A lower initial dose of bosutinib for patients with chronic myeloid leukemia patients resistant and/or intolerant to prior therapy: a single-arm, multicenter, phase 2 trial (BOGI trial).

Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy.

Does lower dose pilocarpine have a role in radiation-induced xerostomia in the modern radiotherapy era? A single-center experience based on patient-reported outcome measures.

PURPOSE: This study aims to investigate the efficacy of lower dose pilocarpine in alleviating late dry mouth symptoms in head and neck cancer patients received radiotherapy. METHODS: Eighteen head and neck cancer patients experiencing persistent dry mouth were enrolled in this study. All participants started pilocarpine treatment a median of 6 months post-radiotherapy. Initially, patients received pilocarpine at 5 mg/day, with a gradual increase to the recommended dose of 15 mg/day. A Patient-Reported Outcome Measurement (PROMs) questionnaire assessed symptoms' severity related to hyposalivation. RESULTS: All patients reported symptomatic dry mouth above grade 2 before starting the medication. Pilocarpine treatment continued based on patients' self-assessment, with a median duration of 12 months (range, 3-36 months). The median daily maintenance dose was 10 mg (range, 5 to 20 mg). Total PROMs scores significantly decreased following medication, from 13 points (range 7-18 points) to 7 points (range 4-13 points) (p = 0.001). Significant improvements were observed in questions related to dry mouth (p < 0.001), water intake during eating (p = 0.01), carrying water (p = 0.01), taste (p < 0.001), and water intake during speech (p < 0.001). Initial and maintenance doses of pilocarpine were lower, and the duration of pilocarpine usage was shorter in patients treated with intensity-modulated radiation therapy compared to conformal radiotherapy (12 months vs. 25 months, p = 0.04). CONCLUSION: Pilocarpine may be considered at doses lower for late-term dry mouth. With modern radiotherapy techniques effectively preserving the parotid gland, short-term use may be recommended in these patients. Future studies may enhance the development of a more robust patient selection criteria model.

Budget and health impact of switching eligible patients with atrial fibrillation to lower- dose dabigatran.

Objectives: To assess the comparative budget and health impact of lower-dose dabigatran versus reduced doses of apixaban and rivaroxaban in atrial fibrillation (AF) patients eligible for a lower-/reduced-dose due to individual patient characteristics in the Netherlands. Methods: A budget impact model was developed in accordance with ISPOR guidelines. A 3-year-time horizon was considered, and analyses were conducted from a Dutch healthcare payer's perspective. The model applies published data to local AF-epidemiology, allowing calculations to estimate clinical events (strokes and haemorrhages) and costs. The analyses were based on real-world outcomes from patients with AF receiving a first direct oral anticoagulant (DOAC) prescription for low-dose dabigatran (110 mg) and a reduced dose of apixaban (2.5 mg) or rivaroxaban (15 mg). Two situations of switching treatments from one to another DOAC were modelled: switching from apixaban to dabigatran and from rivaroxaban to dabigatran. Base case results were given as savings per 100 patient-year, per total Dutch population, and events avoided. A univariate sensitivity analysis was conducted to explore the uncertainty around epidemiological and event costs input data. Scenario analyses were performed to estimate the effect of different market shares and potential price reductions due to future patent expiry for the total real-world population from the Netherlands. Results: The 3-years outcomes of switching patients eligible for a lower-/reduced-dose due to individual patient characteristics from apixaban or rivaroxaban to dabigatran resulted in cost savings estimated at €157 or €72 thousand per 100 patient-years, respectively, or €146 million per total Dutch population. Looking into the clinical events, dabigatran reflected the lowest number of mortalities, ischemic strokes, major bleeding, non-major bleeding, and haemorrhagic stroke compared to apixaban and rivaroxaban. The sensitivity analysis consistently reflected cost savings, with the ischeamic stroke events having the biggest impact. Accounting for the Dutch situation, both scenarios showed total savings ranging from €45 to €229 million over 3 years. Conclusions: Switching eligible AF-patients from reduced-dose apixaban or rivaroxaban to lower-dose dabigatran has the potential to reduce healthcare payer's budget expenditures and provide health gains. Cost savings can potentially be further enhanced by market share adjustments and further price reductions.

