Increased risk of hypocalcemia with decreased kidney function in patients prescribed bisphosphonates based on real-world data from the MID-NET® in Japan: a new-user cohort study.

BACKGROUND: In the post-marketing stage, cases of hypocalcemia associated with bisphosphonate preparations (BPs) have been reported in patients with decreased kidney function, despite warning against use of BPs in such patients in the package insert (PI) of Japan. The purpose of this study was to investigate the safety of BPs in patients with decreased kidney function. METHODS: The cohort study was conducted in patients with osteoporosis and newly prescribed bisphosphonate utilizing real-world data from MID-NET® in Japan. The adjusted hazard ratios (aHRs) for hypocalcemia (a corrected serum Ca level < 8.00 mg/dL) relative to the normal group were calculated in each decreased kidney function group (mild, moderate or severe group). RESULTS: A total of 14,551 patients were included in the analysis, comprising 2,601 (17.88%) with normal (eGFR ≥ 90 mL/min/1.73m2), 7,613 (52.32%) with mild (60 ≤ eGFR < 90 mL/min/1.73m2), 3,919 (26.93%) with moderate (30 ≤ eGFR < 60 mL/min/1.73m2), and 418 (2.87%) with severe kidney function (eGFR < 30 mL/min/1.73m2). The aHRs (95% confidence interval) for hypocalcemia were 1.85 (0.75-4.57), 2.30 (0.86-6.21), and 22.74 (8.37-61.78) in the mild, moderate, and severe groups, respectively. The increased risk of hypocalcemia depending on kidney function was also observed even when calculating the aHR for each specific BP such as alendronate sodium hydrate, minodronic acid hydrate, and sodium risedronate hydrate. Furthermore, similar results were obtained in the sensitivity analysis by altering the outcome definition to a 20% or more reduction in corrected serum Ca level from the baseline, as well as when focusing on patients with more than one laboratory test result per 30 days during the follow-up period. CONCLUSIONS: These findings suggest that the risk of hypocalcemia during BP prescription is higher in patients with decreased kidney function, particularly those with severely decreased kidney function. The quantitative real-world evidence on the safety risk of BPs obtained in this study has led to the PI revision describing a relationship between hypocalcemia risk and decreased kidney function as a regulatory action in Japan and will contribute to promoting the proper use of BPs with appropriate risk management in clinical practice.

Recent Status of Phase I Clinical Trials for Brain Tumors: A Regulatory Science Study of Exploratory Efficacy Endpoints.

BACKGROUND: Appropriate exploratory efficacy data from Phase I trials are vital for subsequent phases. Owing to the uniqueness of brain tumors (BTs), use of different strategies to evaluate efficacy is warranted. We studied exploratory efficacy evaluation in Phase I trials involving BTs. METHODS: Using Clarivate's Cortellis™, 42 Phase I trials of BT interventions conducted from 2020 to 2022 were analyzed for efficacy endpoints, which were set as primary endpoints (PEs) or secondary endpoints (SEs). Additionally, these metrics were compared in two subgroups: trials including only BTs (Group-A) and those including BTs among mixed solid tumors (Group-B). RESULTS: Selected studies included a median of 1.5 PEs (range, 1-6) and 5 SEs (range, 0-19). Efficacy endpoints were included as PEs and SEs in 2 (5%) and 31 (78%) trials, respectively. Among the latter 31 trials that included 94 efficacy endpoints, 24, 22, 20, 9, and 8 reflected overall response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and disease control rate (DCR), respectively. ORR for BT was determined using various methods; however, the Response Evaluation Criteria in Solid Tumors (RECIST) was used less frequently in Group-A than in Group-B (p = 0.0039). CONCLUSIONS: Recent Phase I trials included efficacy endpoints as SEs, with ORR, PFS, or OS included in ~ 50% trials and DOR or DCR in ~ 25%. No established criteria exist for imaging evaluation of BTs. Phase I trials involving mixed solid tumor cohorts revealed challenges in designing methods to assess the exploratory efficacy of BTs.

Efficacy Endpoints in Phase II Clinical Trials for Meningioma: An Analysis of Recent Clinical Trials.

