Redefining the importance of polylactide-co-glycolide acid (PLGA) in drug delivery.

The limitations of non-biodegradable polymers have paved the way for biodegradable polymers in the pharmaceutical and biomedical sciences over the years. Poly (lactic-co-glycolic acid) (PLGA), also known as "Smart polymer", is one of the most successfully developed biodegradable polymers due to its favorable properties, such as biodegradability, biocompatibility, controllable drug release profile, and ability to alter surface with targeting agents for diagnosis and treatment. The release behavior of drugs from PLGA delivery devices is influenced by the physicochemical properties of PLGA. In this review, the current state of the art of PLGA, its synthesis, physicochemical properties, and degradation are discussed to enunciate the boundaries of future research in terms of its applicability with the optimized design in today's modern age. The fundamental objective of this review is to highlight the significance of PLGA as a polymer in the field of cancer, cardiovascular diseases, neurological disorders, dentistry, orthopedics, vaccine therapy, theranostics and lastly emerging epidemic diseases like COVID-19. Furthermore, the coverage of recent PLGA-based drug delivery systems including nanosystems, microsystems, scaffolds, hydrogels, etc. has been summarized. Overall, this review aims to disseminate the PLGA-driven revolution of the drug delivery arena in the pharmaceutical and biomedical industry and bridge the lacunae between material research, preclinical experimentation, and clinical reality.

Development, validation, and application of an RP-HPLC method for concurrent quantification of Minoxidil and Finasteride in a topical solution for hair regrowth.

A topical solution comprising of Minoxidil (MXL) and Finasteride (FNS) for alopecia is formulated in the present work, which essentially contains a lipid-Lauroglycol FCC as a penetration enhancer. The objective of the proposed work was to develop a rapid, simple, and robust reverse phase high performance liquid chromatographic (RP-HPLC) method to determine MXL and FNS in the said formulation. Herein, the chromatographic conditions were optimized based on the theoretical principles of separation and physicochemical properties such as pKa and log P of both the Active Pharmaceutical Ingredients (APIs). The separation was accomplished on an Inertsil® ODS-3 C18 column (150mm×4.6mm; 5µm of particle size) at 25°C by using a mobile phase composed of 70:30 v/v ratio of Methanol and Milli-Q water along with 0.5% Triethylamine at pH 6.4 adjusted with Ortho Phosphoric Acid. Drug peaks showed a good resolution at 210nm. The retention times for MXL and FNS were found to be 2.40min and 6.39min, respectively. The developed method was found to be linear (R2≥0.998) in a concentration range of 5-100µg/mL for both the drugs. The method was validated according to the ICH guidelines Q2 (R1). The ability of the method to differentiate between the types formulations was demonstrated by the in vitro diffusion data performed using a highly sophisticated Strat-M® membrane. The cumulative amount of drug released (MXL and FNS) at the end of 24hours was maximum for the topical formulation containing lipids prepared using isopropyl alcohol and propylene glycol as the base.

Assessing the effects of manual dexterity and playing computer games on catheter-wire manipulation for inexperienced operators.

AIM: To investigate the effect of playing computer games and manual dexterity on catheter-wire manipulation in a mechanical aortic model. MATERIAL AND METHODS: Medical student volunteers filled in a preprocedure questionnaire assessing their exposure to computer games. Their manual dexterity was measured using a smartphone game. They were then shown a video clip demonstrating renal artery cannulation and were asked to reproduce this. All attempts were timed. Two-tailed Student's t-test was used to compare continuous data, while Fisher's exact test was used for categorical data. RESULTS: Fifty students aged 18-22 years took part in the study. Forty-six completed the task at an average of 168 seconds (range 103-301 seconds). There was no significant difference in the dexterity score or time to cannulate the renal artery between male and female students. Students who played computer games for >10 hours per week had better dexterity scores than those who did not play computer games: 9.1 versus 10.2 seconds (p=0.0237). Four of 19 students who did not play computer games failed to complete the task, while all of those who played computer games regularly completed the task (p=0.0168). CONCLUSION: Playing computer games is associated with better manual dexterity and ability to complete a basic interventional radiology task for novices.

