Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Objective

Low‐dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results of previous studies demonstrated that adenosine, acting at one or more of its receptors, mediates the antiinflammatory effects of methotrexate in animal models of both acute and chronic inflammation. We therefore sought to establish which receptor(s) is involved in the modulation of acute inflammation by methotrexate and its nonpolyglutamated analog MX‐68 (N‐[[4‐[(2,4‐diaminopteridin‐6‐yl)methyl]‐3,4‐dihydro‐2H‐1,4‐benzothiazin‐7‐yl]‐carbonyl]‐L ‐homoglutamic acid).

Methods

We studied the effects of low‐dose methotrexate (0.75 mg/kg intraperitoneally [IP] every week for 5 weeks), MX‐68 (2 mg/kg IP 2 days and 1 hour before induction of inflammation), dexamethasone (1.5 mg/kg IP 1 hour before induction of inflammation), or vehicle control on acute inflammation in an air‐pouch model in A_2A and A₃ receptor knockout mice.

Results

Low‐dose weekly methotrexate treatment increased the adenosine concentration in the exudates of all mice studied and reduced leukocyte and tumor necrosis factor α accumulation in the exudates of wild‐type mice, but not in those of A_2A or A₃ receptor knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was equally effective at suppressing leukocyte accumulation in A_2A knockout, A₃ knockout, and wild‐type mice, indicating that the lack of response was specific for methotrexate and MX‐68.

Conclusion

These findings confirm that adenosine, acting at A_2A and A₃ receptors, is a potent regulator of inflammation. Moreover, these results provide strong evidence that adenosine, acting at either or both of these receptors, mediates the antiinflammatory effects of methotrexate and its analog MX‐68.

     

Patterns of relapse in stage I–II uterine papillary serous carcinoma treated with adjuvant intravaginal radiation (IVRT) with or without chemotherapy

Objective

To evaluate patterns of relapse in early stage uterine papillary carcinoma (UPSC) patients receiving adjuvant intravaginal radiotherapy (IVRT) with or without chemotherapy.

Methods

From 1/1996 to 12/2010, 77 women with stage I–II UPSC underwent surgery followed by IVRT (median 21 Gy). Stage IA patients without residual disease at surgery were excluded. IVRT and chemotherapy (carboplatin/taxane) was given to 61 (79%) patients and IVRT alone to 16 (21%). The median follow-up was 62 months for surviving patients.

Results

Of the 77 patients, 11 (14%) relapsed as follows: vaginal 2 (3%), pelvic 5 (6%), para-aortic 5 (6%), peritoneal 6 (8%), and other distant sites 8 (10%). Of the 5 pelvic relapses, 2 were isolated and were salvaged. In those treated without chemotherapy, only 1/16 developed recurrence (mediastinal). The 5-year vaginal, pelvic, para-aortic, peritoneal, and distant recurrence rates were 2.7% (C.I. 0–6.2%), 5.8% (C.I. 0.6–11.0%), 5.4% (C.I. 0.6–10.1%), 5.3% (C.I. 0.5–10.1%) and 6.6% (C.I. 1.4–11.8%), respectively. The 5-year disease-free survival (DFS), and overall survival (OS) were 88% (C.I. 81–95%), and 91% (C.I. 84–97%), respectively. The only predictor of worse 5-year pelvic control was stage (96.2% stage IA vs 87.7% for stage IB-II, p = 0.043).

Conclusions

In stage I–II UPSC patients who predominantly receive adjuvant chemotherapy, IVRT as the sole form of adjuvant RT provides excellent locoregional control. The risk of isolated pelvic recurrence is too low to warrant routine use of external pelvic RT.     

Implementation science for the adductor canal block: A new and adaptable methodology process

BACKGROUNDFollowing the successful Perioperative Surgical Home (PSH) practice for total knee arthroplasty (TKA) at our institution, the need for continuous improvement was realized, including the deimplementation of antiquated PSH elements and introduction of new practices. AIMTo investigate the transition from femoral nerve blocks (FNB) to adductor canal nerve blocks (ACB) during TKA. METHODSOur 13-month study from June 2016 to 2017 was divided into four periods: a three-month baseline (103 patients), a one-month pilot (47 patients), a three-month implementation and hardwiring period (100 patients), and a six-month evaluation period (185 patients). In total, 435 subjects were reviewed. Data within 30 postoperative days were extracted from electronic medical records, such as physical therapy results and administration of oral morphine equivalents (OME). RESULTSOur institution reduced FNB application (64% to 3%) and increased ACB utilization (36% to 97%) at 10 mo. Patients in the ACB group were found to have increased ambulation on the day of surgery (4.1 vs 2.0 m) and lower incidence of falls (0 vs 1%) and buckling (5% vs 27%) compared with FNB patients (P < 0.05). While ACB patients (13.9) reported lower OME than FNB patients (15.9), the difference (P = 0.087) did not fall below our designated statistical threshold of P value < 0.05.CONCLUSIONBy demonstrating closure of the “knowledge to action gap” within 6 mo, our institution’s findings demonstrate evidence in the value of implementation science. Physician education, technical support, and performance monitoring were deemed key facilitators of our program’s success. Expanded patient populations and additional orthopedic procedures are recommended for future study.     