BACKGROUND: Response Evaluation Criteria in Solid Tumors (RECIST)-based response rates are commonly used as efficacy endpoints in phase II clinical trials for solid tumors. However, no consensus has been reached concerning adequate efficacy endpoints for phase II clinical trials targeting meningioma. Irregularity of lesions after resection, and varying degrees of dysplasia and histologic subtypes make establishing an appropriate efficacy evaluation difficult. METHODS: We analyzed primary efficacy endpoints (PEEs) and background factors from 48 trials retrieved from ClinicalTrials.gov ( https://clinicaltrials.gov/ ) using the search criteria "meningioma," "interventional," "phase II," and "study start 4/1/2001 to 3/31/2021." Primary purpose of the study was efficacy endpoint setting in overall population and three subgroups. RESULTS: Among 45 PEEs set in the 39 trials included; 33 trials with single PEE, and six trials with double PEEs, 17/45 (38%) trials adopted progression-free survival (PFS) rate, 15/45 (33%) trials response rate (seven Macdonald criteria or modified, three RECIST, three volumetric estimation, one RANO criteria, one unknown), 10/45 (22%) PFS, 1/45 (2%) OS, and 2/45 (4%) other endpoints. Although 26 PEEs were time-to-event endpoints, 19 of the 26 PEEs were single-arm studies. CONCLUSIONS: Time-to-event efficacy endpoints were often compared to historical data, and two-dimensional evaluation is more suitable than one-dimensional one. Accumulation of prognostic data is essential to standardize time-to-event efficacy endpoints. Considering the difficulty of setting design for phase II clinical studies targeting meningioma, evaluation might be done with multiple efficacy endpoints.

Analysis and enhancement of risk management for ethnic differences in antineoplastic drugs in Japan.

BACKGROUND: Risk management in the post-marketing phase is crucial to minimize health problems caused by drugs. Because ethnic factors may affect drug safety, the objective of this study was to explore concrete approaches to reflecting ethnic factors in risk management under multi-regional drug development. METHODS: We assessed Pharmaceuticals and Medical Devices Agency (PMDA) review reports on antineoplastic drugs approved as new molecular entities in the last 10 years to identify any differences in the incidence of adverse drug reactions (ADRs) related to myelosuppression, hepatic impairment, renal impairment, and interstitial lung disease between Japanese and non-Japanese populations. In addition, we investigated how those ADRs were handled in the labeling of each drug. RESULTS: In total, 44 drugs were available for comparing the incidence of ADRs between Japanese and non-Japanese populations. Of these, 32 drugs had a higher incidence of ADRs in the Japanese population. However, the incidence of ADRs in the Japanese population was described in the labeling for 7 drugs, and only the incidence in the overall population in multi-regional phase III trials was described in the labeling for the remaining 25 drugs. Of these 25 drugs, two drugs were immediately placed under emergency safety control measures after approval because of the high incidence of ADRs in Japanese patients. CONCLUSIONS: For drugs that might cause serious ADRs and with a higher incidence in the Japanese population, information should be provided on the incidence in the Japanese population as well as in the overall population.

Transcatheter aortic valve implantation under lower activated clotting time in a patient with hemorrhagic gastric cancer: a case report.

BACKGROUND: Perioperative management of transcatheter aortic valve implantation (TAVI) in patients with a high risk of bleeding requires careful consideration. CASE PRESENTATION: A 74-year-old man complained of chest pain and was admitted to our hospital. Close examination revealed severe aortic stenosis (AS) and hemorrhagic gastric cancer. Hemorrhage from gastric cancer was controlled using endoscopic hemostasis. While both gastric cancer and AS required surgery, we decided to perform transfemoral transcatheter aortic valve implantation (TAVI) under monitored anesthesia. To reduce bleeding from gastric cancer, we carefully adjusted the heparin dose to maintain the activated clotting time (ACT) between 180 and 200 s. TAVI with a balloon-expandable valve was completed without thrombotic complications. Laparoscopic distal gastrectomy was performed on the 6th day after TAVI. CONCLUSIONS: We report the successful management of TAVI in a patient with hemorrhagic gastric cancer. In TAVI for patients with hemorrhagic diseases, careful consideration of antithrombotic therapy is required.

Assessing the Risk of Decrease in Kidney Function in Patients Prescribed Direct-Acting Antivirals for Hepatitis C Utilizing the MID-NET® Medical Information Database Network in Japan.

