Twice-weekly Regimen Research Articles

Adherence to preventive treatment for latent tuberculosis infection in close contacts of pulmonary tuberculosis patients: A cluster-randomized controlled trial in China

ObjectivesThis study examined adherence rates to tuberculosis preventive treatment (TPT) among close contacts of individuals with pulmonary tuberculosis (PTB) and identified factors associated with TPT adherence in China. MethodsA multicenter, cluster-randomized, open-label control trial was carried out across three sites involving 34 counties in China. Close contacts of bacteriologically confirmed rifampin and isoniazid-susceptible PTB cases were identified and screened for latent tuberculosis infection (LTBI). Eligible participants were randomly assigned to either the 3H2P2 group, which consisted of a 3-month, twice-weekly regimen of rifapentine and isoniazid, or the 6H group, which entailed a 6-month daily regimen of isoniazid. To assess the factors influencing adherence, a two-level logistic regression model was utilized. ResultsOut of the 2434 close contacts who initiated TPT, 2121 (87.1%) completed the regimen. Of the 313 individuals who did not complete TPT, 60.1% refused to continue, and 27.8% discontinued due to adverse effects. The two-level logistic regression model revealed several factors associated with enhanced TPT adherence: enrollment in the 3H2P2 group (odds ratio [OR] = 2.09), management by a TB dispensary responsible for TPT (OR = 2.55), supervision by healthcare workers (OR = 6.40), and clinician incentives (OR = 2.49). Conversely, the occurrence of any adverse effects (OR = 0.08) was identified as a risk factor for nonadherence. ConclusionAdministering TPT to individuals with LTBI is feasible among close contacts. Adherence to TPT can be enhanced through shorter, safer treatment regimens and supportive interventions, such as directly supervised therapy for TPT recipients and incentives for healthcare providers managing TPT.

Tuberculosis preventive treatment among individuals with inactive tuberculosis suggested by untreated radiographic abnormalities: a community-based randomized controlled trial

ABSTRACT Epidemiological and interventional studies have been rarely conducted among those with positive interferon-γ release assay (IGRA) results and radiologically inactive tuberculosis (TB) lesions on chest radiograph. This study aimed to estimate the effectiveness and safety of a six-week twice-weekly regimen (rifapentine plus isoniazid) among this key population in rural China. First, chest digital radiography was conducted to screen individuals with inactive TB lesions. Then, the identified participants were further evaluated and eligible participants with IGRA-positive results were included in subsequent randomized controlled trial (RCT). Of 44,500 recruited residents, 2,988 presented with radiographically inactive TB among 43,670 with complete results of chest radiography and questionnaire, and 28.61% (855/2,988) tested IGRA positive. Subsequently, 677 eligible participants were included in this RCT (345 in the preventive treatment group and 332 in the untreated control group). The treatment completion rate was 80.00% (276/345), and 11.88% (41/345) participants reported side-effects including two cases of hepatotoxicity (0.58%, 2/345). In the intention-to-treat analysis, the cumulative incidence rate of microbiologically confirmed active TB during a two-year follow-up was 1.16 (95% confidence interval [CI]: 0.03–2.29) in the preventive treatment group and 1.51 (95% CI: 0.20–2.82) in the control group (p = .485). Subgroup analyses showed that the protective rates were 55.42% (95% CI: 10.33–93.07%) and 80.17% (95% CI: 25.36–97.96%) for participants with fibrosis and for those aged ≥60 years, respectively. The expected treatment effect was not observed for the six-week regimen in this study. Future studies with sufficient sample size are needed to verify our findings.

Pharmacokinetic modelling of caspofungin to develop an extended dosing regimen in paediatric patients.

Echinocandins are commonly used in treatment and prophylaxis of invasive fungal diseases. Intravenous daily dosing for prophylaxis in the outpatient setting can however become a hurdle for adequate compliance in the paediatric population. Simulations were performed to assess extended twice-weekly dosing for antifungal prophylaxis using caspofungin. A population pharmacokinetic model was developed based on previously published data from children aged 3 months to 17 years. Using the final model, Monte Carlo simulations were performed to assess the dose needed for adequate exposure in a twice-weekly setting. Mean weekly AUC0-24 h/MIC together with reported AUC0-24 h from previously reported paediatric trials were used to guide adequate exposure. A two-compartment model with linear elimination and allometric scaling using fixed exponents was found most adequate to describe the given paediatric populations. Simulations showed that a 200 mg/m2 twice-weekly regimen with maximal 200 mg total dose should result in exposures matching registered daily dosing as well as commonly used pharmacokinetic/pharmacodynamic targets.