Advanced Ovarian Cancer: Primary or Interval Debulking? Five Categories of Patients in View of the Results of Randomized Trials and Tumor Biology: Primary Debulking Surgery and Interval Debulking Surgery for Advanced Ovarian Cancer.

BACKGROUND: Standard treatment of stage III and IV advanced ovarian cancer (AOC) consists of primary debulking surgery (PDS) followed by chemotherapy. Since the publication of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial, clinical practice has changed and many AOC patients are now treated with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). The best option remains unclear. Ovarian cancer is a heterogenic disease. Should we use the diversity in biology of the tumor and patterns of tumor localization to better stratify patients between both approaches? METHODS: This analysis was based on results of five phase III randomized controlled trials on PDS and IDS in AOC patients, three Cochrane reviews, and four meta-analyses. RESULTS: There is still no evidence that NACT-IDS is superior to PDS. Clinical status, tumor biology, and chemosensitivity should be taken into account to individualize surgical approach. Nonserous (type 1) tumors with favorable prognosis are less chemosensitive, and omitting optimal PDS will lead to less favorable outcome. For patients with advanced serous ovarian cancer (type 2) associated with severe comorbidity or low performance status, NACT-IDS is the preferred option. CONCLUSION: We propose stratifying AOC patients into five categories according to patterns of tumor spread (reflecting the biologic behavior), response to chemotherapy, and prognosis to make a more rational decision between PDS and NACT-IDS. IMPLICATIONS FOR PRACTICE: Trial results regarding effect and timing of debulking surgery on survival of patients with advanced ovarian cancer have been inconsistent and hence difficult to interpret. This review examines all randomized trials on primary and interval debulking surgery in advanced ovarian cancer, including the results of the newly published CHORUS (chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer) trial. On the basis of findings presented in this review and in view of recent molecular data on the heterogeneity of ovarian tumors, we propose prognostic categorization for patients with advanced ovarian cancer to better distinguish those who would optimally benefit from primary debulking from those who would better benefit from interval debulking following neoadjuvant chemotherapy.

Management of Acute Pulmonary Embolism: Consensus Statement for Indian Patients.

Pulmonary embolism (PE) is an important cause of morbidity and mortality among hospitalized patients. Although the exact epidemiology of PE is not known in India, Some of the studies show that more frequently it is missed and not managed appropriately leading to significant cardiovascular morbidity and mortality. Justification and purpose: Indian guidelines for the diagnosis and treatment of acute PE are not yet formulated. The objective of this consensus statement is to propose a diagnostic and management approach for acute PE in India. PROCESS: A working group of 15 experts in the management of acute PE (cardiologists, pulmonologist, haematologist, emergency specialist and intensivists). This consensus statement makes recommendations for diagnosis and management for PE based on literature review, including Indian data.

Quiescent-inflow single-shot magnetic resonance angiography using a highly undersampled radial k-space trajectory.

PURPOSE: We hypothesized that high undersampling factors could be used in conjunction with radial quiescent-inflow single-shot magnetic resonance angiography (MRA) to accelerate the data acquisition and enable multislice acquisitions. METHODS: Seven subjects were imaged on a 1.5 T MRI system. For multislice quiescent-inflow single-shot MRA, the venous saturation radiofrequency pulse, in-plane saturation radiofrequency pulse, and quiescent interval were applied only once before the first slice. RESULTS: The mean (standard deviation) measurements for the intra-arterial signal-to-noise ratio were as follows: Cartesian 1 slice-29.3 (5.5); radial 1 slice, 92 views-22.3 (3.6); radial 1 slice, 46 views-18.5 (2.0); radial 2 slices, 46 views-18.3 (3.2); and radial 3 slices, 32 views-21.7 (3.9), normalized for pixel size to 15.8. Horizontal striping was present with multislice radial quiescent-inflow single-shot MRA (especially with the three-slice acquisition) due to variable T1 relaxation between the concurrently acquired slices, but the image quality remained diagnostic. Vascular pathology in patients with peripheral arterial disease was well shown by all techniques. CONCLUSION: Very high undersampling factors in excess of 18 have been demonstrated for nonenhanced MRA using a radial quiescent-inflow single-shot technique, enabling the acquisition of two to three slices per cardiac cycle. Scan time for a complete peripheral MRA could be shortened to 2 min or less.

