First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.

BACKGROUND: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. PATIENTS AND METHODS: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). RESULTS: With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. CONCLUSIONS: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

The value of interventional radiology in clinical trial teams: experience from the BATTLE lung cancer trials.

AIM: To report on the multidisciplinary approach, focusing specifically on the role of the interventional radiologist (IR), used to support the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) and BATTLE-2 trials. MATERIALS AND METHODS: Patients who underwent percutaneous image-guided biopsy for the BATTLE and BATTLE-2 trials were reviewed. A radiology-based, three-point, lesion-scoring system was developed and used by two IRs. Lesions were given a score of 3 (most likely to yield sufficient material for biomarker analysis) if they met the following criteria: size >2 cm, solid mass, demonstrated imaging evidence of viability, and were technically easy to sample. Lesions not meeting all four criteria were scored 2 with the missing criteria noted as negative factors. Lesions considered to have risks that outweighed potential benefits receive a score of 1 and were not biopsied. Univariate and multivariate analyses were performed to evaluate the score's ability to predict successful yield for biomarker adequacy. RESULTS: A total of 555 biopsies were performed. The overall yield for analysis of the required biomarkers was 86.1% (478/555), and 84% (268/319) and 88.9% (210/236) for BATTLE and BATTLE-2, respectively (p=0.09). Lesions receiving a score of 3 were adequate for biomarker analysis in 89% of cases. Lesions receiving a score of 2 with more than two negative factors were adequate for molecular analysis in 69.2% (IR1, p=0.03) and 74% (IR2, p=0.04) of cases. The two IRs scored 78.4% of the lesions the same indicating moderate agreement (kappa=0.55; 95% confidence interval [CI]: 0.48, 0.61). CONCLUSIONS: IRs add value to clinical trial teams by optimising lesions selected for biopsy and biomarker analysis.

Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a lethal neoplasm exhibiting resistance to most treatment regimens and requires effective therapeutic options. Though an effective strategy in many cancer, targeted therapy is relatively unexplored in MPM because the therapeutically important oncogenic pathways and networks in MPM are largely unknown. MATERIALS AND METHODS: We carried out gene expression microarray profiling of 53 surgically resected MPMs tumors along with paired normal tissue. We also carried out whole transcriptomic sequence (RNA-seq) analysis on eight tumor specimens. Taqman-based quantitative Reverse-transcription polymerase chain reaction (qRT-PCR), western analysis and immunohistochemistry (IHC) analysis of mitotic arrest deficient-like 1 (MAD2L1) was carried out on tissue specimens. Cell viability assays of MPM cell lines were carried out to assess sensitivity to specific small molecule inhibitors. RESULTS: Bioinformatics analysis of the microarray data followed by pathway analysis revealed that the mitotic spindle assembly checkpoint (MSAC) pathway was most significantly altered in MPM tumors with upregulation of 18 component genes, including MAD2L1 gene. We validated the microarray data for MAD2L1 expression using quantitative qRT-PCR and western blot analysis on tissue lysates. Additionally, we analyzed expression of the MAD2L1 protein by IHC using an independent tissue microarray set of 80 MPM tissue samples. Robust clustering of gene expression data revealed three novel subgroups of tumors, with unique expression profiles, and showed differential expression of MSAC pathway genes. Network analysis of the microarray data showed the cytoskeleton/spindle microtubules network was the second-most significantly affected network. We also demonstrate that a nontaxane small molecule inhibitor, epothilone B, targeting the microtubules have great efficacy in decreasing viability of 14 MPM cell lines. CONCLUSIONS: Overall, our findings show that MPM tumors have significant deregulation of the MSAC pathway and the microtubule network, it can be classified into three novel molecular subgroups of potential therapeutic importance and epothilone B is a promising therapeutic agent for MPM.

Effect of Various Toothpaste Tablets on Gloss and Surface Roughness of Resin-based Composite Materials.

OBJECTIVES: To evaluate the effect of various toothpaste tablets on gloss and surface roughness of resin-based composite. METHODS AND MATERIALS: Sixty-four resin-based composite specimens were divided into four groups of 16 specimens each. Gloss and roughness were measured before and after simulated brushing with three types of toothpaste tablets and one conventional toothpaste: CT: Chewtab Toothpaste Tablets; AT: Anticavity Toothpaste Tablets; HC: Charcoal Toothpaste Tablets; CP: Cavity Protection toothpaste. The Kruskal-- Wallis procedure was performed to compare the differences by groups. Post-hoc comparisons were conducted with Bonferroni corrections (α=0.05). RESULTS: There was a significant drop in gloss for all groups. CT and AT maintained the highest gloss with means of 81.6 GU and 74.1 GU, respectively. The lowest gloss of 24.5 GU was observed for HC. There was a significant increase in roughness for all groups except for CT. CT had the lowest roughness with a mean of 0.034 µm, while HC had the highest roughness with a mean of 0.074 µm. There was a significant correlation between post-brushing gloss and post-brushing roughness (p<0.001, r=-0.884). CONCLUSION: Chewtab Toothpaste Tablets had the least effect on gloss and roughness, while Charcoal Toothpaste Tablets had the most negative effect on the surface properties of resin-based composites.