Protective efficacy of 6-week regimen for latent tuberculosis infection treatment in rural China: 5-year follow-up of a randomised controlled trial.

BackgroundEnlarging tuberculosis (TB) preventive treatment among at-risk populations is a critical component of the End TB Strategy. There is an urgent need to develop suitable latent tuberculosis infection (LTBI) testing and treatment tools according to the local TB epidemic and available resources worldwide.MethodsBased on an open-label randomised controlled trial conducted since 2015 in China among rural residents aged 50–70 years with LTBI, the protective efficacy of a 6-week twice-weekly regimen of rifapentine plus isoniazid was further evaluated in a 5-year follow-up survey.Results1298 treated participants and 1151 untreated controls were included in the 5-year protective efficacy analysis. In the per-protocol analysis, the incidence rate was 0.49 (95% CI 0.30–0.67) per 100 person-years in the untreated control group and 0.19 (95% CI 0.07–0.32) per 100 person-years in the treated group; the protection rate was 61.22%. Subgroup analysis showed that the protection rate was 76.82% in the per-protocol analysis among participants with baseline interferon (IFN)-γ levels in the highest quartile (≥3.25 IU·mL−1). Multiple logistic regression analysis indicated that participants with baseline body mass index <18.5 kg·m−2 and with pulmonary fibrotic lesions had increased hazard of developing active disease with an adjusted hazard ratio (aHR) of 3.64 (95% CI 1.20–11.00) and 5.99 (95% CI 2.20–16.27), respectively. In addition, individuals with higher baseline IFN-γ levels showed an increased risk of TB occurrence (aHR 2.27, 95% CI 1.13–4.58).ConclusionsOur findings suggest the 6-week twice-weekly regimen of rifapentine plus isoniazid for LTBI treatment might be an optional tool for TB control in the Chinese population.

Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously treated individuals with haemophilia A or B.

The hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on-demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies. To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously-treated individuals with hemophilia A or B. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearchingof journals and conference abstract books. In addition, we searched MEDLINE and Embase and online trial registries. Most recent search of Group's Coagulopathies Trials Register: 24 February 2021. Randomised controlled trials (RCTs) and quasi-RCTs evaluating people with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia. Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the GRADE criteria to assess the certainty of the evidence. Ten trials (including 608 participants) were eligible for inclusion. Eight of the trials (477 participants) had arms comparing two or more prophylactic regimens to one another and four of the trials (n = 258) compared prophylaxis to on-demand treatment (two trials had multiple arms and were included in both comparisons). Comparison of two or more prophylactic regimens For trials comparing one prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, three trials reported the primary outcome of joint bleeding, and none showed a dfference between dosing regimens (low-certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice-weekly regimen of FIX likely results in reduced total bleeds compared to a once-a-week regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (one trial, 10 participants, low-certainty evidence). Transient low-titer anti-FVIII inhibitors were reported in one of the trials. Blood-transmitted infections were not identified. Other adverse events reported include hypersensitivity, oedema, and weight gain. These were, however, rare and unrelated to study drugs (very low-certainty evidence). Comparison of prophylactic and on-demand regimens Four of the trials (258 participants) had arms that compared prophylaxis to on-demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on-demand treatment, MD -30.34 (95% CI -46.95 to -13.73) (two trials, 164 participants, low-certainty evidence). One of these trials (84 participants) also reported the long-term effects of prophylaxis versus on-demand therapy showing improved joint function, quality of life, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI). In one trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improves joint health compared to an on-demand regimen with an estimated change difference of 0.94 points (95% CI 0.23 to 1.65) and improves total pain scores, MD -17.20 (95% CI -27.48 to -6.92 (moderate-certainty evidence). Two trials (131 participants) reported that prophylaxis likely results in a slight increase in adverse events, risk ratio 1.71 (1.24 to 2.37) (moderate-certainty evidence). No inhibitor development and blood-transmitted infections were identified. Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect. AUTHORS' CONCLUSIONS: There is evidence from RCTs that prophylaxis, as compared to on-demand treatment, may reduce bleeding frequency in previously-treated people with hemophilia. Prophylaxis may also improve joint function, pain and quality of life, even though this does not translate into a detectable improvement of articular damage when assessed by MRI. When comparing two different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved efficacy. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons. Well-designed RCTs and prospective observational controlled studies with standardised definitions and measurements are needed to establish the optimal and most cost-effective treatment regimens.

