A polyexponential deconvolution method. Evaluation of the “gastrointestinal bioavailability” and meanin vivo dissolution time of some ibuprofen dosage forms

A new deconvolution algorithm (DCON) suitable for pharmacokinetic applications is presented. It requires that both the impulse and input responses, typically systemic drug levels, be well described by polyexponential equations. DCON has a wider range of applications than an earlier method (DECONV) from which it is derived. A FORTRAN program is provided, making implementation of the technique a simple matter. DCON is demonstrated to evaluate the GI bioavailability, defined as the rate and the extent of gastrointestinal drug release, of various ibuprofen dosage forms. The GI drug release kinetics exemplifies a pharmacokinetic system which cannot be evaluated using the previous deconvolution algorithm (DECONV) because of an initial zero drug level response. This limitation is not found in DCON. It is also demonstrated how the mean in vivo dissolution time MDT can be evaluated by deconvolution.     

Radiotherapy alone in breast cancer. I. Analysis of tumor parameters, tumor dose and local control: the experience of the Gustave-Roussy Institute and the Princess Margaret Hospital

This retrospective study involved 463 breast cancer patients treated by radiotherapy alone at the Princess Margaret Hospital and at the Institut Gustave-Roussy. These patients either had operable tumors, but were unfit for general anesthesia, or had inoperable tumors due to local contraindications to surgery. Results were analyzed according to tumor response, local recurrence rate, tumor size, tumor fixation, nodal fixation and tumor dose. Conventional statistical analysis of local control showed two significant factors: tumor dose and tumor size. Multivariate analysis permitted to define an "individual risk" (IR) of local recurrence according to three independent factors: tumor size, tumor fixation, and nodal fixation. It was shown that the IR was a good prognostic factor for local control. Increase in tumor dose gave a similar effect in the local recurrence relative risk for all the IR groups. According to the slope of the dose-effect curve, it was deduced that a dose increase of 15 Gy can decrease the relative risk of local recurrence 2-fold. In fact, it was shown that tumor dose was the most significant independent factor on local control, able to produce up to a 10-fold increase compared to 2-fold decrease for tumor size. If the IR of local recurrence is known, a theoretical predictive value on local control, taking into account the tumor dose, can be determined according to the present data.     

Malignant obstructive jaundice: treatment with external-beam and intracavitary radiotherapy

Eleven patients with obstructive jaundice from unresectable cholangiocarcinoma, metastatic porta hepatis adenopathy, or direct compression from a pancreatic malignancy were treated at the Stanford University Medical Center from 1978-1983 with an external drainage procedure followed by high-dose external-beam radiotherapy and by an intracavitary boost to the site of obstruction with Iridium192 (Ir192). A median dose of 5000 cGy was delivered with 4-6 Mv photons to the tumor bed and regional lymphatics in 9 patients, 1 patient received 2100 cGy to the liver in accelerated fractions because of extensive intrahepatic disease, and 1 patient received 7000 "equivalent" cGy to his pancreatic tumor bed and regional lymphatics with neon heavy particles. An Ir192 wire source later delivered a 3100-10,647 cGy boost to the site of biliary obstruction in each patient, for a mean combined dose of 10,202 cGy to a point 5 mm from the line source. Few acute complications were noted, but 3/11 patients (27%) subsequently developed upper gastrointestinal bleeding from duodenitis or frank duodenal ulceration 4 weeks, 4 months, and 7.5 months following treatment. Eight patients died--5 with local recurrence +/- distant metastasis, 2 with sepsis, and 1 with widespread systemic metastasis. Autopsies revealed no evidence of biliary tree obstruction in 3/3 patients. Mean survival time from initial laparotomy and bypass was 16.1 months, and from radiotherapy completion was 8.3 months. Evolution of radiation treatment techniques for biliary obstruction in the literature is reviewed. High-dose external-beam therapy followed by high-dose Ir192 intracavitary boost is well tolerated and provides significant palliation. Survival of these aggressively managed patients approaches that of patients with primarily resectable tumors.     