An association between kidney disease and direct-acting antivirals against hepatitis C (DAAs) has been suggested, however the warning on the package insert (PI) of the drug varies among DAAs. In this study, the risk of decreased kidney function associated with DAAs marketed in Japan was investigated to determine whether the risk of kidney disease is a common adverse event and class effect of DAAs. Data for patients who were new users of DAAs marketed in Japan, with eGFR ≥ 45 mL/min/1.73 m2 and without specific risk factors, were extracted from the MID-NET® medical information database network in Japan. Changes from the baseline on estimated glomerular filtration rate (eGFR) categories (eGFR ≥ 90, 90 > eGFR ≥ 60, 60 > eGFR ≥ 45, 45 > eGFR ≥ 30, 30 > eGFR ≥ 15, 15 > eGFR; unit: mL/min/1.73 m2) were used for evaluating the risk of decreased kidney function. Exposure groups for DAAs and relevant concomitant drugs were categorized into 10 patterns based on the PI. Among the 10 patterns, a significant increase in the incidence rate ratio (P < 0.01) was observed in the prescription patterns of concomitant use of telaprevir with peginterferon alpha and ribavirin, concomitant use of daclatasvir hydrochloride with asunaprevir, and ombitasvir hydrate combined with paritaprevir hydrate and ritonavir, which were concomitantly used with ribavirin; such an increase was not observed in the other prescription patterns. The effects of DAAs on kidney function may differ among drugs, suggesting the possibility that the risk of kidney disease is not a class effect of DAAs and should be evaluated individually for each DAA.

Thoracoscopic infrared ablation to create a box lesion as a treatment for atrial fibrillation.

BACKGROUND: Creating a box lesion in the posterior wall of the left atrium from the epicardial side of the beating heart remains a challenge. Although a transmural lesion can be created by applying radiofrequency (RF) energy at clampable sites, it is still difficult to create a transmural lesion at unclampable sites because the inner blood flow in the unclampable free wall weakens the thermal effect on the outside. Our aim was to apply the newly developed infrared coagulator to create linear transmural lesions on the beating heart thoracoscopically to treat atrial fibrillation (AF). CASE PRESENTATION: A 71-year-old male was referred to our hospital with a diagnosis of hypertrophic cardiomyopathy and permanent atrial fibrillation. The patient was first diagnosed with atrial fibrillation 20 years before. Direct current cardioversion had been performed every few years a total of four times, but sinus rhythm restoration had always been temporary. On February 27, 2020, thoracoscopic PV isolation together with infrared roof- and bottom-line ablation to create a box lesion and left atrial appendage amputation (LAAA) were performed. The coagulator could be applied to clinical thoracoscopic surgery to successfully create a box lesion without any complication. The patient restored a regular sinus rhythm, it has been maintained for eleven months, and there have been no adverse events. CONCLUSIONS: The infrared coagulator might have enough potential to create transmural lesions on the beating heart in thoracoscopic AF surgery.

Guidelines for clinical evaluation of anti-cancer drugs.

Clinical studies intended for regulatory approval must demonstrate the clinical benefits of the drug in a target population. Clinical development of a drug proceeds by stepwise clinical studies; after safety and pharmacokinetics are evaluated and the recommended dosage and administration are determined, efficacy and safety are evaluated in an exploratory manner, and finally clinical benefits are compared with conventional standard therapies. Guidelines for the clinical evaluation of anti-cancer drugs in Japan were established in 1991 and amended in 2006 after molecular-targeted drugs were introduced. Recent progress in the development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti-cancer drugs. It is often difficult to conduct a confirmatory randomized controlled study using overall survival as the primary endpoint in rare molecular subtypes, and the primary evaluation of the efficacy of some drugs and subsequent approval is based on the tumor response. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study. However, this requires robust monitoring to detect possible ethnic differences in pharmacokinetics and drug efficacy. Development using the conditional approval system for drugs enforced in 2020 may be considered, when clinical utility is evaluated based on surrogate endpoints. Because of these changes, we have revised the guidelines for the clinical evaluation of anti-cancer drugs in Japan. To promote global development of anti-cancer drugs involving Japan, the guidelines have been translated into English.