A retrospective, descriptive study of patients with Mycosis fungoides treated by phototherapy (oral PUVA, NB-UVB) with a twice-weekly regimen at the Institute of Dermatology, Bangkok, Thailand, with an experiential timeline of 13years.

Phototherapy has been a first-line treatment for early-stage mycosis fungoides (MF) since 1976. Oral 8-methoxypsoralen plus ultraviolet A (oral PUVA) and narrow-band ultraviolet B (NB-UVB) are favorable modalities owing to their availability. In previous studies, phototherapy was conducted thrice per week initially, which is not feasible for many patients. To evaluate the initial clinical responses and time to relapse in patients with early-stage MF treated with oral PUVA and NB-UVB at a twice-weekly regimen. We reviewed the records of patients with biopsy-proven MF who received oral PUVA or NB-UVB in 2002-2014. Demographic data, staging, response to initial course of phototherapy, and initial relapse-free interval were collected. Among 70 patients, 14 (20%) and 56 (80%) were treated with oral PUVA and NB-UVB, respectively. The majority had early-stage MF (IA, 22.9%, IB, 57.1%, and IIA, 4.3%). Oral PUVA led to a complete response (CR) in 2 (14.3%) patients and partial response (PR) in 7 (50%) patients; 17 (30.4%) and 25 (44.6%) patients, respectively, achieved CR and PR with NB-UVB. The number of treatments was similar in both groups. The cumulative dose was 520.7J/cm2 for PUVA and 41.6J/cm2 for NB-UVB. There was no initial relapse in the 2 (100%) patients and in 10 (58.8%) patients treated with oral PUVA and NB-UVB at 18months and 9.14months of follow-up, respectively. Patients with early-stage MF can achieve clinical response with oral PUVA and NB-UVB, with a twice per week regimen. The initial relapse-free interval was longer than 1year.

P1519A TWICE-WEEKLY HEMODIALYSIS : A SINGLE CENTER STUDY

Abstract Background and Aims Conventional hemodialysis consists of a thrice-weekly in-center Hemodialysis with a mean duration of 4 hours per session. The concept of incremental dialysis has allowed a better adjustment of its prescription guided by clinical and biological parameters. Thereby a twice-weekly regimen may maintain a good quality of life, a good survival rate and adequate dialysis in comparison to a thrice-weekly hemodialysis. The aim of our study was to investigate the profile of patients undergoing a twice-weekly regimen in our center. Method It is a monocenter transversal-descriptive study gathering patients on a twice-weekly regimen in the center of hemodialysis of Fattouma Bourguiba University Hospital in Monastir Tunisia. Results We identified 32 patients with a sex ratio of 2.2 (22 men and 10 women) with a mean age of 48,96 +/- 13,74 years. Regarding the intitial nephropathy, a chronic glomerulopathy was seen in 16 patients, a chronic tubulo-interstitial nephritis In 5 patients, and kidney polykystosis among 3 patients and in 8 patients the initial nephropathy remained undetermined. The indications for a twice-weekly HD regimen were: defavourable socio-economic conditions in 9 patients, a medical reason in 17 patients and a rejection of thrice-weekly regimen in 6 patients. The mean diuresis was 850 +/- 560 cc/24h and only one patient with anuria. The mean interdialytic weight gain was 2, 64 +/- 0, 83 Kg. Normal blood pressure and volemia were reported in 27 patients (84, 37 %). The mean number of anti-hypertensive drugs used was 1,5 per patient. The mean percentage of Urea reduction was 68, 8 % and a mean Kt/V of 1.26. The average of both kalemia and calcemia was respectively 5.27 mmol/l and 1, 94 mmol/l and the mean dosage of phosphoremia was 1, 63 mmol/l. The average of PTH and Hemoglobine was respectively 403 pg/ml and 9, 97 g/dl. Conclusion According to these results, a twice-weekly hemodialysis should be guided by the residual kidney function, clinical status (volemia), cardiovascular symptoms and comorbidities, biological parameters (Hemoglobine, potassium, phosphore) and the nutritional state. By meeting the above criteria, many studies have shown that a twice-weekly regimen or incremental dialysis help preserve the residual kidney function with a good quality of life.