Attenuated Dose Dasatinib in Newly Diagnosed Chronic Myeloid Leukemia Chronic Phase Patients in India.

BACKGROUND: BCR-ABL Tyrosine kinase inhibitors (TKI's) are most successful of targeted therapies and are currently considered the cornerstone in the management of patients with chronic myeloid leukemia (CML). A recent study reported excellent outcomes of Dasatinib 50mg with better sustained response. Therefore, we aim to evaluate the molecular responses and safety of upfront Dasatinib 50mg in Indian CML-Chronic Phase patients. METHODS: It was an observational single-centre study. CML-CP patients started on Dasatinib 50mg daily were offered to participate in this study. Data of imatinib was collected retrospectively as a comparator group. RESULTS: Between June 2020 to Feb 2022, fifty patients were included in the dasatinib 50mg once daily group. Median age was 40 yrs. ranging from (19 to73) years. At a median follow up of 9.2 months, 49 patients completed three months treatment, out of which 48 patients were evaluated as one patient stopped medication after a month due to financial constraints. The response rate at three months for dasatinib 50mg daily and Imatinib were 68.75% and 69.7% respectively. At 12 months, 68% and 66.6% patients achieved major molecular response [MMR] in dasatinib 50mg and imatinib groups respectively. CONCLUSION: In conclusion, low dose dasatinib is safe and effective as an upfront therapy in CML-CP. Early molecular response [EMR] rates were comparable in low dose dasatinib and imatinib arm but deep molecular responses were significantly higher in low dose dasatinib arm. Dasatinib, taken daily at a dose of 50mg, may offer a new, alternative choice as generic versions are available now for frontline therapy in CML-CP.

Lower-dose psycholytic therapy - A neglected approach.

Lysergic acid diethylamide (LSD) and similar psychoactive drugs have been used in psychotherapy since 1949, when the first clinical study with lower-dose LSD showed therapeutically relevant effects. This caused an intense interest among psychotherapists and researchers, alike, on an international scale. In 1960, the use of serial lower-dose LSD/psilocybin sessions in a psychoanalytical framework, which was dominant at the time, was named "psycholytic therapy". Psycholytic therapy was usually conducted in clinical environments, on both an inpatient and outpatient basis. Psycholytic therapy was developed and established over a 15-year period on the European continent, where it was used at 30 clinical treatment centers and by more than 100 outpatient psychotherapists. Psycholytic approaches were employed minimally in North America, where the psychedelic approach (use of one or two high-dose sessions for "personality-transforming mystical experiences") became the dominant method in use. The leading figure in psycholytic therapy was Professor Hanscarl Leuner in Germany, who laid the ground with his uniquely fine grained analysis of the LSD reaction in a 1962 monograph. He was central in establishing and distributing psycholytic therapy in Europe and abroad. The article provides comprehensive background information and outlines the essential features of psycholytic therapy. Evidence for the efficacy of psycholytic therapy is reviewed and a case for the inclusion of the psycholytic approach in the field of substance-assisted psychotherapy is made.

Clinical outcomes of patients who received a lower dose of non-vitamin K antagonist oral anticoagulants for the medical management of acute pulmonary embolism.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are used to treat acute pulmonary embolism (PE). However, lower NOAC doses are often prescribed because of increased risk of NOAC complications. OBJECTIVE: We sought to determine the incidence and clinical outcomes of patients with acute provoked PE receiving lower NOAC doses. METHOD: 140 patients with acute PE with only NOACs used for medical management was enrolled and were followed up for 6 months. The composite primary endpoint was all-cause death, venous thromboembolism recurrence, and residual thrombus on follow-up computed tomography. RESULTS: Of the 140 patients, 99 (70.7%) received the standard NOAC dose and 41 (29.3%) received the lower dose. The crude incidences of the primary endpoint were 19 (19.2%) in patients who received the standard NOAC dose and 13 (31.7%) in those who received the lower dose. Compared with patients who received the standard dose, those who received the lower dose had no differences in the rate of primary endpoints (hazard ratio 1.140, 95% confidence interval 0.536-2.423, p = 0.733) during a median of 185 days. CONCLUSION: We found that up to 30% of patients received the lower dose of NOACs for acute PE in clinical practice. Clinical outcomes with appropriate underdoing of NOAC treated in acute PE might not increase compared to the standard NOAC doses.