Sentinel node procedures in gynecologic cancers: an overview.

The aim of this study was to assess the value of sentinel lymph node procedures in gynecologic cancers. A systematic literature overview, using the PubMed database, was performed. In early stage vulvar, endometrial and cervical cancer, lymph node status is the most important prognostic factor. Lymphadenectomy, performed for adequate staging, is associated with high morbidity rates. Sentinel node procedures hold the promise of adequate staging with less treatment-related morbidity. Sentinel lymph node procedures in patients with early-stage vulvar cancer are associated with low recurrence rates, excellent survival, lower morbidity and shorter hospital stay compared to classical inguinal dissection. Therefore, these procedures should be the standard of care in early-stage unilateral vulvar cancer. Reports on sentinel lymph node procedures in endometrial and cervical cancer are ambiguous. The procedures in these cancers are reported in small studies only. Detection rates vary depending on the used injection sites and the used tracers. Bilateral detection rates are low and are not mentioned by default. Large controlled multi-institutional studies are necessary to evaluate the validity and the prognostic significance of the sentinel lymph node procedures in endometrial and cervical cancer.

Prophylactic Mechanical Circulatory Support Use in Elective Percutaneous Coronary Intervention for Patients With Stable Coronary Artery Disease.

BACKGROUND: Mechanical circulatory support (MCS) devices can be used in high-risk percutaneous coronary intervention (PCI). Our objective was to describe trends and outcomes of prophylactic MCS use in elective PCI for patients with stable coronary artery disease in the American College of Cardiology National Cardiovascular Data Registry's CathPCI registry. METHODS: Among 2 108 715 consecutive patients with stable coronary artery disease undergoing elective PCI in the CathPCI registry between 2009 and 2018, we examined patterns of prophylactic use of MCS. Propensity score models with inverse probability of treatment weighting compared effectiveness (in-hospital death, cardiogenic shock, or new heart failure) and safety (stroke, tamponade, major bleeding, or vascular complication requiring treatment) between patients treated with intra-aortic balloon pump versus other MCS (Impella or extracorporeal membrane oxygenation). RESULTS: Overall, 6905 (0.3%) patients underwent elective PCI with prophylactic MCS. MCS use trended up from 0.2% of elective PCIs in 2009 to 0.6% in 2018 (P<0.0001), driven by other MCS (P<0.0001), whereas intra-aortic balloon pump use remained low and constant (P=0.12). In-hospital major adverse cardiac events and cardiovascular complications occurred in 7.1% and 18.8% of elective PCI patients with prophylactic MCS use and 0.5% and 2.3% of patients without prophylactic MCS use. Intra-aortic balloon pump use was associated with a higher risk of major adverse cardiac events (9.6% versus 6.0%, adjusted odds ratio, 1.59 [95% CI, 1.32-1.91]) but lower risk of complications (18.2% versus 19.1%, adjusted odds ratio, 0.88 [95% CI, 0.77-0.99]) than use of other MCS. CONCLUSIONS: The use of prophylactic MCS has increased over time for elective PCI in patients with stable coronary artery disease. Intra-aortic balloon pump was associated with higher major adverse cardiac events but lower risk of procedural complications compared with other MCS.

Evidence for two different modes of tripeptide disappearance in human intestine. Uptake by peptide carrier systems and hydrolysis by peptide hydrolases.