An important role for BRCA1 in breast cancer progression is indicated by its loss in a large proportion of non-familial breast cancers

The presence of BRCA1 protein was determined immunohistochemically in normal and benign breast biopsies, non-familial breast carcinomas and breast carcinomas from one or more individuals from 8 BRCA1 families. Strikingly, little staining was detected in breast carcinomas from BRCA1 families, regardless of the position or type of mutation, whereas strong immunostaining was observed in 28/28 of non-malignant breast biopsies. Furthermore, BRCA1 staining was reduced in non-familial breast carcinomas, since loss of nuclear BRCA1 staining was evident in 19% of non-familial breast carcinomas whilst a similar proportion (20%) showed absence of either cytoplasmic or nuclear BRCA1 staining. Statistical analysis indicates that breast cancer is characterised by a reduction in levels of nuclear BRCA1 in familial (p < 0.001) and non-familial breast cancer (p = 0.001). In non-familial breast cancer absence of nuclear BRCA1, but not cytoplasmic BRCA1, is more common in high grade breast carcinomas (p = 0.03) and in patients with evidence of lymph node involvement (p = 0.05). Correlation between the absence of BRCA1 protein with high grade is consistent with previous findings of a correlation between mutations in the BRCA1 gene and high grade. Our findings provide new evidence in support of BRCA1 as a tumour suppressor protein in non-familial breast cancer. Int. J. Cancer (Pred. Oncol.) 79:334–342, 1998. © 1998 Wiley-Liss, Inc.     

Single-incision total laparoscopic hysterectomy with conventional laparoscopy ports

ObjectiveTo study the feasibility of performing single-incision total laparoscopic hysterectomy using conventional ports and instruments.MethodsPatients undergoing laparoscopic surgery at Galaxy Care Laparoscopic Institute, Pune, India, between January 2007 and December 2010 were selected for participation. All procedures were performed using conventional laparoscopic instruments and trocars. Operative data—including operative time (from incision to port closure), blood loss, additional ports used, energy sources used, and intraoperative complications—were recorded.ResultsTwenty-three procedures were performed during the study period. All procedures were completed via single incision only. Operative time, blood loss, and hospital stay were comparable with those associated with conventional laparoscopy.ConclusionIt is debatable whether laparoscopic surgery via a single incision would threaten the position of the current gold standard of conventional laparoscopic procedures. The present study showed that single-incision laparoscopic surgery using conventional instruments is feasible and effective.     

Correlation of tumor necrosis factor levels in the serum and cerebrospinal fluid with clinical outcome in Japanese encephalitis patients

To investigate the prognostic role of tumour necrosis factor (TNF) in Japanese encephalitis virus (JEV) infection, we measured the immunoreactive forms of TNF concentrations in the serum and cerebrospinal fluid (CSF) of 47 laboratory-confirmed cases of JE. It was observed that TNF levels were elevated (>15 pgm/ml) in all the 47 serum samples (range 19.4–923.8 pg/ml), while in 46/47 CSF samples TNF was elevated (range 10.8–376 pg/ml). The mean (SD) TNF levels in the serum of fatal cases was 234.34 pg/ml (304.40) as compared to the mean of 85.31 pg/ml (SD 153.92) in nonfatal cases. Similar observations were also made with respect to the TNF levels in the CSF; the mean of fatal cases was 69.39 pg/ml (SD 39.00) in contrast to the mean of 62.41 pg/ml (SD 75.25) of nonfatal cases. The increase in TNF levels did not show any correlation to the duration of illness. It was further observed that the mortality rate increased with increasing concentrations of TNF in the serum and CSF. Correlation of laboratory parameters to final outcome revealed that TNF concentrations above 50 pg/ml in serum correlated significantly (P = .05) with a fatal outcome, whilst high levels of JEV-IgM antibodies (>500 units) in the CSF correlated with a nonfatal outcome (P = .03). These results suggest that TNF can be used as a possible prognosticator of a fatal outcome in JEV infection. J Med Virol 51:132–136, 1997. © 1997 Wiley-Liss, Inc.     

The effects of maternal protein deprivation on the fetal rat pancreas: major structural changes and their recuperation

There is evidence that low birth weight and poor growth in early life cause a long-term predisposition to non-insulin-dependent diabetes. Morphological changes were assessed in fetal rat pancreas subjected to both pre- and post-natal maternal protein deprivation (LP). Further groups were subjected to purely prenatal maternal protein deprivation (preLP) and purely postnatal maternal protein deprivation (postLP), as well as a control group. The results show that the LP and postLP groups had fewer but larger islets than the control group, while the preLP group had more numerous, smaller islets. All three low protein groups had more irregularly shaped islets than the control group. There was a reduction in the amount of beta cells within each islet in all three protein-deprived groups. The LP and postLP groups showed a reduction in the percentage of islet tissue and beta cells per pancreas, but the percentage of islet tissue expressed per unit body weight was similar in all four groups. These results show that in maternal protein deprivation, homeostatic mechanisms ensure a constant amount of pancreatic endocrine tissue per unit of body weight. However, there remain major structural changes in the size, shape, and composition of the islets. These results support the theory that early development profoundly affects the structure of the pancreas and may play a role in the later development of adult diseases, such as non-insulin-dependent diabetes mellitus. © 1997 by John Wiley & Sons, Ltd.     

Bexarotene and erlotinib for aerodigestive tract cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) and cyclin D1 are overexpressed in lung carcinogenesis. The rexinoid, bexarotene, represses cyclin D1 and EGFR expression in vitro. It was hypothesized that combining bexarotene with the EGFR inhibitor, erlotinib, would augment clinical activity. PATIENTS AND METHODS: In vitro studies and a phase I clinical trial were performed. Twenty-four patients with advanced aerodigestive tract cancers were enrolled; 79% had non-small-cell lung cancer (NSCLC). The primary objective was to determine the maximum-tolerated dose. Clinical activity was a secondary objective. RESULTS: Combining erlotinib with bexarotene enhanced growth suppression in vitro compared with each single-agent treatment. This cooperatively repressed cyclin D1 expression. Clinically, the most frequent toxicities were mild hypertriglyceridemia and skin rash. Two serious treatment-related adverse events occurred (creatine phosphokinase elevation attributed to antilipid therapy and a case of generalized pain). Five objective responses (four partial and one minor) were observed in NSCLC patients. Responses were observed in males and smokers. EGFR sequence analyses did not reveal activating mutations in tumors from assessable responding patients. Median time to progression was 2.0 months; overall survival time was 14.1 months; and 1-year survival rate was 73.8%. CONCLUSION: The recommended phase II doses are erlotinib 150 mg/d and bexarotene 400 mg/m2/d orally. These agents can be administered in combination at the recommended single-agent doses without added toxicity. Overall survival and clinical features of responding patients differ from prior reports of single-agent erlotinib treatment. These findings are encouraging and warrant further investigation of this regimen.     

Modeling positioning uncertainties of prostate cancer external beam radiation therapy using pre-treatment data

Purpose

To investigate the influence of treatment plan data and image guidance (IG) on positioning uncertainty during prostate cancer (PCa) radiotherapy (RT).

Methods

Body mass index (BMI), planning target volume (PTV), bladder volume (BV), and rectal cross section area (RCS) were collected for 267 consecutive PCa patients undergoing daily IGRT. Radiographic isocenter corrections to intra-prostatic fiducials for 12,490 treatment fractions were used to derive random (RE) and systematic (SE) inter-fraction uncertainties for the cardinal axes. These data were used to simulate RE and SE for weekly IG and Action Level (AL)-IG treatment protocols.

Results

SE and RE were 2–5 and 3–4 mm in the cardinal axes, respectively, during simulation of no IG. Without IG, positive correlations (p < 0.01) were noted for (1) anterior-posterior RE vs. RCS and BV and (2) cranio–caudal RE vs. RCS, BV and BMI. The RE increase was 3 mm for the highest quartile of RCS, BV and BMI. Daily IGRT eliminated this relationship. 3D IG corrections of 1 cm or more occured in 27% of treatment fractions and in 97% of patients.

Conclusion

PCa patients with elevated pre-treatment BV, RCS and BMI have increased inter-fractionation positioning uncertainty and appear the primary candidates for daily IGRT.