Study of twice-weekly injections of Teriparatide by comparing efficacy with once-weekly injections in osteoporosis patients: the TWICE study

SummaryA 48-week, multicenter, randomized, double-blind, double-dummy, active-controlled, non-inferiority trial (the TWICE study) conducted in Japanese primary osteoporosis patients with a high risk of fractures demonstrated that a 28.2-μg twice-weekly regimen of teriparatide can provide comparable efficacy to a 56.5-μg once-weekly regimen of teriparatide, while also improving safety.IntroductionWhile a 56.5-μg once-weekly regimen of teriparatide has high efficacy for osteoporosis, treatment continuation rates are low, with one of the major causes being adverse drug reactions such as nausea or vomiting. The TWICE study was therefore conducted to investigate whether a twice-weekly regimen with 28.2-μg teriparatide can provide comparable efficacy to the 56.5-μg once-weekly regimen while improving safety.MethodsA 48-week, multicenter, randomized, double-blind, double-dummy, active-controlled, non-inferiority trial was conducted in Japan. Patients with primary osteoporosis aged ≥ 65 years at high risk of fractures (n = 553) were randomly allocated to the 28.2-μg twice-weekly group (n = 277) or the 56.5-μg once-weekly group (n = 276). The primary endpoint was the percentage change in lumbar spine (L2–L4) bone mineral density (BMD) at final follow-up.ResultsThe percentage changes in lumbar spine (L2–L4) BMD at final follow-up in the 28.2-μg twice-weekly and 56.5-μg once-weekly groups were 7.3% and 5.9%, respectively; the difference (95% confidence interval [CI]) in percentage change was 1.3% (0.400–2.283%). Since the lower limit of the 95% CI was above the pre-specified non-inferiority margin (− 1.6%), non-inferiority of the 28.2-μg twice-weekly group was demonstrated. Adverse drug reactions were significantly less frequent in the 28.2-μg twice-weekly group (39.7% vs 56.2%; p < 0.01); the incidence of major adverse drug reactions was lower, and the number of subjects who discontinued due to adverse drug reactions was less in the 28.2-μg twice-weekly group.ConclusionsA 28.2-μg twice-weekly regimen of teriparatide can provide comparable efficacy to a 56.5-μg once-weekly regimen while improving safety.Clinical trial registrationJapicCTI-163477.

Short-course regimens of rifapentine plus isoniazid to treat latent tuberculosis infection in older Chinese patients: a randomised controlled study.

Latent tuberculosis infection (LTBI) management is now a critical component of the World Health Organization's End TB Strategy.In this randomised controlled trial (Chinese Clinical Trial Registry identifier ChiCTR-IOR-15007202), two short-course regimens with rifapentine plus isoniazid (a 3-month once-weekly regimen and a 2-month twice-weekly regimen) were initially designed to be evaluated for rural residents aged 50-69 years with LTBI in China.Due to the increasingly rapid growth and unexpected high frequency of adverse effects, the treatments were terminated early (after 8 weeks for the once-weekly regimen and after 6 weeks for the twice-weekly regimen). In the modified intention-to-treat analysis on the completed doses, the cumulative rate of active disease during 2 years of follow-up was 1.21% (14 out of 1155) in the untreated controls, 0.78% (10 out of 1284) in the group that received the 8-week once-weekly regimen and 0.46% (six out of 1299) in the group that received the 6-week twice-weekly regimen. The risk of active disease was decreased, with an adjusted hazard ratio of 0.63 (95% CI 0.27-1.43) and 0.41 (95% CI 0.15-1.09) for the treatments, respectively. No significant difference was found in the occurrence of hepatotoxicity (1.02% (13 out of 1279) versus 1.17% (15 out of 1279); p=0.704).The short regimens tested must be used with caution among the elderly because of the high rates of adverse effects. Further work is necessary to test the ultrashort regimens in younger people with LTBI.