Designation Products: Boron Neutron Capture Therapy for Head and Neck Carcinoma.

The Japanese Ministry of Health, Labour and Welfare approved a drug called borofalan (10 B), a treatment system, and a dose calculation program for boron neutron capture therapy (BNCT) in March 2020. The application pertaining to the products submitted to the Pharmaceuticals and Medical Devices Agency was supported by a Japanese, open-label, uncontrolled trial (Study 002) in patients with unresectable, locally recurrent head and neck squamous cell carcinoma after chemoradiotherapy or radiotherapy, or in those with unresectable locally advanced or locally recurrent (LA/LR) head and neck nonsquamous cell carcinoma. The drug was administered as a single intravenous dose using infusion rates of 200 mg/kg per hour for the first 2 hours after the start of administration and 100 mg/kg per hour during irradiation. Neutron irradiation was performed using the devices at a single dose of 12 Gy-equivalent for oral, pharyngeal, or laryngeal mucosa for up to 60 minutes from 2 hours after the start of drug administration. The primary endpoint was the overall response rate (ORR). The results of Study 002 showed that the ORR based on an assessment of the Independent Central Review Committee per RECIST version 1.1 was 71.4% (90% confidence interval [CI], 51.3%-86.8%). The lower limit of the 90% CI exceeded the prespecified threshold for ORR. When BNCT is applied to patients with unresectable LA/LR head and neck cancer, precautions should be taken, and patients should be monitored for possible onset of dysphagia, brain abscess, skin disorder, crystal urine, cataract, and/or carotid hemorrhage. IMPLICATIONS FOR PRACTICE: Borofalan (10 B), a treatment system and a dose calculation program for boron neutron capture therapy (BNCT), demonstrated significant efficacy in an open-label, uncontrolled trial in which overall response rate was the primary endpoint for patients with unresectable locally advanced or locally recurrent head and neck cancer. Although no information about survival benefits was obtained, BNCT will become an effective treatment option that is expected to manage local lesions that are intractable with any standard therapy. In addition, BNCT is expected to maintain quality of life of the intended patient population, on account of its high tumor selectivity and low invasiveness.

Garcin Syndrome Due to Meningeal Carcinomatosis from Gastric Cancer.

A 58-year-old woman presented to our hospital with complaints of dysphagia. Esophagogastroduodenoscopy showed an esophagogastric junction tumor with multiple duodenal intramural metastases, and computed tomography showed peritoneal metastasis. In the middle of her fourth cycle of chemotherapy, she displayed symptoms of a left-sided multi-cranial nerve palsy. She was diagnosed with Garcin syndrome caused by meningeal carcinomatosis from gastric cancer based on the results of gadolinium-enhanced brain magnetic resonance imaging and cytology of the cerebrospinal fluid. It is important not to overlook meningeal irritation symptoms or paralysis of cranial nerves and to consider the possibility of Garcin syndrome caused by meningeal carcinomatosis.

Thoracoscopic stapler-closure of left atrial appendage and epicardial clamp-isolation of pulmonary veins in a patient with non-valvular atrial fibrillation and short bowel: a case report.

BACKGROUND: Thromboembolic occlusion of the superior mesenteric artery (SMA) is a serious event in patients with atrial fibrillation (AF). Extensive bowel resection is frequently required, and the resulting short bowel syndrome hampers the intake of anticoagulant or anti-arrhythmic medication. CASE SUMMARY: We report the case of thoracoscopic surgery consisting of stapler-closure of the left atrial appendage and bilateral epicardial clamp-isolation of the pulmonary veins performed in a 66-year-old male patient with symptomatic persistent non-valvular AF who became unable to take in anticoagulants or anti-arrhythmic drugs because of thromboembolic SMA occlusion and subsequent total resection of the small intestine. The patient has been free from thromboembolic or arrhythmic symptoms during 6 months of follow-up despite taking no anticoagulant or anti-arrhythmic drugs. Electrocardiographic monitoring demonstrated a stable sinus rhythm for 48 h at postoperative Months 3 and 6. Echocardiography manifested an improvement of the left ventricular ejection fraction from a preoperative value of 44-69% at postoperative Month 6. DISCUSSION: The present technique may contribute to treating patients with symptomatic non-valvular AF and a complication similar to that of the present case.