Lower dose of ethambutol may reduce ocular toxicity without radiological deterioration for Mycobacterium avium complex pulmonary disease.

BACKGROUND: Ethambutol ocular toxicity is a major problem during combination chemotherapy for Mycobacterium avium complex (MAC) pulmonary disease (MAC-PD) due to years-long therapy for MAC. OBJECTIVES: This study aimed to identify the lower dose of daily ethambutol that can reduce ocular toxicity. METHODS: We retrospectively reviewed the medical records of 312 patients who visited The University of Tokyo Hospital between January 2007 and December 2017 for nontuberculous mycobacterial pulmonary disease. Seventy-six patients with MAC-PD who were treated with combination chemotherapy for the first time were analyzed in this study. RESULTS: Ethambutol was discontinued because of visual symptoms in 13 patients (17%), 7 of whom were diagnosed with ethambutol ocular neuropathy. The dose per body weight was significantly higher in patients who developed ocular neuropathy than in those who did not (15.4 mg/kg/d vs. 12.5 mg/kg/d, respectively; p = 0.048). We assigned patients to higher or lower dose groups according to the median dose of 12.5 mg/kg/d. Although ocular neuropathy developed in 6 out of 38 patients in the higher dose group, ocular neuropathy developed in 1 out of 38 patients in the lower dose group (16% vs. 3%, respectively; p = 0.038). The failures of sputum culture conversion and radiological improvement were not significantly different between the two groups (p = 0.638 and 0.305, respectively). Macrolide resistance developed in one patient per group during follow-up (3% per group, p = 0.945). CONCLUSIONS: A lower dose of ethambutol may reduce ocular toxicity without radiological deterioration for pulmonary MAC infection.

[Relationship between Dose Discontinuation or Dose Reduction for Safety Reasons in Clinical Trials and Lower-dose Prescriptions in the Post-marketing Setting].

Dosage of pharmaceuticals is determined and approved based on pivotal clinical trial results in Phase 3. However, in the post-marketing setting, it is often adjusted according to conditions of individual patients. Some pharmaceuticals are used at a lower dose than the approved dose for safety reasons or in elderly patients. In this study, we examined the relationships between dose discontinuation or dose reduction, for safety reasons as well as participation of elderly patients in clinical trials, and lower-dose prescriptions in the post-marketing setting. We collated the dataset of 113 eligible pharmaceuticals from those that were approved in Japan between 2005 and 2014. Subsequently, we calculated the proportions of patients who withdrew from the study, whose medication was discontinued, or dose reduced due to adverse events, and of elderly patients (over sixty-five years old) to those who were exposed to the approved dose range in the pivotal clinical trials. Then their relationships with lower-dose prescription in the post-marketing setting were examined using Mann-Whitney U test. The proportions of patients who withdrew from the study (p=0.0019), whose medication was discontinued owing to adverse events (p=0.0007), or whose dose was reduced owing to adverse events (p<0.0001) were significantly higher for "lower-dose prescription drugs" than those for other drugs; however, the proportion of elderly patients did not show this significant increase in the "lower-dose prescription drugs" group.

Efficacy and Tolerability of Erlotinib 100 mg/d vs. Gefitinib 250 mg/d in EGFR-Mutated Advanced Non-small Cell Lung Cancer (E100VG250): An Open-Label, Randomized, Phase 2 Study.