Abstract B171: PK/PD modeling of the first-in-class, potent and selective covalent CDK7 inhibitor, SY-1365, provides mechanistic basis for intermittent dosing regimens in preclinical efficacy models of hematologic and solid tumors

Abstract Introduction: CDK7 has recently emerged as an attractive gene control target in cancers driven by transcriptional dependencies, including triple-negative breast cancer (TNBC) and acute myeloid leukemia (AML). SY-1365 is a first-in-class, potent, and selective covalent CDK7 inhibitor that has shown durable and complete responses in xenograft models of AML and various solid tumors. To advance the development of this CDK7 inhibitor in patients, the current work assessed the relationship between SY-1365 pharmacokinetics (PK), pharmacodynamics (PD) measured as CDK7 target occupancy, and efficacy in mouse xenograft models of AML (HL-60) and TNBC (HCC70). Methods: SY-1365 was dosed intravenously in several xenograft experiments across a range of dose levels (5-40 mg/kg) and dose frequencies (daily to weekly). PK and changes in CDK7 occupancy were measured following single and repeat dosing, and efficacy studies measured the resultant dose-dependent changes in tumor volume over time after repeat dosing of SY-1365. To account for the temporal differences in PK, PD and tumor growth inhibition (TGI), a mathematical modeling approach was taken to integrate the resulting datasets. In addition, an assay to determine CDK7 occupancy in human PBMCs was developed to support the ongoing phase 1 study. Results: The PK in mouse was proportional with respect to dose and exhibited a terminal elimination half-life (t1/2) of 4 h. The PK/PD model was able to describe the PK, PD, and efficacy in HL-60 and HCC70 xenografts, with similar exposure and CDK7 occupancy profiles observed in these two xenografts. The model demonstrated a CDK7 turnover t1/2 of 69 h, longer than that reported for other oncogenic kinases targeted with covalent inhibitors where daily dosing is required (e.g., EGFRi, BTKi), with optimal efficacy achieved when target engagement was sustained over the dosing interval. This provides a mechanistic basis for intermittent dosing based on the dose-dependent TGI, including tumor regressions, observed with SY-1365 in in vivo models of TNBC and AML. Conclusions: The PK/PD relationship for target engagement and efficacy of the first-in-class potent and selective covalent CDK7 inhibitor, SY-1365, has been characterized in preclinical models through a mathematical modeling approach. Assays were developed to enable target occupancy quantification in xenograft tumors, and in human PBMCs as a surrogate tissue to support clinical investigation. Further investigations into tumor molecular profiles driving response are currently under way. In summary, this work supported the selection of an initial twice-weekly dosing regimen in the ongoing phase 1 trial of SY-1365 in adult patients with advanced solid tumors (NCT03134638). Citation Format: Nigel J. Waters, Shanhu Hu, Brett Matzuka, Graeme Hodgson, Yixuan Ren, Yoon Choi, Kevin Dykstra, Christopher Roberts, Kevin Sprott, Emmanuelle di Tomaso, Christian Fritz. PK/PD modeling of the first-in-class, potent and selective covalent CDK7 inhibitor, SY-1365, provides mechanistic basis for intermittent dosing regimens in preclinical efficacy models of hematologic and solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B171.

Nutritional Issues with Incremental Dialysis: The Role of Low-Protein Diets.