The intestinal fate of two tripeptides (triglycine and trileucine), which differ markedly in solubility and molecular weight, have been investigated by jejunal perfusion in healthy human volunteers. Rates of glycine or leucine uptake from test solutions containing triglycine or trileucine were greater than from test solutions containing corresponding amounts of free glycine or free leucine, respectively. The rate of glycine uptake from a 100 mM triglycine solution was greater than that from a 150 mM diglycine solution. At each infused load of triglycine (e.g., 1,000 mumol/min) the rates (micromoles/minutes per 30 cm) of either triglycine disappearance (810 +/- 40) or glycine absorption (2,208 +/- 122) were markedly greater than the luminal accumulation rates of either diglycine (56 +/- 10) or free glycine (110 +/- 18). The luminal accumulation rate of free leucine during infusion of a 5 mM trileucine solution was over threefold greater than that of free glycine during the infusion of a 5 mM triglycine solution. Luminal fluid exhibited no hydrolytic activity against triglycine, but contained some activity against trileucine. Saturation of free amino acid carrier system with a large load of leucine did not affect glycine absorption rate from a triglycine test solution, but isoleucine markedly inhibited the uptake from a trileucine solution. When the carrier system for dipeptides was saturated with a large amount of glycylleucine, the disappearance rate of triglycine was considerably reduced while that of trileucine remained unaffected. After addition of glycylleucine to tripeptide solutions, there was a minimal increase in the luminal accumulation of diglycine, while dileucine accumulation was incresed by 62-fold.

A hepatocellular carcinoma-specific adenovirus variant, CV890, eliminates distant human liver tumors in combination with doxorubicin.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death in the world. Tumor resection remains the only curative treatment but is often not possible because of advanced stage and frequently unsuccessful because of intrahepatic or distant tumor recurrence. alpha-Fetoprotein (AFP), a tumor marker currently used for the diagnosis and management of HCC, is an oncofetal protein expressed in a majority of HCCs but rarely in normal hepatocytes. Because AFP gene expression is tightly regulated at the level of transcription, AFP transcriptional regulatory elements (TRE) are excellent candidates for generating HCC-specific oncolytic adenoviruses. We devised a new strategy for the AFP TRE to control an artificial E1A-IRES-E1B bicistronic cassette in an adenovirus 5 vector (Ad5) and constructed an HCC-specific oncolytic virus, CV890. In vitro, CV890 expression of the E1A and E1B genes, virus replication, and cytopathic effects were examined by Northern blot, Western blot, virus yield assay, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in AFP-producing cell lines (HepG2, Huh7, Hep3B, PLC/PRF/5, and SNU449), non-AFP-producing cell lines (Sk-Hep-1, Chang liver cell, LNCaP, HBL-100, PA-1, UM-UC-3, SW 780, Colo 201, and U118 MG), and non-AFP-producing human primary cells (lung fibroblast, bladder smooth muscle, and mammary epithelial). CV890 efficiently replicates in and destroys AFP-producing HCC cells as well as wild-type Ad5, but replication is highly attenuated in non-AFP-producing HCC cells or non-HCC cells. CV890 produced 5,000-100,000-fold less virus than wild-type Ad5 in non-AFP-producing cells. CV890 was attenuated 100-fold more than CV732, a virus containing the AFP TRE driving the E1A gene alone, in non-AFP-producing cells. These studies demonstrated that expression of both E1A and E1B genes under the control of a bicistronic AFP-E1A-IRES-E1B cassette yielded improvements in virus specificity equivalent to driving the E1A and E1B genes with two independent TREs yet requires only one TRE thereby conserving genomic space within the virus. Significantly, CV890 produced nearly the same yield of virus in cells that produced AFP over a 75-fold range, from a low of 60 ng AFP/10(6) cells/10 days to as high as 4585 ng AFP/10(6) cells/10 days. In vivo, antitumor efficacy of CV890 was examined in BALB/c-nu/nu mice containing large s.c. HepG2 or Hep3B tumor xenografts. Tumor volume of distant xenografts dropped below baseline 4 weeks after a single i.v. injection. Combination of CV890 with doxorubicin demonstrated synergistic antitumor efficacy, yielding complete elimination of distant Hep3B tumors 4 weeks after a single i.v. administration of both compounds. Our results support the clinical development of CV890 as an antineoplastic agent for the treatment of localized or metastatic HCC.

Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel.

CV787, a PSA+ prostate cell-specific adenovirus variant, is currently in Phase I/II clinical trials for the treatment of prostate cancer. We have previously demonstrated that a single administration of CV787 at 1 x 10(11) particle/animal could eliminate established tumors within 6 weeks in nude mouse xenografts (Yu et al., Cancer Res., 59: 4200-4203, 1999). We now demonstrate that CV787-mediated replication-dependent cytotoxicity is synergistic with the chemotherapeutic agents paclitaxel (Taxol) or docetaxel (Taxotere) both in vitro and in vivo. In vitro, cells were pretreated with CV787 24 h before taxane, pretreated with taxane 24 h before CV787, or treated with both agents simultaneously. Cell viability was determined at various time points by 3-[4,5-dimethylthiazole-2-4]-2,5-diphenyl-2H-tetrazolium bromide assay, and virus yield was examined by plaque assay. Addition of taxane to CV787 resulted in a synergistic increase of cytotoxicity toward the human prostate cancer cell line LNCaP, regardless of the timing of administration. There was no reduction in virus replication or specificity of CV787-based cytopathogenicity for prostate cancer cells (approximately 10,000 to 1) with the taxanes. p53 expression was significantly elevated in the cells treated with CV787 and taxane. In vivo, using the PSA+ LNCaP xenograft model of prostate cancer, a single i.v. dose of 1 x 10(8) particles CV787 and docetaxel in combination eliminates large preexistent distant tumors. Toxicity studies do not show a synergistic increase of toxicity of CV787 and taxane. These experiments demonstrate a synergistic antitumor efficacy for CV787 when combined with taxane and demonstrate an in vivo single-dose curative therapeutic index for CV787 of over 1000:1.

Docetaxel followed by hormone therapy after failure of definitive treatments for clinically localized/locally advanced prostate cancer: preliminary results.

An increasingly important issue in the management of prostate cancer is the occurrence of biochemical failure (ie, increasing serum prostate-specific antigen [PSA] levels) in patients with clinically localized prostate cancer who initially underwent definitive treatments with curative intent (prostatectomy and/or radiation therapy). This pilot trial evaluated chemotherapy followed by hormone therapy for a defined period in patients with biochemical (and possibly clinical) recurrence after initial local therapies for localized/locally advanced prostate cancer. Patients who developed increasing PSA > 4 ng/mL after initial prostatectomy and/or radiation therapy received docetaxel, 70 mg/m(2) every 3 weeks for up to 6 courses, followed by 4 months of total androgen suppression (using a luteinizing hormone-releasing hormone agonist plus bicalutamide, 50 mg/d) and 8 months of peripheral androgen blockade (using finasteride, 5 mg/d, plus bicalutamide, 50 mg/d). Twenty-seven patients have enrolled to date, 23 of whom received four or six cycles of docetaxel before hormonal therapies. Seventeen (74%) of 23 patients who completed four to six cycles of chemotherapy had a > or =40% decrease in PSA, and 16 (89%) of 18 patients who completed 4 months of total androgen suppression achieved PSA values of < or =0.1. The most common hematologic toxicity was grade (3/4) neutropenia; grade 3 nonhematologic toxicities were rare, and no grade 4 nonhematologic toxicities were reported. Thus, the preliminary results suggest that docetaxel before hormonal therapy includes a PSA response in many prostate cancer patients with biochemical failure after definitive local therapies.