Background: Erlotinib-based combination therapy leads to increased efficacy but also toxicity for EGFR-mutated NSCLC. Reducing the dose of erlotinib could improve treatment tolerability, but few evidences are available regarding its efficacy at reduced dose. This randomized phase-2 study intends to compare the efficacy and tolerability between lower dose erlotinib (100 mg/d) and standard dose gefitinib (250 mg/d) in EGFR-mutated NSCLC. Methods: Patients with EGFR-mutated advanced NSCLC were randomized at 1:1 ratio to receive erlotinib 100 mg/d or gefitinib 250 mg/d until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR). Results: Between April 2013 and September 2018, 171 patients were randomized to receive erlotinib (n = 85) and gefitinib (n = 86); 74 in the erlotinib group and 83 in the gefitinib group were include in analysis. DCR with erlotinib and gefitinib were 91% [95% CI 81.7-95.3] and 93% [85.1-96.6], respectively (P = 0.613). Response rate was 62% [50.8-72.4] in the erlotinib group and 53% [42.4-63.4] in the gefitinib group (P = 0.247). No significant difference was observed between erlotinib and gefitinib in median progression-free survival [10.1 vs. 11.3 months, HR = 1.295 [0.893-1.879], P = 0.171] and median overall survival [26.6 vs. 28.7 months, HR = 0.999 [0.637-1.569], P = 0.998]. Subgroup analyses by line of treatment, EGFR subtypes and status of central nervous system (CNS) metastasis found similar results. More toxicity [any-grade, 80 [96%] vs. 66 [89]; grade 3-4, 11 [13%] vs. 4 [5%]] and toxicity-related discontinuation [10 [12%] vs. 3 [4%]] occurred with gefitinib compared with erlotinib. But no significant difference was observed. Conclusion: Lower dose erlotinib (100 mg/d) achieved comparable efficacy compared with standard dose gefitinib (250 mg/d) in EGFR-mutated NSCLC. Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT01955421.

Pharmacogenomics and pharmacokinetics of efavirenz 400 or 600 mg in 184 treatment-naive HIV-infected patients in China.

Background: The pharmacogenomics and pharmacokinetics/pharmacodynamics of 400 mg efavirenz have rarely been reported. Materials & methods: A total of 184 treatment-naive HIV-infected patients were randomly assigned (1:1) to receive a lower dose (tenofovir disoproxil 200 mg, efavirenz 400 mg and lamivudine) or a standard dose regimen. Relationships between pharmacogenomics and efavirenz pharmacokinetics/pharmacodynamics were explored at 48 weeks. Results: There was no relationship between pharmacogenomics and adverse reactions of the central nervous system and antiretoviral efficacy. CYP2B6 516G>T, 785A>G, 18492C>T and ABCB1 3435C>T T/C were associated with higher efavirenz plasma levels in the standard but not the lower dose group. No relationship was found between pharmacogenomics and antiretoviral efficacy. Patients who were <60 kg had higher efavirenz concentration compared with those with weight ≥60 kg when using 600 mg efavirenz, this was not observed with 400 mg efavirenz. Conclusion: The effect of pharmacogenomics and body weight on the efavirenz concentration was significant in the 600 mg group but not in the 400 mg group.

Evaluation of pharmacokinetic, pharmacodynamic, efficacy, and safety data of low-dose ticagrelor versus standard dose in East Asians: a systematic review.

East Asians are prone to higher systemic exposure and increased risk of bleeding compared to other races after administration of antiplatelet agent(s). The aim of this systematic review was to compare and evaluate the appropriateness of a lower dose versus standard dose of ticagrelor in East Asians. A systematic search was conducted in PubMed, EMBASE, and Cochrane databases for studies comparing low versus standard doses of ticagrelor in East Asian populations; a total of seven studies were included in the review. Pharmacokinetic (PK), pharmacodynamic (PD), clinical efficacy, and safety data were collected. PK data demonstrated that the Cmax and area under the curve (AUC) of ticagrelor increased dose-proportionally. PD data indicated that while the low dose of ticagrelor resulted in less antiplatelet activity in three of the five PD studies, in the other studies, there were no differences between low and standard doses. There were two clinical studies included in this review, which showed that the efficacy was similar between the low and standard doses, but both studies were limited by the number of patients included. While there were generally greater incidence of adverse events observed in the standard ticagrelor dose, the magnitude or actual difference between the two doses is difficult to determine due to lack of consistent data. In East Asians, the appropriateness of the low-dose ticagrelor cannot be determined based on the currently available evidence. Additional large-scale and longer duration studies are warranted.

Effectiveness of injecting lower dose subcutaneous sterile water versus saline to relief labor back pain: Randomized controlled trial.