A gentle start of dialysis is a welcome possibility for both patients and physicians. Incident dialysis patients often maintain residual kidney function (RKF) for a considerable period of time; the start of dialysis is often driven mainly by uremic symptoms. Recently, the combination of a low-protein diet, along with a less-frequent dialysis schedule, has regained interest as an alternative option in selected and motivated patients. In addition, there is renewed interest in a low-protein diet in patients with moderate to advanced chronic kidney disease (CKD). Dietary regimens have additional objectives now: obtaining better control of phosphate and potassium levels; preventing or reducing metabolic acidosis, protein catabolism, and malnutrition; and reducing uremic symptoms. In the eighties and early nineties, data from uncontrolled studies showed that combining a very low-protein diet with once weekly hemodialysis was a feasible approach. However, these diets were very demanding with poor patient compliance and had a high risk of smoldering malnutrition. However, recent experience has shown that the new protein-free foods have better palatability and nutritional properties; this has increased adherence to dietary prescriptions. Dietary regimens are now tailored to the patient's needs and habits. A multidisciplinary approach is considered crucial for updating medical needs and dietary prescriptions, ensuring adherence to the combined program, and avoiding the development of malnutrition and inadequate dialysis. Monitoring RKF is another key factor for the success of the program due to the importance of optimal timing of the transition to twice-weekly regimens and, eventually, thrice-weekly hemodialysis.

Rationale for Investigator-Assigned Prophylaxis Dosing Frequency in the Leopold I Study

The LEOPOLD I study (part B) in severe hemophilia A was a multicenter, phase II/III, open-label trial to assess the safety, tolerability, and efficacy of prophylaxis treatment with BAY 81-8973, an unmodified recombinant factor VIII product. Dose and dose frequency of the prophylaxis regimen during the study were at the investigators' discretion. A questionnaire was sent to sites poststudy to determine what elements led to the assignment of patients to a twice-weekly regimen rather than 3 times weekly. Seventeen specific questions were posed, plus 1 labeled as "other," allowing the investigator to insert a rationale not otherwise specified.Responses to the questionnaire were received for 13 of 17 patients (76%) assigned to twice-weekly prophylaxis. The 2 most frequent responses were "treatment options were discussed with the patients" (67%) and "patient preference" (61%). Additional responses in descending frequency included "prophylaxis regimen was adapted to the patient's physical activity and schedule" (28%) and "already on a twice-weekly regimen before the study," "sedentary lifestyle," "noncompliance with a 3-times-weekly regimen," and "other" (17% each). "Minimal arthropathy," "no target joints," and "patient's age" were included at 11% each.These results demonstrate that discussions between patient and doctor are appropriately considered paramount to treatment decisions. The other elements mentioned are known parameters thought to contribute to bleeding phenotype in hemophilia. DisclosuresHumphries:Bayer: Employment. Church:Bayer: Employment. Lalezari:Pfizer: Honoraria; Bayer: Honoraria; TEVA pharmaceuticals: Consultancy. Poulsen:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Investigator for Clinical Trials; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Investigator for Clinical Trials, Mentor, Speakers Bureau; SOBI: Speakers Bureau; Ferring: Speakers Bureau; Pfizer: Consultancy. Yoon:Bayer Inc: Employment. Maas Enriquez:Bayer Pharma AG: Employment.

Urinary Specific Gravity (USG) as an Assessment Tool for the Management of Dehydration in Head and Neck Cancer Patients Receiving Chemo-Radiation with Weekly Cisplatin

Background: Concomitant chemo-radiation therapy (CRT) with cisplatin is the mainstay of treatment for patients with locally advanced head and neck cancer. Nephrotoxicity is a well-documented adverse effect of cisplatin, which is exacerbated by dehydration, a common complication in this group of patients. This study prospectively assessed the utility of urine specific gravity (USG) as a guide for fluid replacement, and its preventive effect in cisplatin induced nephrotoxicity. Methods: Patients with head and neck cancer who received CRT with weekly cisplatin at our institution were included in the analysis. All patients received 1 L normal saline (NS) with 1 g of magnesium and 10 mEq of potassium pre and post cisplatin. USG was measured weekly, patients with USG>1.020 was considered dehydrated and received 2 L NS twice weekly. Those patients with USG>1.025 while on the twice-weekly regimen were deemed very dehydrated and received 2 L NS daily. The primary objective was renal toxicity of any grade. Results: 44 patients were identified and completed CRT in less than 7.5 weeks. Eighteen of 44 patients (41%) had initial USG>1.020 and were started on NS twice weekly. By week 5, 44 of 44 patients (100%) needed supplemental fluid hydration with only 4 of 44 (9%) requiring daily IV fluids (IVF). No patient experienced renal toxicity of any grade. Five patients (11%) had grade I hypomagnesemia. Conclusion: USG is a very sensitive marker of dehydration and can be used as a guide for fluid replacement which can minimize cisplatin induced nephrotoxicity in this population.