[Staged Hybrid Treatment for a Coronary Artery Pseudoaneurysm after Percutaneous Coronary Intervention;Report of a Case].

We herein report a case of a coronary artery pseudoaneurysm caused by previous catheter intervention, who was treated with a staged hybrid procedure of coronary artery bypass grafting (CABG) and subsequent percutaneous catheter intervention. A 59-year-old man underwent an urgent percutaneous coronary stent placement for acute myocardial infarction at segment 1 of the right coronary artery, where later coronary pseudoaneurysm developed. Prior to closure of the aneurysm by covered stent placement, he underwent CABG to segment 3 using the right internal thoracic artery graft, in case the implanted covered stent should acutely thrombose in the future. The graft flow was increased by producing an artificial stenosis just proximal to the anastomosis. The present technique would be a safe and viable option of therapeutic strategy to fix coronary artery pseudoaneurysms that have been formed at the proximal segment of main coronary arteries.

En Bloc Left Pulmonary Vein and Appendage Isolation in Thoracoscopic Surgery for Atrial Fibrillation.

BACKGROUND: We evaluated the safety and rhythm control effectiveness in en bloc isolation of the left pulmonary vein (PV) and appendage conducted as part of the thoracoscopic procedure for bilateral PV isolation, non-PV ablation, and appendage closure for atrial fibrillation (AF). METHODS: Procedural safety was evaluated by reviewing the surgical records. Rhythm control was examined in accordance with the Heart Rhythm Society guidelines at postoperative months 1, 3, 6, and 12, and yearly thereafter. The sinus rhythm rates at postoperative years 1 and 2 were compared with the corresponding data from our previous procedure without the en bloc technique. RESULTS: Starting in 2014, the en bloc technique was applied to 238 nonvalvular AF patients and successfully performed in all but 23 patients. The mean operation time was 88 minutes. There were no hospital deaths or major procedure-related complications. The mean follow-up period was 1.7 years. The sinus rhythm rates at postoperative years 1 and 2 were 85% and 80% in paroxysmal, 76% and 70% in persistent, and 67% and 61% in long-standing persistent AF, respectively, without antiarrhythmic drug use. Compared with the previous procedure (n = 324), sinus rhythm rates were higher in long-standing persistent AF (67% vs 50% at 1 year and 61% vs 40% at 2 years; p = 0.04). No patients suffered cardiogenic thromboembolisms without anticoagulation. CONCLUSIONS: Thoracoscopic en bloc left PV and appendage isolation was safely achieved in most patients. Using this technique may contribute to better rhythm control results than not using it in cases of long-standing persistent AF.

A Mass Filling the Right Atrium: Primary Cardiac Rhabdomyosarcoma.

A 43-year-old woman presented with worsening shortness of breath and lower-extremity edema. Echocardiography and computed tomography showed obstruction of blood flow due to a mass filling the right atrium. Emergency surgery was performed for circulatory failure. Primary cardiac rhabdomyosarcoma was diagnosed based on a histological examination. The patient died about two months after the diagnosis despite surgical excision and radiation therapy. The poor prognosis may have resulted from the grossly incomplete removal of the tumor and chemotherapy intolerance. We herein report a case of primary cardiac rhabdomyosarcoma filling the right atrium and offer possible reasons for the poor prognosis.

Thoracoscopic stapler-and-loop technique for left atrial appendage closure in nonvalvular atrial fibrillation: Mid-term outcomes in 201 patients.