Serum digoxin concentrations in a representative digoxin — Consuming adult population

Summary As part of health examination of a representative sample of an adult population (n=8000) serum digoxin concentration was measured in 661 patients on continuous digoxin therapy. The prescribed mean daily dose of digoxin was significantly higher in men (223 µg) than in women (201 µg); the dose significantly decreased with increasing age. The mean serum digoxin concentration was the same in men and women and it differed insignificantly between age groups, although older persons tended to have a higher concentration. The age — adjusted mean steady state digoxin concentration was 1.02 ng/ml in men and 0.98 ng/ml in women; in about 60% the concentration was within the therapeutic range (0.80–2.00 ng/ml). The concentrations were clearly related to daily dose of digoxin. At equal dose levels old persons tended to have higher concentrations than younger persons. The interindividual variation in serum digoxin concentrations was very wide. However, when digoxin measurements in the same subjects were repeated about three months later, a good correlation between the two measurements was found. The interval between the last dose of digoxin and the collection of blood (up to 41 h) had relatively little effect on individual serum digoxin concentrations. Patients on concomitant thiazide or loop diuretic therapy had the same mean serum digoxin concentration as those not-receiving a diuretic. The mean concentration was significantly higher in patients taking a thiazide or loop diuretic combined with triamterene. The difference may have been due to an interaction between triamterene and digoxin.     

HFRT和CFRT模式对乳腺癌患者外周血淋巴细胞的影响

目的 探讨不同放疗分割模式即大分割放疗（hypofractionated radiotherapy, HFRT)和常规分割放疗（conventional fractionation radiotherapy, CFRT)对乳腺癌患者外周血淋巴细胞的影响。方法 回顾性分析2019年11月至2021年8月在徐州市中心医院接受保乳术后放射治疗的40例早期乳腺癌患者。随机分为观察组（HFRT,n = 20）与对照组（CFRT,n = 20）,比较2组患者放疗前及放疗中的外周血淋巴细胞计数(peripheral lymphocyte count,PLC)变化。结果 大分割组和常规分割组患者的基线PLC无统计学差异（1.53 ± 0.54 vs 1.64 ± 0.56;P > 0.05）。2组的PLC在放疗过程中稳定下降,大分割组淋巴细胞减少发生率低于常规分割组（32.5% vs 50.0%),但差异无统计学意义（P > 0.05）;大分割组的最低点PLC高于常规分割组（0.91 ± 0.28 vs 0.55 ± 0.22;P < 0.001）。大分割组治疗期间的最低PLC与基线阶段的比值明显高于常规分割组（0.64 ± 0.24 vs 0.38 ± 0.21,P < 0.05）。结论 与常规分割放疗方案相比,乳腺癌患者接受大分割放疗发生放射诱导淋巴细胞减少的风险更低。     

放射治疗对乳腺癌患者外周血免疫系统相关指标的影响

目的:研究分析放射治疗对乳腺癌患者免疫系统相关指标的影响。方法:选取在医院就诊的6例病理诊断为乳腺癌Ⅱ~Ⅲ期患者,将所有患者放射治疗前(0 Gy)静脉血样本定义为对照组、放射治疗20 Gy和50 Gy照射后静脉血样本分别定义为20 Gy组和50 Gy组,于放射治疗10次后、25次后采集不同放射治疗累积剂量24 h后静脉血8 ml;采用流式细胞术检测所有受检者不同剂量放射治疗后外周血淋巴细胞亚群百分数、外周血淋巴细胞凋亡及细胞周期的改变;实时荧光定量聚合酶链反应(q RT-PCR)法检测外周血淋巴细胞微小核糖核酸(miRNA)的改变。结果:乳腺癌患者20 Gy组和50 Gy组照射后与对照组比较,淋巴细胞亚群CD3⁺、CD4⁺/CD8-和CD4⁺/CD8⁺表达水平均呈下调趋势,CD4^-/CD8⁺呈上升趋势,但差异均无统计学意义;20 Gy组T细胞抗原受体(TCR)/CD3明显下调,与对照组比较差异有统计学意义(Z=-2.008,P<0.05),50 Gy组TCR/CD3有所回升,但差异无统计学意义。不同剂量的两组照射后乳腺癌患者mi RNA-150、mi RNA-210表达水平随剂量增加呈降低趋势,50 Gy组表达水平明显降低,与对照组相比差异有统计学意义(Z=-2.242,Z=-2.402;P<0.05)。结论:放射治疗未引起乳腺癌患者明显的免疫功能抑制,可能是通过改变mi RNA-150、mi RNA-210的通路而抑制肿瘤的生长。     