Abstract PR12: Selective targeting of MYC mRNA by chemically stabilized antisense oligonucleotides

Abstract Despite its well-characterized properties as a proto-oncogene in numerous cancers, direct potent and selective inhibition of MYC or its protein product c-Myc with cell-permeable synthetic agents remains a significant challenge. Systemic inhibition of c-Myc activity in mice by expression of dominant negative MYC transgenes has been shown to dramatically decrease tumor burden with apparently tolerable side effects (Soucek et al, Nature 2008). In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC at the transcriptional, translational, and post-translational level. Here we describe the application of synthetic antisense oligonucleotides designed to target specific sequences of the MYC mRNA (MYCASOs). We have incorporated several chemical features into MYCASOs, including the addition of locked nucleic acid (LNA) bases at the 5' and 3' ends, phosphorothioate linkers, and internal DNA bases in order to increase mRNA target affinity and cleavage, cellular permeability, stability, and systemic distribution in vivo. Treatment of MYC¬-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and c-Myc protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5' rapid amplification of cDNA ends (RACE) assay. MYCASO-treatment of cancer cell lines leads to significant inhibition of cellular proliferation and induces apoptosis in c-Myc-dependent myeloma and leukemia cell lines while decreasing c-Myc-mediated gene expression. In vivo administration of MYCASOs simply dissolved in saline was performed in mice by tail vein injection. MYCASOs are well tolerated up to 25 mg per kg on a twice-weekly dosing regimen. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment leads to detectable cleavage of the MYC transcript, decreases c-Myc levels within tumors, and significantly decreases tumor burden. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of c-Myc activity, and promising therapeutic agents for MYC-driven tumors. Citation Format: Christopher J. Ott, Raj Bandaru, Taylor Gill, Junyan Tao, Xin Chen, Yixian Zhang, James E. Bradner. Selective targeting of MYC mRNA by chemically stabilized antisense oligonucleotides. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR12.

Let us give twice-weekly hemodialysis a chance: revisiting the taboo.

Let us give twice-weekly hemodialysis a chance: revisiting the taboo.

Abstract A42: Sensitivity and resistance to a p-AKT inhibitor in an erlotinib-sensitive model for lung cancer

Abstract Activating mutations in EGFR, such as the L858R mutation, are effective predictors of response to EGFR tyrosine kinase inhibitor (TKI) therapy. While most patients initially respond to EGFR TKIs, the majority relapse within 6-12 months, underscoring the importance of identifying therapies that enhance and prolong EGFR TKI activity in patients. Agents targeting additional nodes in the EGFR pathway have the potential to overcome such resistance but single-agent activity must be understood first. We utilized mice engineered to develop erlotinib-sensitive lung adenocarcinomas driven by the human EGFR L858R mutation to evaluate the efficacy of a p-AKT inhibitor, MK-2206, currently in clinical trials for a variety of solid tumor malignancies. MK-2206 concentration and target activity were assessed in short-term PK/PD studies in both the lungs and blood of tumor-bearing mice. MK-2206 was then evaluated in an efficacy study using a twice-weekly dosing regimen, both as a single agent and in combination with other TKIs. MK-2206 alone resulted in tumor regression or tumor growth inhibition in ∼50% of the mice, but exhibited greater efficacy in combination with other upstream pathway inhibitors. Temporal evaluation of tumor growth inhibition indicated that MK-2206 was most effective at early time points and did not produce a sustained pathway and growth response as treatment continued. Analysis of gene expression changes in mice treated with MK-2006 alone vs. MK-2206 in combination with EGFR TKIs highlighted the pathways perturbed by both drugs.

