agriculture, mechanized transplanting on zero-tilled/unpuddled field and need-based application of water, fertilizer and chemicals might be a successful approach for sustainable rice production system in the current scenario. In this review study, various challenges in productivity and sustainability of rice cultivation system and possible alternatives and solutions to overcome such challenges are discussed in details.

Bone infection: a clinical priority for clinicians, scientists and educators.

Bone infection has received increasing attention in recent years as one of the main outstanding clinical problems in orthopaedic-trauma surgery that has not been successfully addressed. In fact, infection may develop across a spectrum of patient types regardless of the level of perioperative management, including antibiotic prophylaxis. Some of the main unknown factors that may be involved, and the main targets for future intervention, include more accurate and less invasive diagnostic options, more thorough and accurate debridement protocols, and more potent and targeted antimicrobials. The underlying biology dominates the clinical management of bone infections, with features such as biofilm formation, osteolysis and vascularisation being particularly influential. Based on the persistence of this problem, an improved understanding of the basic biology is deemed necessary to enable innovation in the field. Furthermore, from the clinical side, better evidence, documentation and outreach will be required to translate these innovations to the patient. This review presents the findings and progress of the AO Trauma Clinical Priority Program on the topic of bone infection.

Endodontic implications of a patient with arteriovenous malformation: a case report and literature review.

AIM: To present the endodontic management of a patient diagnosed with a high-flow arteriovenous malformation (AVM) requiring root canal treatment and to discuss the relevant endodontic literature for this rare but significant problem. SUMMARY: AVM is a complex communication of an artery and a vein in which the oxygenated blood is forced away from the intended tissue. The incidence of its occurrence in the face and neck is rare, and when present, the most common sign is gingival bleeding. Arteriovenous malformation is both a diagnostic and therapeutic challenge for dentists. Also, there is ambiguity regarding the precautions to be taken whilst doing endodontic procedures in such cases. Hence, there is a need to understand the disease process and its implications in order to prevent life-threatening complications during treatment. This case report highlights the successful endodontic management of a cariously exposed right maxillary second premolar in a patient diagnosed with high-flow AVM. On an orthopantomogram, the AVM was spreading in the left submandibular space involving the left ramus area. The clinical findings of limited mouth opening with inter-appointment swelling and trismus during treatment made the case unusual and challenging. This paper addresses the current understanding of the classification, diagnosis, clinical features and endodontic management, together with specific guidelines and recommendations whilst performing endodontic procedures in AVM cases. KEY LEARNING POINTS: The classification and oral manifestations of AVM must be known and understood. Practitioners should be aware of the radiographic appearance of AVM. Recommended precautions should be taken when carrying out restorative and endodontic procedures in a patient with AVM. Antibiotic prophylaxis may be considered before endodontic treatment in a patient with AVM. Multidisciplinary treatment planning may be required.

Detecting Neurodevelopmental Toxicity of Domoic Acid and Ochratoxin A Using Rat Fetal Neural Stem Cells.

Currently, animal experiments in rodents are the gold standard for developmental neurotoxicity (DNT) investigations; however, testing guidelines for these experiments are insufficient in terms of animal use, time, and costs. Thus, alternative reliable approaches are needed for predicting DNT. We chose rat neural stem cells (rNSC) as a model system, and used a well-known neurotoxin, domoic acid (DA), as a model test chemical to validate the assay. This assay was used to investigate the potential neurotoxic effects of Ochratoxin A (OTA), of which the main target organ is the kidney. However, limited information is available regarding its neurotoxic effects. The effects of DA and OTA on the cytotoxicity and on the degree of differentiation of rat rNSC into astrocytes, neurons, and oligodendrocytes were monitored using cell-specific immunofluorescence staining for undifferentiated rNSC (nestin), neurospheres (nestin and A2B5), neurons (MAP2 clone M13, MAP2 clone AP18, and Doublecortin), astrocytes (GFAP), and oligodendrocytes (A2B5 and mGalc). In the absence of any chemical exposure, approximately 46% of rNSC differentiated into astrocytes and neurons, while 40.0% of the rNSC differentiated into oligodendrocytes. Both non-cytotoxic and cytotoxic concentrations of DA and OTA reduced the differentiation of rNSC into astrocytes, neurons, and oligodendrocytes. Furthermore, a non-cytotoxic nanomolar (0.05 µM) concentration of DA and 0.2 µM of OTA reduced the percentage differentiation of rNSC into astrocytes and neurons. Morphometric analysis showed that the highest concentrations (10 µM) of DA reduced axonal length. These indicate that low, non-cytotoxic concentrations of DA and OTA can interfere with the differentiation of rNSC.

The association of waist circumference with walking difficulty among adults with or at risk of knee osteoarthritis: the Osteoarthritis Initiative.

OBJECTIVE: Excess weight is a known risk factor for functional limitation and common in adults with knee osteoarthritis (OA). We asked to what extent high waist circumference was linked with developing difficulty with walking speed and distance over 4 years in adults with or at risk of knee OA. METHOD: Using data from the Osteoarthritis Initiative (OAI), we employed World Health Organization (WHO) categories for Body Mass Index (BMI) and waist circumference (small/medium and large). Difficulty with speed was defined by slow gait: <1.2 m/s during a 20-m walk, and difficulty with distance was defined by an inability to walk 400 m. We calculated risk ratios (RR) to examine the likelihood of developing difficulty with distance and speed using obesity and waist circumference as predictors with RRs adjusted for potential confounders (i.e., age, sex, race, education, physical activity, and OA status). RESULTS: Participants with obesity and large waists were 2.2 times more likely to have difficulty with speed at 4 years compared to healthy weight and small/medium waisted participants (Adjusted RR 2.2 [95% Confidence interval (CI) 1.6, 3.1], P < .0001). Participants with obesity and a large waist circumference had 2.4 times the risk of developing the inability to walk 400 m compared with those with a healthy BMI and small/medium waist circumference (Adjusted RR 0.9 [95% CI 1.6, 3.7], P < .0001). CONCLUSIONS: Waist circumference may be a main risk factor for developing difficulty with speed in adults with or at risk of knee OA.

Randomized phase II study of modified FOLFOX-6 in combination with ramucirumab or icrucumab as second-line therapy in patients with metastatic colorectal cancer after disease progression on first-line irinotecan-based therapy.

BACKGROUND: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind VEGF receptors 1 and 2 (VEGFR-1 and -2), respectively. This randomized phase II study evaluated the antitumor activity and safety of icrucumab and ramucirumab each in combination with mFOLFOX-6 in patients with metastatic colorectal cancer after disease progression on first-line therapy with a fluoropyrimidine and irinotecan. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive mFOLFOX-6 alone (mFOLFOX-6) or in combination with ramucirumab 8 mg/kg IV (RAM+mFOLFOX-6) or icrucumab 15 mg/kg IV (ICR+mFOLFOX-6) every 2 weeks. Randomization was stratified by prior bevacizumab therapy. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, safety, and PK. RESULTS: In total, 158 patients were randomized, but only 153 received treatment (49 on mFOLFOX-6, 52 on RAM+mFOLFOX-6, and 52 on ICR+mFOLFOX-6). Median PFS was 18.4 weeks on mFOLFOX-6, 21.4 weeks on RAM+mFOLFOX-6, and 15.9 weeks on ICR+mFOLFOX-6 (RAM+mFOLFOX-6 versus mFOLFOX-6, stratified hazard ratio [HR] 1.116 [95% CI 0.713-1.745], P = 0.623; ICR+mFOLFOX-6 versus mFOLFOX-6, stratified HR 1.603 [95% CI 1.011-2.543], P = 0.044). Median survival was 53.6 weeks on mFOLFOX-6, 41.7 weeks on RAM+mFOLFOX-6, and 42.0 weeks on ICR+mFOLFOX-6. The most frequent adverse events reported on the ramucirumab arm (RAM+mFOLFOX-6) were fatigue, nausea, and peripheral sensory neuropathy; those on the icrucumab arm (ICR+mFOLFOX-6) were fatigue, diarrhea, and peripheral sensory neuropathy. Grade ≥3 serious adverse events occurred at comparable frequency across arms. CONCLUSIONS: In this study population, combining ramucirumab or icrucumab with mFOLFOX-6 did not achieve the predetermined improvement in PFS. CLINICALTRIALSGOV: NCT01111604.

Pazolimus: pazopanib plus sirolimus following progression on pazopanib, a retrospective case series analysis.

BACKGROUND: To explore the activity of pazopanib (P) + sirolimus (S) in patients who progressed after previous clinical benefit on pazopanib. METHODS: Eight patients with progressing metastatic high grade soft tissue sarcoma (STS) whose disease advanced on P following a response duration of at least 4 months were offered re-challenge of P supplemented by off-label S and a single patient with progressing metastatic chondrosarcoma was offered the combination as compassionate treatment. Patients were treated in two centers: Hadassah Medical Center and Tel Aviv Medical Center. Patients received oral P 200-600 mg once a day supplemented by S 3-4 mg taken separately, 12 h after the P dose. RESULTS: Patients received treatment from December 2012 to February 2016. Four progressed on the combination and their treatment was terminated. Two patients were undergoing treatment when data was summarized. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: one partial response (PR), four stable disease (SD), and four progressive disease (PD), corresponding to five PR and four PD on the Choi criteria. Median progression free survival was 5.5 months (range 4-17). CONCLUSIONS: Our series showed that the combination of P + S has activity in STS patients selected by previous response to P and in a patient with chondrosarcoma, suggesting this can serve as a mechanism to reverse resistance to P and extend the chemotherapy-free window.

Provincial elections and timing of cancer drug funding.

BACKGROUND: Concerns have been raised about the potential influence of political pressures on drug funding decisions. We evaluated the temporal relationship between cancer drug funding and provincial elections in 9 Canadian provinces. METHODS: New indications for cancer drugs between January 2003 and December 2012 were identified, and the dates of official provincial funding dates and election dates between 1 January 2003 and 31 December 2014 were retrieved. The probability of drug funding announcements in the 60-day period preceding a provincial election was evaluated using binomial probability distribution analysis. RESULTS: Data from 9 provinces (all Canadian provinces except Quebec) were available. During the period of interest, 69 new indications for 39 individual drugs were identified. Variation in the availability of funding dates was identified. At the time of data collection, 2 provinces did not have data available for all 69 indications. For the 9 provinces, the number of funded indications during the 60-day period preceding an election ranged from 0 to 3; however, no differences in the proportion of indications funded pre-election were identified. Additional analyses also failed to demonstrate any significant associations with the 90-day period before an election, or the 60- and 90-day periods after an election. CONCLUSIONS: We observed no clear temporal relationship between provincial election dates and funding decisions in this recent Canadian sample of new indications for cancer drugs.

Report from the 17th Annual Western Canadian Gastrointestinal Cancer Consensus Conference; Edmonton, Alberta; 11-12 September 2015.

The 17th annual Western Canadian Gastrointestinal Cancer Consensus Conference (wcgccc) was held in Edmonton, Alberta, 11-12 September 2015. The wcgccc is an interactive multidisciplinary conference attended by health care professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management of gastric cancer.

A case-control study assessing bone mineral density in severe haemophilia A in the UK.

It has been shown that bone mineral density (BMD) may be lower in patients with haemophilia (PWH). A comparison to control subjects is required to thoroughly assess current BMD in PWH in the UK. The objective of this study was to test the hypothesis that BMD is lower in PWH than in controls, and in patients with more severely affected joints or lower activity levels. In this case-control study, 37 patients with severe haemophilia A were recruited from two haemophilia centres in the UK. A group of 37 age, gender and ethnicity-matched control participants were recruited. All participants had a bone density scan, a musculoskeletal assessment, a blood test for vitamin D and completed a functional activity questionnaire. Of the case group, 5% had osteoporosis and 24% had BMD lower than expected for age. No control participants had osteoporosis, 3% had osteopenia and 14% had BMD lower than expected for age. Ninety one per cent of case participants and 92% of control participants had reduced 25(OH)D levels. Case participants had significantly lower BMD than control participants, and case participants with more severely affected joints, lower activity levels, HIV, history of hepatitis C or lower BMI had significantly lower BMD. Patients with severe haemophilia have a higher risk of low BMD than men without haemophilia. Patients with more severely affected joints and lower activity levels have lower BMD. It remains unclear whether patients with low BMD reached adequate peak bone mass. Low vitamin D may be present in the majority of PWH.