Eighth international mesothelioma interest group.

The eighth International Mesothelioma Interest Group (IMIG) meeting was held in Chicago, IL, United States, in 19-22 October 2006 to discuss mesothelioma - the cancer often linked to asbestos exposure. It is a very aggressive malignancy with a median survival of less than 1 year from diagnosis. Millions of people have been exposed worldwide to asbestos, especially during the second half of the twentieth century when asbestos use increased significantly. The tons of asbestos utilized in the past remain a health hazard for current and future generations because asbestos is difficult to be disposed off. This makes asbestos and mesothelioma research a public health issue in addition to a medical problem. Moreover, the very high costs of asbestos litigation have a significant impact on the whole economy. In the United States, up until 2001, defendant companies had paid 54 billion dollars in claims and estimated future liabilities ranged from 145 to 210 billion. Therefore, asbestos research is of great interest to a large audience that includes patients, millions of asbestos-exposed individuals, scientists, physicians, public health officials, politicians, unions of asbestos workers, lawyers and the public at large. During the past few years, there has been significant progress in understanding the process of mineral fiber carcinogenesis and mesothelioma pathogenesis. With improved understanding of the pathogenesis of mesothelioma, new diagnostic, preventive and therapeutic options are being developed. A total of 247 papers were presented at the IMIG: the abstracts of these presentations were published in Lung Cancer, Supplement 1, October 2006. Here, experts in different disciplines critically review some of the most exciting presentations of the IMIG meeting. The result is a comprehensive review of the research field of asbestos carcinogenesis and mesothelioma, and of the progress that has been made in recent years in both basic and clinical sciences.

Behaviour change interventions to influence antimicrobial prescribing: a cross-sectional analysis of reports from UK state-of-the-art scientific conferences.

BACKGROUND: To improve the quality of antimicrobial stewardship (AMS) interventions the application of behavioural sciences supported by multidisciplinary collaboration has been recommended. We analysed major UK scientific research conferences to investigate AMS behaviour change intervention reporting. METHODS: Leading UK 2015 scientific conference abstracts for 30 clinical specialties were identified and interrogated. All AMS and/or antimicrobial resistance(AMR) abstracts were identified using validated search criteria. Abstracts were independently reviewed by four researchers with reported behavioural interventions classified using a behaviour change taxonomy. RESULTS: Conferences ran for 110 days with >57,000 delegates. 311/12,313(2.5%) AMS-AMR abstracts (oral and poster) were identified. 118/311(40%) were presented at the UK's infectious diseases/microbiology conference. 56/311(18%) AMS-AMR abstracts described behaviour change interventions. These were identified across 12/30(40%) conferences. The commonest abstract reporting behaviour change interventions were quality improvement projects [44/56 (79%)]. In total 71 unique behaviour change functions were identified. Policy categories; "guidelines" (16/71) and "service provision" (11/71) were the most frequently reported. Intervention functions; "education" (6/71), "persuasion" (7/71), and "enablement" (9/71) were also common. Only infection and primary care conferences reported studies that contained multiple behaviour change interventions. The remaining 10 specialties tended to report a narrow range of interventions focusing on "guidelines" and "enablement". CONCLUSION: Despite the benefits of behaviour change interventions on antimicrobial prescribing, very few AMS-AMR studies reported implementing them in 2015. AMS interventions must focus on promoting behaviour change towards antimicrobial prescribing. Greater focus must be placed on non-infection specialties to engage with the issue of behaviour change towards antimicrobial use.

Comparison of alveolar bone loss, alveolar bone density and second metacarpal bone density, salivary and gingival crevicular fluid interleukin-6 concentrations in healthy premenopausal and postmenopausal women on estrogen therapy.