INTRODUCTION: The aim of this study was to investigate the effect of a lower dose subcutaneous sterile water injection technique versus subcutaneous saline injection, on the relief of low-back pain for women during childbirth, and to explore the lasting effects of pain relief after administration (followed at 15, 30, 45, 90 and 120 minutes). METHODS: A prospective randomized controlled single-blinded study was conducted, with trial registration (NCT02813330). Women received one-time injections (sterile water or saline) and the effectiveness was observed at 15, 30, 45, 90 and 120 minutes after the intervention. RESULTS: The intervention group had statistically significant pain reduction. Assessment of subsequent pain, followed at 30, 45, 90 and 120 minutes, reflected an increasing change with a statistically significant difference. The intervention group had more burning sensations than the control group with a statistically significant difference. CONCLUSIONS: The modified technique of double injections of subcutaneous 'water/ saline' resulted in significant relief of low-back pain during childbirth.

Is it reasonable to use a lower DOACs dose in some patients with VTE? Yes.

In the Hokusai-VTE trial, 733 patients were treated with the reduced dose edoxaban regimen, which maintained efficacy and safety compared with the 60 mg dose, and was safer than warfarin. The prophylactic doses of apixaban and rivaroxaban reduced the risk of recurrent venous thromboembolism (VTE) in the extended treatment trials. Dabigatran 110 mg was approved by the European Medicine Agency for VTE treatment. Further data from registries and real-world studies will help to clarify whether patients, with other specific characteristics, can benefit from the reduced dose of direct oral anticoagulants.

Comparing two lower-dose cisplatin programs for radio-chemotherapy of locally advanced head-and-neck cancers.

Radio-chemotherapy is a common treatment for locally advanced squamous cell head-and-neck cancers (LA-SCCHN). Cisplatin (100 mg/m2) every 3 weeks is very common but associated with considerable toxicity. Therefore, cisplatin programs with lower daily doses were introduced. There is a lack of studies comparing lower-dose programs. In this study, 85 patients receiving radio-chemotherapy with 20 mg/m2 cisplatin on 5 days every 4 weeks (group A) were retrospectively compared to 85 patients receiving radio-chemotherapy with 30-40 mg/m2 cisplatin weekly (group B). Groups were matched for nine factors including age, gender, performance score, tumor site, T-/N-category, surgery, hemoglobin before radio-chemotherapy, and radiation technique. One- and 3-year loco-regional control rates were 83 and 69 % in group A versus 74 and 63 % in group B (p = 0.12). One- and 3-year survival rates were 93 % and 73 % in group A versus 91 and 49 % in group B (p = 0.011). On multivariate analysis, survival was significantly better for group A (HR 1.17; p = 0.002). In groups A and B, 12 and 28 % of patients, respectively, did not receive a cumulative cisplatin dose ≥180 mg/m2 (p = 0.016). Toxicity rates were not significantly different. On subgroup analyses, group A patients had better loco-regional control (p = 0.040) and survival (p = 0.005) than group B patients after definitive radio-chemotherapy. In patients receiving adjuvant radio-chemotherapy, outcomes were not significantly different. Thus, 20 mg/m2 cisplatin on 5 days every 4 weeks resulted in better loco-regional control and survival in patients receiving definitive radio-chemotherapy and may be preferable for these patients. Confirmation of these results in a randomized trial is warranted.

A double blind randomised controlled trial comparing standard dose of iron supplementation for pregnant women with two screen-and-treat approaches using hepcidin as a biomarker for ready and safe to receive iron.