BACKGROUND: Left atrial appendage (LAA) closure can be an alternative to oral anticoagulation to prevent cardiogenic thromboembolisms in patients with nonvalvular atrial fibrillation. OBJECTIVE: The purpose of this study was to retrospectively evaluate the safety, completeness, and mid-term prevention of our thoracoscopic stapler-and-loop technique for LAA closure. METHODS: Patients operated on between October 2008 and February 2017 were reviewed. Endoscopic stapler and ligation loops were used. Patients received 1 month of anticoagulation before discontinuation. Hospital death and procedure-related major complications (thromboembolism, hemorrhagic events, phrenic palsy) were the primary composite endpoint for safety, and cardiogenic thromboembolisms were the endpoint for prevention. Brain magnetic resonance imaging investigated new thromboembolic spots 1 year after surgery. RESULTS: There were 201 patients (118 men, 83 women) with a mean age of 74 years (range 68-94) years, mean CHA2DS2-VASc score (± SD) 4.1 ±1.4, and mean HAS-BLED score 2.9 ± 1.0. Mean operation time was 28 minutes. All LAAs were removed, and intraoperative transesophageal echocardiography confirmed completeness of the closure in each patient. No hospital deaths or major procedure-related complications occurred. Follow-up results for 198 patients (98%) over a mean period of 48 months (range 12-110) revealed that 2 patients developed cardiogenic thromboembolisms (0.25 event per 100 patient-years). Magnetic resonance imaging of 51 patients with a mean CHA2DS2-VASc score of 4.7 ± 1.6 revealed 1 new small spot in each of 2 patients (3.9%; 3.9 spots per 100 patient-years). CONCLUSION: Our thoracoscopic stapler-and-loop technique swiftly, safely, and completely closed LAAs in patients with nonvalvular atrial fibrillation and provided acceptable mid-term prevention without anticoagulation.

A new pH-responsive peptide tag for protein purification.

This paper describes a new pH-responsive peptide tag that adds a protein reversible precipitation and redissolution character. This peptide tag is a part of a cell surface protein B (CspB) derived from Corynebacterium glutamicum. Proinsulin that genetically fused with a peptide of N-terminal 6, 17, 50, or 250 amino acid residues of CspB showed that the reversible precipitation and redissolution depended on the pH. The transition occurred within a physiological and narrow pH range. A CspB50 tag comprising 50 amino acid residues of N-terminal CspB was further evaluated as a representative using other pharmaceutical proteins. Below pH 6.8, almost all CspB50-Teriparatide fusion formed an aggregated state. Subsequent addition of alkali turned the cloudy protein solution transparent above pH 7.3, in which almost all the CspB50-Teriparatide fusion redissolved. The CspB50-Bivalirudin fusion showed a similar behavior with slightly different pH range. This tag is offering a new protein purification method based on liquid-solid separation which does not require an affinity ligand. This sharp response around neutral pH is useful as a pH-responsive tag for the purification of unstable proteins at a non-physiological pH.

A role for the locus coeruleus in the analgesic efficacy of N-acetylaspartylglutamate peptidase (GCPII) inhibitors ZJ43 and 2-PMPA.

N-acetylaspartylglutamate (NAAG) is the third most prevalent and widely distributed neurotransmitter in the mammalian nervous system. NAAG activates a group II metabotropic glutamate receptor (mGluR3) and is inactivated by an extracellular enzyme, glutamate carboxypeptidase II (GCPII) in vivo. Inhibitors of this enzyme are analgesic in animal models of inflammatory, neuropathic and bone cancer pain. NAAG and GCPII are present in the locus coeruleus, a center for the descending noradrenergic inhibitory pain system. In the formalin footpad model, systemic treatment with GCPII inhibitors reduces both phases of the inflammatory pain response and increases release of spinal noradrenaline. This analgesic efficacy is blocked by systemic injection of a group II mGluR antagonist, by intrathecal (spinal) injection of an alpha 2 adrenergic receptor antagonist and by microinjection of an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist directly into the contralateral locus coeruleus. Footpad inflammation increases release of glutamate in the contralateral locus coeruleus and systemic treatment with a GCPII inhibitor blocks this increase. Direct injection of GCPII inhibitors into the contralateral or ipsilateral locus coeruleus reduces both phases of the inflammatory pain response in a dose-dependent manner and the contralateral effect also is blocked by intrathecal injection of an alpha 2 adrenergic receptor antagonist. These data support the hypothesis that the analgesic efficacy of systemically administered GCPII inhibitors is mediated, at least in part, by the contralateral locus coeruleus via group II mGluR, AMPA and alpha 2 adrenergic receptors.

Comparison of the analgesic effect of intravenous acetaminophen with that of flurbiprofen axetil on post-breast surgery pain: a randomized controlled trial.