Once-a-week vs conventional daily radiation treatment for lung cancer: final report.

This is the final report of a prospective randomized clinical trial which began in 1982 and explored once-a-week hypofractionation in lung cancer patients with unresectable, non-metastatic, measurable, loco-regionally advanced disease. Stratification to this protocol has been done by histology, stage, and performance status categories. Patients with ipsilateral supraclavicular and/or brain metastases as the only evidence of distant spread, have been included in the study, but were stratified and analyzed separately. The two protocol arms were: (I) Conventional daily radiation [5 x W]-5 daily fractions of 2 Gy each to a total dose of 60 Gy in 6 weeks, protecting the spinal (SC) at 45 Gy and (II) Once-a-week radiation [1 x W]-one weekly fraction of 5 Gy each to a total tumor dose of 60 Gy in 12 weeks protecting the SC at 30 Gy. A total of 150 patients have been entered. Of these, 30 pts. are inevaluable, but the reasons of non-compliance, progression of disease or death due to intercurrent disease were of equal incidence in both groups. Of the 120 evaluable patients, 63 were treated 5 x W and 57 with 1 x W therapy. Complete tumor responses are similar in both arms with 1 x W pts demonstrating a numerical advantage (26% vs 17%). The average follow-up of the entire series is 3 yrs with a range of 12-66 months. Survival data is comparable in both groups with the 12 and 24 month actuarial survival of 49% and 23% for the 5 x W arm and 59% and 29% for the 1 x W arm. 1 x W patients continue to show a better tolerance than 5 x W pts. There are sufficient long-term survivors in both arms to assess chronic toxicity. The number of patients alive at 12, 18, and 24 months were 25, 11, and 5 for the 5 x W arm and 29, 16, and 7 for the 1 x W arm. No significant differences in late reactions have been noted. The longest surviving patient in the 1 x W arm is now 48 months after treatment.

A prospective randomized trial comparing once-a-week vs daily radiation therapy for locally-advanced, non-metastatic, lung cancer: a preliminary report.

This is the first report of an on-going Phase III protocol for patients with locally-advanced, non-metastatic, measurable lung cancer. The study randomizes two arms: 6000 rad using 500 rad fractions once a week (1 X W) for 12 weeks with spinal cord (SC) protection at 3000 rad; and 6000 rad using 200 rad fractions daily (5 X W) for 6 weeks with SC protection at 4500 rad. Both arms use an initially large loco-regional field that is further reduced when tumor doses reach 3000 rad in (1 X W) arm and 5000 rad in (5 X W) arm. The protocol was activated April 1982; as of August 1984, it had accrued 100 patients of whom 68 were evaluable [29 (1 X W) and 39 (5 X W)]. There have been no major differences in tumor responses or failure patterns between the (1 X W) and (5 X W) arms; response rates have been 69 and 64%; CR 31 and 20%; total incidence of local failures 20 and 23%; and overall incidence of distant failures 34 and 43%, respectively. The (1 X W) arm has been far better tolerated with 76% of its patients free of any esophagitis and 97% without weight loss, as compared to only 33 and 67% in the (5 X W), respectively. The (1 X W) arm has not conveyed loss in tumor control effectiveness, in-treatment progression, or higher incidence of distant spread. Subacute and chronic complications have been minimal with either treatment. No fatal or life-threatening toxicities have occurred; the incidence of severe complications has been 7% in the (1 X W) arm and 8% in the (5 X W) arm. Nevertheless, the number of patients alive and at risk greater than or equal to 12 months is still relatively small; definitive statements regarding very late toxic reactions cannot yet be made. Compared to their protocyptes [a (1 X W) Pilot Study and the 6000 rad/6 weeks arm of RTOG Protocol 73-01], results in the present protocol arms have not been different from what was expected. Once a week RT yields results that appear no different from those achieved with conventional RT in lung cancer.

Radiosurgery for cerebral arteriovenous malformations: assessment of early phase magnetic resonance imaging and significance of gadolinium-DTPA enhancement.