BACKGROUND: Until recently, WHO recommended daily iron supplementation for all pregnant women (60 mg/d iron combined with 400ug/d folic acid) where anaemia rates exceeded 40 %. Recent studies indicate that this may pose a risk to pregnant women. Therefore, there is a need to explore screen-and-treat options to minimise iron exposure during pregnancy using an overall lower dosage of iron that would achieve equivalent results as being currently recommended by the WHO. However, there is a lack of agreement on how to best assess iron deficiency when infections are prevalent. Here, we test the use of hepcidin a peptide hormone and key regulator of iron metabolism, as a potential index for 'safe and ready to receive' iron. DESIGN/METHODS: This is a 3-arm randomised-controlled proof-of-concept trial. We will test the hypothesis that a screen-and-treat approach to iron supplementation using a pre-determined hepcidin cut-off value of <2.5 ng/ml will achieve similar efficacy in preventing iron deficiency and anaemia at a lower iron dose and hence will improve safety. A sample of 462 pregnant women in rural Gambia will be randomly assigned to receive: a) UNU/UNICEF/WHO international multiple micronutrient preparation (UNIMMAP) containing 60 mg/d iron (reference arm); b) UNIMMAP containing 60 mg/d iron but based on a weekly hepcidin screening indicating if iron can be given for the next 7 days or not; c) or UNIMMAP containing 30 mg/d iron as in (b) for 12 weeks in rural Gambia. The study will test if the screen-and-treat approach is non-inferior to the reference arm using the primary endpoint of haemoglobin levels at a non-inferiority margin of 0.5 g/dl. Secondary outcomes of adverse effects, compliance and the impact of iron supplementation on susceptibility to infections will also be assessed. DISCUSSION: This trial is expected to contribute towards minimising the exposure of pregnant women to iron that may not be needed and therefore potentially harmful. If the evidence in this study shows that the overall lower dosage of iron is non-inferior to 60 mg/day iron, this may help decrease side-effects, improve compliance and increase safety. The potential for the use of hepcidin for a simple point-of-care (PoC) diagnostic for when it is most safe and effective to give iron may improve maternal health outcomes. TRIAL REGISTRATION: ISRCTN21955180.

Chemoradiation of locally advanced squamous cell carcinoma of the head-and-neck (LASCCHN): Is 20mg/m(2) cisplatin on five days every four weeks an alternative to 100mg/m(2) cisplatin every three weeks?

OBJECTIVES: To compare chemoradiation with 100mg/m(2) cisplatin every three weeks to 20mg/m(2) on five days every four weeks for locally advanced squamous cell carcinoma of the head-and-neck (LASCCHN). MATERIALS AND METHODS: In 230 patients receiving chemoradiation for LASCCHN, 100mg/m(2) cisplatin every three weeks (N=126) and 20mg/m(2) cisplatin on five days every four weeks (N=104) were retrospectively compared. Chemoradiation plus eleven characteristics (T-/N-classification, performance score, gender, age, tumor site, grading, surgery, radiation technique, pre-chemoradiation hemoglobin, cumulative cisplatin dose) were analyzed for locoregional control (LRC), metastases-free survival (MFS) and overall survival (OS). Chemoradiation groups were compared for adverse events. RESULTS: On univariate analyses, chemoradiation had no impact on LRC (p=0.53), MFS (p=0.67) and OS (p=0.14). On multivariate analysis of LRC, T-classification (p=0.045) and hemoglobin (p<0.001) were significant. On multivariate analysis of MFS, performance score (p=0.028) was significant. On multivariate analysis of OS, performance score (p=0.009) and hemoglobin levels (p=0.002) achieved significance. Chemoradiation with 100mg/m(2) cisplatin was associated with more pneumonia/sepsis (p=0.003), grade ⩾2nausea/vomiting (p<0.001), grade ⩾2 nephrotoxicity (p=0.005), grade ⩾2 xerostomia (p=0.002), grade ⩾3 hematotoxicity (p=0.052) and grade ⩾2 ototoxicity (p=0.048). CONCLUDING STATEMENT: 20mg/m(2) cisplatin on five days every four weeks was associated with fewer adverse events than 100mg/m(2) cisplatin every three weeks. 100mg/m(2) cisplatin was not significantly superior to 20mg/m(2) cisplatin regarding LRC, MFS and OS. Given the limitations of a retrospective study, 20mg/m(2) cisplatin appeared preferable. The results should be confirmed in a randomized trial.

Extreme hydronephrosis due to uretropelvic junction obstruction in infant (case report).

BACKGROUND: Hydronephrosis is the one of the most common congenital abnormalities of urinary tract. The left kidney is more commonly affected than the right side and is more common in males. AIM OF THE STUDY: To determine the role of ultrasonography, renal dynamic scintigraphy and lowerdose computed tomography urography in preoperative diagnostic workup of infant with extreme hydronephrosis. CASE REPORT: We presented the boy with antenatally diagnosed hydronephrosis. In serial, postnatal ultrasonography, renal scintigraphy and computed tomography urography we observed slightly declining function in the dilated kidney and increasing pelvic dilatation. Pyeloplasty was performed at the age of four months with good result. CONCLUSIONS: Results of ultrasonography and renal dynamic scintigraphy in child with extreme hydronephrosis can be difficult to asses, therefore before the surgical procedure a lower-dose computed tomography urography should be performed.