OBJECTIVE: Acetaminophen is known to be a relatively weak analgesic with fewer side effects than nonsteroidal anti-inflammatory drugs (NSAIDs). This study aimed to determine whether intravenous (iv) acetaminophen produces comparable analgesic effects to those of flurbiprofen (positive control drug), an intravenously injectable NSAID, after partial mastectomies. The primary outcome assessed was pain intensity during the first 24 h after the operation, and the secondary outcome was the satisfaction rating at discharge. METHODS: After obtaining Institutional Ethics Committee approval, a series of 40 consecutive female patients who were scheduled for partial mastectomies were enrolled. Participants were randomly divided into two groups: an acetaminophen (1000 mg × 3) group (group A) and a flurbiprofen (50 mg × 3) group (group F). Each drug was administered 15 min before the end of surgery, and at 6 and 12 h after the operation. Postoperative pain was evaluated using a 100-mm visual analog scale (VAS) at 3, 6, and 24 h postoperatively. Satisfaction rating was evaluated on a 5-point scale (very good, good, well, bad, and very bad). RESULTS: VAS scores (mm) with movement in groups A and F at 3, 6, and 24 h after the surgery were 22 vs. 28, 14 vs. 24, and 12 vs. 20.5 (median), respectively, with no significant differences between the two groups. Eighteen of 20 patients in group A and 20 of 20 patients in group F expressed a satisfaction rating of greater than good. CONCLUSIONS: Acetaminophen produces an equivalent analgesic effect to flurbiprofen in post-partial mastectomy patients.

Acetaminophen and non-steroidal anti-inflammatory drugs interact with morphine and tramadol analgesia for the treatment of neuropathic pain in rats.

PURPOSE: Although non-steroidal anti-inflammatory drugs and acetaminophen have no proven efficacy against neuropathic pain, they are frequently prescribed for neuropathic pain patients. We examined whether the combination of opioids (tramadol and morphine) with indomethacin or acetaminophen produce favorable effects on neuropathic pain and compared the efficacy for neuropathic pain with that for inflammatory pain. METHODS: The carrageenan model was used as the inflammatory pain model while the tibial neuroma transposition (TNT) model was used as the neuropathic pain model. The tibial nerve is transected in the TNT model, with the tibial nerve stump then transpositioned to the lateral aspect of the hindlimb. Neuropathic pain (mechanical allodynia and neuroma pain) is observed after TNT injury. Drugs were administered orally. RESULTS: In the carrageenan model, all drugs produced anti-allodynic effects and all drug combinations, but not tramadol + indomethacin combination, produced synergistic anti-allodynic effects. In the TNT model, tramadol and morphine, but not acetaminophen and indomethacin, produced anti-neuropathic pain effects. In the combination, with the exception of morphine + acetaminophen combination, both acetaminophen and indomethacin reduced the 50% effective dose (ED50) of tramadol and morphine as compared with the ED50s for the single drug study in the TNT model. The ED50s of tramadol and morphine in the carrageenan combination test were not statistically significantly different from the ED50s in the TNT model combination study. CONCLUSIONS: The combination of opioids with indomethacin or acetaminophen produced a synergistic analgesic effect both in inflammatory and neuropathic pain with some exceptions. The efficacy of these combinations for neuropathic pain was not different from that for inflammatory pain.

Comparison of statistical analysis plans in randomize-all phase III trials with a predictive biomarker.

When there are no compelling biologic or early trial data for a candidate predictive biomarker with regard to its ability to predict the effect of an anticancer treatment at the initiation of definitive phase III trials, it is generally reasonable to include all patients as eligible for randomization but to plan for a prospective subgroup analysis based on the biomarker. We assessed such statistical analysis plans, fixed-sequence, fallback, and treatment-by-biomarker interaction approaches, in terms of the probability of asserting treatment efficacy for either the overall patient population or a biomarker-positive subpopulation of patients. If there was some evidence that the treatment would work better in the biomarker-positive subgroup than the biomarker-negative subgroup, then the fixed-sequence approaches would be favored, whereas if evidence was weak that there would be much difference in responsiveness between the two subgroups, then the fallback approach would be favored. If there was substantial uncertainty in the difference in treatment effects between the two subgroups, the treatment-by-biomarker interaction approach could be a reasonable choice as this approach generally provided a high probability of asserting treatment efficacy for the right patient population under homogeneous treatment effects and a qualitative interaction over biomarker-based subgroups. Clin Cancer Res; 20(11); 2820-30. ©2014 AACR.