PURPOSE: To evaluate the initial changes within the nidus of arteriovenous malformations (AVMs) and to assess the reaction to the brain tissue surrounding AVMs after radiosurgery by serial magnetic resonance (MR) imaging. METHODS AND MATERIALS: Twenty-one patients, treated using 60Co gamma knife unit with cerebral AVMs, were retrospectively evaluated. Forty-seven follow-up MR images of the 21 patients were performed including 10 patients with two or more serial gadolinium enhanced studies (Gd-MR). Two or more sequential MR angiographies (MRA) were obtained in 13 patients. Three-dimensional (3D) time-of-flight MRA and two-dimensional (2D) phase contrast MRA were used in 13 patients for evaluating the flow changes of AVMs. The follow-up period after radiosurgery ranged from 3 to 30 months (average 10.8 months) and the interval time of MRI ranged from 34 days to 13 months (average 4.9 months). RESULTS: Reduction of nidus size was observed in 14 of 21 patients (67%) between 4 to 13 months on spin echo (SE) images. Complete obliteration was observed on SE images in 4 of these 14 patients; three were confirmed by conventional angiography. New hyperintense areas surrounding the nidus on T2s-weighted images (T2WI) developed in 9 of the 14 patients who showed nidus reduction between 5 to 17 months after radiosurgery; in three patients, size of the hyperintense area started to decrease between 6 to 7 months after its appearance. Probable radiation necrosis of pons developed in one patient 26 months after radiosurgery. The irradiated area within the AVM nidus was significantly enhanced in 8 of the 10 patients who underwent Gd-MR. The degrees of enhancement within the nidus increased with time in 7 of the 10 patients. Overall, total enhancement of irradiated areas was observed in four of the 10 patients; in three of the four, the enhancement decreased in size and degree, indicating nidus reduction. In three patients who had a partial volume irradiation within the nidus, the enhancing areas corresponded with the exact portions of irradiated volume. The nidus reduction was observed in 7 of the 13 patients on MRA during 5 to 13 months after radiosurgery. MRA was more useful compared to SE images in four of the seven patients in evaluating the size change of AVM nidus, feeding arteries, and draining veins. CONCLUSION: Magnetic resonance imaging and MRA were useful in assessing the progress of nidus reduction. T2-weighted imaging was sensitive to radiation-induced reaction in and around the AVM nidus. The enhancement within the AVM nidus on Gd-MR may represent the initial sign of nidus reduction and demonstrates the exact location of irradiation in the nidus. The changes of the enhancement pattern are presumed to represent the processes of nidus reduction and irradiated reaction within the AVM nidus.

Effects of jejunoileal bypass on the enterohepatic circulation of bile acids, bacterial flora in the upper small intestine, and absorption of vitamin B12.

Eleven morbidly obese patients were studied before and at various time intervals after jejunoileal bypass (JIB). Bile acid deconjugation was assessed with the bile acid breath test and bile acid absorption by analyzing the fecal excretion of both radioactively labeled and unlabeled bile acids. In addition, aerobic and anaerobic cultures of upper small intestinal aspirates, the Schilling vitamin B12 absorption test, and fecal fat analysis were performed. All patients developed marked diarrhea and steatorrhea after JIB. The bile acid breath test was positive in all 11 patients after JIB. In 7 of the 11 patients, this test was already slightly positive before JIB. In every instance, however, the bile acid breath test became significantly more abnormal after the bypass operation. The fecal excretion of labeled bile acids increased significantly. However, the increase in the quantitative excretion of the bile acids did not reach statistical significance. The concentrations of bile acids in fecal water were considerably below the levels required to induce diarrhea. This was mainly the result of a low fecal pH and consequent low aqueous solubility. Jejunoileal bypass effected a major shift in fecal bile acids from the secondary bile acids, lithocholic acid and deoxycholic acid, to the respective primary compounds, chenodeoxycholic acid and cholic acid. There were no significant changes in the small bowel bacteriologic findings after JIB. In 5 out of the 9 patients in whom bacteriologic studies were performed, the cultures were positive before the operation. The Schilling vitamin B12 absorption test showed in all patients a significant drop in the 24-hour urinary 57Co excretion rate after JIB.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiation therapy for transitional cell bladder carcinoma. A ten-year experience.