A comparison of toxicity profiles between the lower and standard dose capecitabine in breast cancer: a systematic review and meta-analysis.

Capecitabine 1000 mg/m(2) bid × 14 days every 21 days (14/21) has been reported to have similar efficacy but more favorable toxicity profile than the approved dosage of 1250 mg/m(2). However, a dose-toxicity relationship of capecitabine in breast cancer patients has not been fully elucidated. We performed a systematic review and meta-analysis to compare a safety profile between capecitabine starting dose of 1000 and 1250 mg/m(2) bid. Studies were identified using PubMed, ASCO, and San Antonio Breast Cancer Symposium abstract databases through December 2015. Eligible trials included phase II/III trials of capecitabine monotherapy at 1000 or 1250 mg/m(2) bid (14/21) for breast cancer patients that reported adequate safety data for all (grade 1-4) or high (grade 3-4) grade hand foot syndrome (HFS), diarrhea, fatigue, nausea, vomiting, stomatitis, neutropenia, thrombocytopenia, or anemia, as well as dose reductions, treatment discontinuation or treatment-related deaths. The summary incidence was calculated using random-effects models. A total of 4833 patients from 34 trials were included. 1218 and 3615 patients were treated with capecitabine 1000 and 1250 mg/m(2) bid, respectively. A significantly lower incidence of dose reduction (15.9 vs. 39.0 %; P = 0.007), high-grade HFS (12.0 vs. 19.0 %; P = 0.01), diarrhea (5.3 vs. 9.1 %; P = 0.01), and neutropenia (1.8 vs. 7.3 %; P < 0.01), and all-grade neutropenia (5.8 vs. 25.4 %; P = 0.01) was seen in capecitabine 1000 mg/m(2) compared to 1250 mg/m(2). Capecitabine monotherapy at 1000 mg/m(2) bid (14/21) has a clinically meaningful and significantly better toxicity profile compared to 1250 mg/m(2) bid (14/21).

An open-label, single-arm, phase I/II study of lower-dose decitabine based therapy in patients with advanced hepatocellular carcinoma.

PURPOSE: We conducted this phase I/II clinical trial to determine the safety and efficacy of lower-dose decitabine based therapy in pretreated patients with advanced HCC. EXPERIMENTAL DESIGN: Patients with advanced HCC were eligible. The administered dose of decitabine was 6 mg/m2/d intravenously on days 1 to 5 of a 28-day cycle. Additional therapies were given based on their disease progression status. The endpoint was to ensure the safety, hepatotoxicity, clinical responses, progression-free survival (PFS) and pharmacodynamics assay of lower-dose decitabine. RESULTS: Fifteen patients were enrolled. The favorable adverse events and liver function profiles were observed. The most beneficial responses were 1 complete response (CR), 6 stable disease (SD) and 8 progressive disease (PD). MRI liver scans post-treatment indicated a unique and specific characteristic. The immunohistochemistry result from the liver biopsy exhibited noteworthy CTL responses. Median PFS was 4 months (95% CI 1.7, 7), comparing favorably with existing therapeutic options. Expression decrement of DNMT1 and global DNA hypomethylation were observed in PBMCs after lower-dose decitabine treatment. CONCLUSION: The lower-dose decitabine based treatment resulted in beneficial clinical response and favorable toxicity profiles in patients with advanced HCC. The prospective evaluations of decitabine administration schemes and tumor tissue-based pharmacodynamics effect are warranted in future trials.

Predictors of response to tiotropium versus salmeterol in asthmatic adults.

BACKGROUND: Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described. OBJECTIVE: We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response. METHODS: Data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute's Asthma Clinical Research Network's Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV1, morning peak expiratory flow (PEF), and asthma control days (ACDs). RESULTS: Although approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n = 90 and 78, respectively) and ACDs (n = 49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (n = 104) than salmeterol (n = 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P < .001) and morning PEF (odds ratio, 2.12; 95% CI, 1.12-4.01; P = 0.021), as did a decreased FEV1/forced vital capacity ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in FEV1/forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not. CONCLUSION: Although these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy.