Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m². The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m² DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m² PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m². Large interpatient variation in peak PCZ plasma levels (91–3215 ng/ml) was seen, with the plasma half-life (t1/2) being approximately 57 min in patients given 135–180 mg/m² PCZ. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) were 350.1±183.8 l/m², 260.7±142.7 l m² h^–1 and 1539±922 ng ml h^–1, respectively, in patients given 180 mg/m² PCZ and the respective values for patients receiving 135 mg/m² were 48.9±23.76 l/m², 33.2±2.62 l m² h^–1, and 4117±302 ng ml h^–1. High PCZ plasma levels (>600 ng/ml) were sustained in all patients treated with 135 mg/m² PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m² PCZ, and a>10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m² with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.This work was supported by NIH grant R01 CA-29360 and S1488, CRC grant M01 RR-05280, and the Joan Levy Cancer Foundation. This paper was presented at the meeting of the American Association for Cancer Research, Orlando, Florida, May 19–22, 1993     

Patient-Reported Quality of Life Before and After Chemoradiation for Intact Pancreas Cancer: A Prospective Registry Study

PurposeOur purpose was to determine the effect of chemoradiotherapy (CRT) on patient-reported quality of life (QOL) for patients with intact pancreas cancer.Methods and MaterialsWe reviewed a prospective QOL registry for patients with intact, clinically localized pancreatic ductal adenocarcinoma treated with CRT between June 2015 and November 2018. QOL was assessed pre-CRT (immediately before CRT, after neoadjuvant chemotherapy) and at the completion of CRT with the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) and its component parts: FACT-General (FACT-G) and hepatobiliary cancer subscore (HCS). A minimally important difference from pre-CRT was defined as ≥ 6, 5, and 8 points for FACT-G, HCS, and FACT-Hep, respectively.ResultsOf 157 patients who underwent CRT, 100 completed both pre- and post-CRT surveys and were included in the primary analysis. Median age at diagnosis was 65 years (range, 23-90). National Comprehensive Cancer Network resectability status was resectable (3%), borderline resectable (40%), or locally advanced (57%). Folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) (75%) or gemcitabine and nab-paclitaxel (42%) were given for a median of 6 cycles (range, 0-42) before CRT. Radiation therapy techniques included 3-dimensional conformal (22%), intensity modulated photon (55%), and intensity modulated proton (23%) radiation therapy to a median dose of 50 Gy (range, 36-62.5). Concurrent chemotherapy was most commonly capecitabine (82%). Sixty-three patients (63%) had surgery after CRT. The mean decline in FACT-G, HCS subscale, and FACT-Hep from pre- to post-CRT was 3.5 (standard deviation [SD], 13.7), 1.7 (SD 7.8), and 5.2 (SD 19.4), respectively. Each of these changes were statistically significant, but did not meet the minimally important difference threshold. Pancreatic head tumor location was associated with decline in FACT-Hep. Nausea was the toxicity with the greatest increase from pre- to post-CRT by both physician-assessment and patient-reported QOL.ConclusionsFor patients with intact pancreatic adenocarcinoma, modern CRT is well tolerated with minimal decline in QOL during treatment.     

Mutational analysis of the BRAF gene in human congenital and dysplastic melanocytic naevi

Eighteen congenital melanocytic naevi (CMN) from 17 patients and 18 dysplastic melanocytic naevi (DMN) from 18 patients were screened for mutations in the BRAF oncogene (present study) and the N-ras oncogene (in the course of two foregoing studies) by single-strand conformational polymorphism (SSCP)/sequencing analysis. BRAF mutations were demonstrated in both types of lesion. As a whole, 17 of 18 CMN (94.4%) and five of 18 DMN (27.7%) harboured either BRAF or N-ras mutations. As the BRAF oncogene is frequently found to be mutated in human cutaneous melanomas, it may constitute a risk factor for melanoma formation within CMN and DMN.     

Clove oil reverses learning and memory deficits in scopolamine-treated mice

The present study was performed to examine the effect of Eugenia caryophyllata (Myrtaceae) on learning and memory, and also evaluate whether it can modulate oxidative stress in mice. Passive avoidance step-down task and elevated plus-maze were used to assess learning and memory in scopolamine-treated mice. Oxidative stress parameters were also assessed in brain samples by estimating the malondialdehyde (MDA) and reduced glutathione (GSH) levels at the end of the study. Scopolamine (0.3 mg/kg, i. p.) produced impairment of acquisition memory as evidenced by a decrease in step-down latency and an increase in transfer latency on day 1, and also impairment of retention of memory on day 2. Pretreatment with clove oil (0.05 mL/kg and 0.1 mL/kg) for 3 weeks significantly reversed the increase in acquisition latency and all the doses (0.025, 0.05, 0.1 mL/kg, i. p.) reversed the increase in retention latency induced by scopolamine (0.3 mg/kg, i. p.) in elevated plus-maze. However, 0.05 mL/kg clove oil attenuated memory deficits in the passive avoidance step-down task. Brain samples showed a significant decrease in MDA levels in the group treated with clove oil (0.05 and 0.025 mL/kg). GSH levels were also increased in clove oil-treated mice though the results were not significant. Thus, it can be concluded that clove oil can reverse the short-term and long-term memory deficits induced by scopolamine (0.3 mg/kg, i. p.) and this effect can, to some extent, be attributed to decreased oxidative stress.     