BACKGROUND: Osteoporosis is an age-related metabolic bone disease characterized by decreased mass and increased susceptibility to fracture. The literature suggests a relationship between oral bone loss and skeletal osteoporosis; however, most studies have produced conflicting results. The purpose of this study was to determine if a relationship exists among alveolar bone loss, alveolar bone density, second metacarpal density, salivary and gingival crevicular fluid interleukin 6 (IL-6), and IL-8 concentrations in premenopausal and postmenopausal healthy women receiving estrogen therapy. METHODS: Twenty-eight healthy women (aged 23-78) were evaluated for this study. A vertical bitewing and hand radiographs were taken, and the subjects were evaluated for the presence of active periodontitis. The bitewing and hand radiographs were digitized, and measurements were made from the cemento-enamel junction to the alveolar crest from both arches. Bone density was evaluated in the maxillary and mandibular alveolar process and at the mid-shaft of the second metacarpal. Percent cortical area and the moment of inertia measurements were also determined. Stimulated whole saliva was collected for a 5-min period using a cube of paraffin as a stimulant and was analyzed for total protein by a colorimetric reaction and IL-6 and IL-8 by ELISA. RESULTS: The results of the study showed that postmenopausal women on estrogen therapy had more alveolar bone loss, more missing teeth, and reduced alveolar and second metacarpal bone density than premenopausal women. In addition, postmenopausal women on estrogen therapy had higher salivary IL-6 concentrations than premenopausal women. Alveolar bone densities were also strongly correlated to second metacarpal densities. CONCLUSIONS: The results of the study suggest that changes in alveolar bone density and levels of bone resorptive cytokines in saliva may be secondary to changes in menopausal status. These changes may predispose loss of alveolar bone with resultant loss of teeth.

Failure of the porous-coated anatomic prosthesis in total knee arthroplasty due to severe polyethylene wear.

Four hundred and eighty-seven total knee arthroplasties were performed by a single surgeon with use of a porous-coated anatomic prosthesis between 1982 and 1989. There were thirty-two clinical failures (7 per cent) due to severe wear of the surfaces of the tibial and patellar polyethylene components. Thirty patients had a revision. The average time to failure of the implant was four and one-half years. The initial clinical symptoms of failure by wear consisted of a painless effusion with a decreased range of motion. Subsequent pain was considered as the criterion for failure necessitating operative intervention. Increased weight and decreased age of the patient and a thinner tibial component were significant predictors of an increased risk of failure (p < 0.01). Examination of retrieved tibial components revealed extensive delamination caused by fracture of the polyethylene at a depth of about one millimeter below the surface. Cracks that had propagated in from the medial and lateral peripheries of the tibial component toward the center of the condyles were also a common finding. It appears that the design of the implant as well as clinical factors (the age and weight of the patient) contributed to the mechanical failure of the polyethylene of these implants.

Rapamycin enriches for CD4(+) CD25(+) CD27(+) Foxp3(+) regulatory T cells in ex vivo-expanded CD25-enriched products from healthy donors and patients with multiple sclerosis.

BACKGROUND: CD4(+) CD25(bright+) regulatory T cells (Treg) can be expanded to clinical doses using CD3/CD28 Ab-coated beads plus IL-2. However, this method requires high purity of the starting population to prevent overgrowth by non-regulatory T cells. Rapamycin, an agent that inhibits T-cell proliferation but selectively spares Treg, may be a means to expand Treg from less pure CD25-enriched cells. METHODS: CD25-enriched cells were prepared by a single-step immunomagnetic-selection using anti-CD25 microbeads. The cells were activated with a single addition of anti-CD3/CD28 beads and expanded in ex vivo 15-5% HS and autologous CD4(+) CD25(-) feeder cells,+/-rapamycin (0.01-20 ng/mL). IL-2 was added on day 3. Cells were rested for 2 days in ex vivo 15-5% HS and tested for phenotype, intracellular Foxp3 protein and suppressor activity. RESULTS: In the absence of rapamycin, CD25-enriched fractions expanded >17 000-fold by 21 days. Although suppressor activity was detected to day 14, it declined significantly by 21 days as non-regulatory cells expanded. The addition of rapamycin inhibited expansion of non-regulatory T cells at doses > or =1 ng/mL while increasing suppressor activity and the percentage of CD4(+) CD25(+) CD27(+) Foxp3(+) cells. Rapamycin did not enrich for Foxp3(+) cells in expanded cultures of CD4(+) CD25(-) cells. Treg were also readily expanded in cultures of CD25-enriched cells obtained from patients with multiple sclerosis in the presence of rapamycin. DISCUSSION: The addition of 1-20 ng/mL rapamycin to CD25-enriched cultures increased the purity of cells with the phenotype and function of Treg. This approach may alleviate the need for rigorous enrichment of Treg prior to activation and expansion for potential clinical use.

Analysis of capsular tissue from patients undergoing primary and revision total hip arthroplasty.

Late aseptic loosening of revision total hip replacements is a common cause of failure. At revision surgery, a foreign pseudo capsule membrane surrounding the implant develops. These tissues are thought to reflect a response due in part to an increase in particulate debris, generated by normal wear of the bearing surfaces. The foreign body membrane consists of macrophages and giant cells lying in between the bone and the implant. The cell types identified at the interface included lymphocytes, histiocytes, macrophages, and giant cells, and their contribution to implant loosening due to bone resorption is the focus of this investigation. Capsular tissues surrounding failed joint arthroplasties were characteristically different by gross morphological observations. The capsular tissue contained a region of tissue approximately 4-6 cell layers in depth lining the capsule, which resembled synovial like cells. This region of the capsular tissue consisted of loosely organized fibrous tissue containing numerous histiocytes and foreign body giant cells demonstrated by hematoxylin and eosin. Immunological staining of the capsular tissue for IL-1 activity showed the reactivity to be localized directly adjacent to the implant in well vascularized areas. Tissue farthest from the implant were less reactive and resembled tissue extracted from primary patients. Quantitative ELISA data for IL-1 activity from these areas reflect the observations observed by immunostaining.