From 1969 to 1979, 185 patients with transitional cell bladder carcinoma were curatively irradiated; 147 were treated with radiation alone (RT) and 38 received a combined radiation + surgery (RT + S). At presentation, 40 percent of the patients had obstructive uropathy which yielded a much lower five-year survival (18%) than when it was absent (50%). The overall five-year disease-free survival was 30 percent and 53 percent for patients treated with radical RT and RT + S, respectively. Among patients subjected to preoperative irradiation, downstaging was seen in 40 percent of postsurgical specimens, with 27 percent of the specimens showing no evidence of tumor; these patients had excellent survival. Severe complications were seen in 3 percent, 10 percent, and 27 percent of patients in the radical RT, RT + S, and radical RT + salvage cystectomy groups. Survival results, pelvic controls, and patterns of failure are presented.

bcl-2/bax ratio as a predictive marker for therapeutic response to radiotherapy in patients with prostate cancer.

OBJECTIVES: Markers predictive of therapeutic response of prostatic tumors to radiotherapy may have major significance in optimizing effective treatment of prostate cancer. Because inherent cellular radioresistance plays a critical role in the failure of radiotherapy, in this study, we investigated whether there is a correlation between the ratio of two apoptosis regulators, bcl-2 (apoptosis suppressor) and bax (apoptosis inducer) in prostatic tumors and the clinical response to radiotherapy in patients with localized prostate cancer. METHODS: A retrospective review of records of 41 patients who underwent external beam radiotherapy for prostate cancer was conducted. On the basis of post-treatment prostate biopsy and prostate-specific antigen (PSA) criteria, the cancers of 20 patients were classified as radiation nonresponders and 21 as radiation responders. Immunohistochemical analysis was performed on paraffin-embedded prostate sections to determine the level of expression of the two apoptotic proteins, bcl-2 and bax, in tumor cells. RESULTS: bcl-2 immunoreactivity was significantly higher in prostatic tumors not responsive to radiotherapy (38.6+/-4.1), compared with the radiation responders (24.1+/-4.6) (P <0.001). Expression of bax protein was lower in nonresponders, but values were not significantly different from the responders. The resulting significantly higher bcl-2/bax ratio (P <0.01) correlated with poor therapeutic responsiveness of prostate cancer to radiotherapy (1.12+/-0.12 and 0.56+/-0.13, for nonresponders and responders, respectively). This correlation (r=0.67) was independent of age, PSA, and Gleason score. CONCLUSIONS: These findings suggest that patients with an elevated bcl-2/bax ratio are at increased risk of their cancer failing to respond to radiotherapy. This study suggests a predictive value for the bcl-2/bax ratio as a potential molecular marker for predicting radioresistance of prostatic tumors.

Sustained ophthalmic delivery of ofloxacin from a pH triggered in situ gelling system.

The poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions due to rapid precorneal elimination of the drug may be overcome by the use of in situ gel-forming systems that are instilled as drops into the eye and undergo a sol-gel transition in the cul-de-sac. The present work describes the formulation and evaluation of an ophthalmic delivery system of an antibacterial agent, ofloxacin, based on the concept of pH-triggered in situ gelation. Polyacrylic acid (Carbopol 940) was used as the gelling agent in combination with hydroxypropylmethylcellulose (Methocel E50LV) which acted as a viscosity enhancing agent. The developed formulation was therapeutically efficacious, stable, non-irritant and provided sustained release of the drug over an 8-h period. The developed system is thus a viable alternative to conventional eye drops.