Comparing the PANSS in Chinese and American inpatients: cross-cultural psychiatric analyses of instrument translation and implementation

This article compares data from the Positive and Negative Syndrome Scale (PANSS) collected from Chinese and American inpatients diagnosed with schizophrenia to show how patterned differences in item ratings may reflect cultural attitudes of the raters. The Chinese sample (N=553) was based on consecutive admissions to four academic hospitals in Changsha, China. Only patients ill for 3 or more years were included in the analysis to match the chronically ill sample represented in the US CATIE sample. A total of 261 PANSS assessments were completed during a month when CATIE subjects had been hospitalized for 15 days or more to optimize equivalence of the US and Chinese samples. Controlling for age and gender, the total PANSS and the three sub-scores were all significantly lower in the Chinese than in the US CATIE sample by 5-8% (all p<.05). However, on 9 items, the Chinese sample scored 10-30% higher than the US sample (all p<.05) and on 5 items they scored over 20% higher (all p<.0001). These items rated increased hostility, poorer attention, lack of judgment and insight, disturbance of volition, and poorer impulse control. We ascribe these differences to cultural variations in the ways individuals relate to others in their social environment within Chinese and American societies.     

Clinical profile of pediatric somatoform disorders

OBJECTIVES: To study the prevalence, pattern, clinical and socio-demographic characteristics of somatoform disorders in children. METHODS: From Aug 2004 to July 2005, children up to 18 years with unexplained physical symptoms were evaluated prospectively using DSM-IV criteria. Detailed evaluation followed for those meeting criteria. RESULTS: The prevalence of Somatoform disorders was 0.59% and 0.78% among out-door and in-door patients respectively. Among 124 children (40 boys and 84 girls) meeting criteria, conversion disorder was the commonest (57.3%), followed by undifferentiated somatoform disorder (25.2%). Girls were significantly more represented among conversion disorder patients compared to other groups of somatoform disorders (78.9 vs. 52.8 %, P=0.002). In conversion disorder, 2/3rd patients presented within 3 months, whereas in other somatoform disorders, 2/3rd patients presented within 3 months after symptoms. Fainting attacks (52.1%) and ataxia (43.7%) in conversion disorder and pain abdomen (52.8%) and headache (52.8%) in other somatoform disorders, were the commonest symptoms. Stressors were identified in 73.4% and acute precipitating stressors were present in 14.4% children. Boys had significantly higher rates of poor inter-personal relations and communication problems within the family (72.5% vs. 41.7%, P=0.001), while girls had significantly higher rates of conflicts with the parents and other family members (21.4% vs. 5%, P=0.02). CONCLUSION: Somatoform disorders, particularly conversion disorder is commoner in girls. Important stressors are poor inter-personal relations and communication problems within the family in boys, and conflicts with family members among girls.     

Advances in the use of surgery and multimodality treatment for N2 non-small cell lung cancer

Introduction: Stage IIIA-N2 non-small cell lung cancer (NSCLC) represents a heterogeneous group of bronchogenic carcinomas with locoregional involvement. Different categories of N2 disease exist, ranging from unexpectedly encountered N2 involvement after detailed preoperative staging or ‘surprise’ N2, to potentially resectable disease treated within a combined modality setting, and finally, bulky N2 involvement treated by chemoradiation.

Areas covered: Large randomised controlled trials and meta-analyses on stage IIIA-N2 NSCLC have been published but their implications for treatment remain a matter of debate. No definite recommendations can be provided as diagnostic and therapeutic algorithms vary according to local, national or international guidelines.

Expert commentary: From the literature, it is clear that patients with stage IIIA-N2 NSCLC should be treated by combined modality therapy including chemotherapy, radiotherapy and surgery. The relative contribution of each modality has not been firmly established. For patients undergoing induction therapy, adequate restaging is important as only down-staged patients will clearly benefit from surgical resection. Each patient should be discussed within a multidisciplinary team to determine the best diagnostic and therapeutic approach according to the specific local expertise. In the near future, it might be expected that targeted therapies and immunotherapy will be incorporated as possible therapeutic options.