Efficacy and safety of reduced-intensity induction therapy with a bortezomib-based regimen in elderly patients with multiple myeloma

The therapeutic effects of bortezomib in untreated and refractory/relapsed multiple myeloma have been demonstrated in several clinical trials, displaying superiority to the conventional treatments. However, many treatment-related toxicities, such as bone marrow suppression, infections and peripheral neuropathy, are well known and lead to treatment discontinuation and dose modification, especially in elderly patients. The purpose of this review is to summarize the published literature concerning the efficacy and safety of reduced-intensity induction therapy with bortezomib-based regimens in elderly patients with multiple myeloma. We used the VISTA trial as a reference and compared it with the seven trials identified in a systematic search. The data suggest that low-dose bortezomib significantly reduces therapy-related toxicities, especially neuropathy, and decreases the rate of discontinuation compared with the twice-weekly regimen, without losing efficacy. In light of this review, we suggest that once-weekly infusion of bortezomib in addition to melphalan-prednisone may be considered as a new standard of care in frontline treatment of elderly patients with symptomatic multiple myeloma.

Pilot Study of Twice-weekly Therapy for Pulmonary Tuberculosis in Taiwan

Taiwan has never implemented supervised intermittent chemotherapy for pulmonary tuberculosis, and its application and results are unknown. The purpose of this study was to evaluate the efficacy and feasibility of a 62-dose, four-drug, 6-month, twice-weekly regimen administered by directly observed therapy for the treatment of pulmonary tuberculosis. From January 2004 through December 2006, a total of 116 patients with suspected or confirmed pulmonary tuberculosis were enrolled. Thirty-two of these patients were excluded from the analysis because of drug resistance, negative culture, self withdrawal and drug reactions. Isoniazid, rifampin, pyrazinamide, and ethambutol were administered daily for 2 weeks, followed by twice weekly at a higher dose for 6 weeks. Thereafter, isoniazid, ethambutol and rifampin were administered twice weekly for 18 weeks. Treatment was directly observed by nurses or outreach workers. Of the 84 evaluable patients, 75 [89.3%, 95% confidence interval (CI): 80.6s-95.0%] patients were considered as successfully treated, three (3.6%, 95% CI: 0.7-10.1%) transferred out, five (6.0%, 95% CI: 2.0-13.3%) were unsuccessful and one (1.2%, 95% CI: 0.03-6.5%) died. Five patients were treatment failure (6.0%, 95% CI: 2.0-13.3%). Three patients had recurrences of pulmonary tuberculosis, and the recurrences were 4, 6 and 15 months after the completion of therapy. Sixpatients (5.2%) had severe adverse drug reactions and had their regimen modified. Prior to this study, intermittent therapy has not been attempted in Taiwan. This four-drug mostly twice-weeldy pulmonary tuberculosis treatment regimen is efficacious and relatively nontoxic, with a higher treatment success rate and a lower death rate. It considerably simplifies treatment and facilitates the execution of directly observed therapy. The reasons for the relatively high failure rate require further studies.

Randomized Comparison of the Stanford V Regimen and ABVD in the Treatment of Advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244

This multicenter, prospective, randomized controlled trial compared the efficacy and toxicity of two chemotherapy regimens in advanced Hodgkin's lymphoma (HL): the weekly alternating Stanford V and the standard, twice-weekly regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients had stage IIB, III, or IV disease or had stages I to IIA disease with bulky disease or other adverse features. Radiotherapy was administered in both arms to sites of previous bulk (> 5 cm) and to splenic deposits, although this was omitted in the latter part of the trial for patients achieving complete remission (CR) in the ABVD arm. A total of 520 patients were randomly assigned and were assessed for the primary outcome measure of progression-free survival (PFS). Five hundred patients received protocol treatment, and radiotherapy was administered to 73% in the Stanford V arm and to 53% in the ABVD arm. The overall response rates after completion of all treatment were 91% for Stanford V and 92% for ABVD. During a median follow-up of 4.3 years, there was no evidence of a difference in projected 5-year PFS and overall survival (OS) rates (76% and 90%, respectively, for ABVD; 74% and 92%, respectively, for Stanford V). More pulmonary toxicity was reported for ABVD, whereas other toxicities were more frequent with Stanford V. In a large, randomized trial, the efficacies of Stanford V and ABVD were comparable when given in combination with appropriate radiotherapy.

Efficacy of two low-dose regimens of conjugated estrogen vaginal cream in postmenopausal women with atrophic vaginitis

Efficacy of two low-dose regimens of conjugated estrogen vaginal cream in postmenopausal women with atrophic vaginitis