视神经萎缩的治疗临床研究

目的 探讨视神经萎缩的有效治疗方法。方法 对324例526例眼视神经萎缩患,用胞二磷胆碱、肌苷做球后注射。结果 临床治愈88例,显效261例,进步106眼,有效率86．9％,收到了较满意的效果。结论 胞二磷胆碱、肌苷可通过卵磷脂的合成改善视神经周围的血液循环,刺激和促进视神经纤维的生物修补,从而导致视神经功能的改善和恢复。     

手术联合术后放疗治疗瘢痕疙瘩的临床研究

目的：研究手术联合术后放疗治疗瘢痕疙瘩的临床效果。方法：瘢痕疙瘩85例,随机分为2组,实验组50例,采用瘢痕疙瘩切除缝合或植皮,术后即时放疗;对照组35例,仅行瘢痕疙瘩切除植皮。结果：术后随访6个月－3年,实验组40例（80％）治愈,无复发;5例（10％）轻度瘢痕增生,局部注射康宁克通－A后未复发;5例（10％）复发;对照组6例（17．14％）治愈,29例（82．86％）复发,实验组治愈率明显高于对照组。结论：手术联合术后放疗是治愈瘢痕疙瘩的有效方法。     

Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies

BackgroundDuctal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC).ObjectiveTo assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC.Design, setting, and participantsA single-center retrospective review of all patients with cT1–4/N0–1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients.Outcome measurements and statistical analysisMetastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models.Results and limitationsA total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation.ConclusionsMen undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed.Patient summaryThis study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.     

Safety of cyclin-dependent kinase4/6 inhibitor combined with palliative radiotherapy in patients with metastatic breast cancer

IntroductionCyclin-dependent kinase (CDK)4/6 inhibitor is a first-line therapy for metastatic ER+/HER2-breast cancer. However, there are limited data on safety of combined radiotherapy (RT) and CDK4/6 inhibition.MethodsWe conducted a retrospective study of women with metastatic breast cancer who received palliative RT within 14 days of CDK4/6 inhibitor use. The primary endpoint was toxicity per Common Terminology Criteria for Adverse Events v5. Secondary endpoints were pain response and local control based on clinical assessment and imaging.ResultsThirty patients underwent 36 RT courses with palbociclib (n = 34 courses, 94.4%) or abemaciclib (n = 2, 5.6%). RT was delivered before, concurrently or after CDK4/6 inhibitors in 7 (19.4%), 8 (22.2%), and 21 (58.3%) of cases with median 3.5 days from RT to closest CDK4/6 inhibitor administration. Median RT dose was 30Gy (range 8–40.05Gy). Treated sites included brain (n = 5, 11.6%), spine (n = 19, 44.2%), pelvis (n = 9, 20.9%), other bony sites (n = 6, 14.0%) and others (n = 4, 9.3%). No acute grade ≥3 non-hematologic toxicity occurred. No increased hematologic toxicity was attributable to RT with grade 3 hematologic toxicities rates 16.7%, 0%, and 6.7% before, during, and 2 weeks after RT completion. All but one patient (29/30) achieved symptom relief. Local control rates were 94.4%, 91.7% at 6 and 12 months.ConclusionsThe use of RT within 2 weeks of CDK4/6 inhibitors had low acceptable toxicity and high efficacy, suggesting that it is safe for palliation of metastatic breast cancer.