Smooth muscle myosin heavy chains combine to form three native myosin isoforms.

Two smooth muscle myosin heavy chains (MHC; SM1 and SM2) of approximately 204 and 200 kDa exist in smooth muscle cells and can be visualized on reducing sodium dodecyl sulfate (SDS)-polyacrylamide gels. Chymotryptic digestion of the native myosin molecule results in two fragments: heavy meromyosin (HMM) and light meromyosin (LMM). LMM is the alpha-helical coiled-coil carboxy terminal half of the molecule containing the difference peptide between SM1 and SM2. Electrophoresis of the LMM fragments on a reducing SDS-polyacrylamide gel resolves two subunits from the two MHC [LM1 from SM1 (approximately 100 kDa) and LM2 from SM2 (approximately 95 kDa), where LM1 and LM2 are LMM from SM1 and SM2, respectively]. CuCl2 oxidation of the LMM fragment forms intramolecular disulfide bonds between adjacent cysteines on the two LMM fragments. When the native LMM is oxidized with CuCl2 and run on a nonreducing SDS-polyacrylamide gel, three bands are observed, which migrate at approximately 195, 190, and 185 kDa (bands 1, 2, and 3). Excision of these bands and electrophoresis on a reducing SDS-polyacrylamide gel show their subunit composition. Band 1 is composed solely of LM1. Band 2 is composed of an equal ratio of LM1 and LM2, and band 3 is composed solely of LM2. Using a variety of biochemical procedures, along with nonreducing SDS-polyacrylamide gels, we interpret these results to indicate that there are three smooth muscle myosin isoforms that result from the various combinations of the two smooth muscle MHC (SM1 homodimer, SM1-SM2 heterodimer, and SM2 homodimer).

Comparison of tissues adjacent to different mechanical stress areas from patients with clinically failed implants.

Implants consisting of metallic and polymeric components are used to treat musculoskeletal diseases. At revision surgery, significant wear products maybe recovered from tissues adjacent to failed implants. The failing implant is clinically associated with pain, and radiographic analysis demonstrates deterioration of the bone surrounding the implant. There is concern that areas of high contact stresses and articulating surfaces lead to the generation of wear particles that trigger a biological response that mediates the lysis of bone. This study compares the tissues retrieved from various areas exposed to different mechanical stresses. Tissues were processed for biochemical and immunohistochemical factors (cytokines) responsible for bone resorption. The results from this study showed by both quantitative enzyme linked immunoassay and qualitatively by immunohistology a marked increase in cytokines, interleukin-1 and tumor necrosis factor, in areas of articulation compared to other areas. Evaluation of tissues histochemically demonstrated the presence of fibroblast, macrophages, and multinucleated giant cells. Overall, the results indicate that the generation of wear particles lead to the production of biological mediators responsible for the failure of the implants.

Hypocalcemic-induced tetany that causes triceps and bilateral quadriceps tendon ruptures.

Traumatic ruptures of the triceps are very rare among tendon injuries. A unique case of hypocalcemic tetany that induced spontaneous triceps tendon avulsion with associated bilateral quadriceps tendon ruptures is reported. The current orthopaedic literature is reviewed, and a new application of an existing surgical treatment for repair of the major tendon ruptures is described.

Non-specific immunohistochemical responses in surgical tissue collected from total joint arthroplasty.

Tissues retrieved during revision arthroplasty (n = 25) were processed for routine immunohistochemical techniques to localize the presence of bone resorbing cytokines (IL-1, TNF alpha, and IL-6), and to identify areas of significant necrosis and metallic deposition. Tissues were processed and embedded according to standard laboratory techniques. Several tissue sections were prepared for each sample collected. Several sequential slides were used to demonstrate a thorough histopathological evaluation. Other slides of the same tissues were processed for immunohistochemical evaluation specifically for the localization of cytokines. To identify specific cytokine reactions, antibodies against cytokines were added in working dilutions overnight. Another set of slides were incubated overnight with nonspecific protein and served as negative controls. At the end of the incubation period, all slides were washed in buffer and a second antibody conjugated with peroxidase was added to both sets of slides for one hour. The slides were developed for peroxidase activity. The results revealed that there were several locations on the tissues that appeared highly reactive for cytokines. However, some of these areas turned out to be nonspecific when compared with negative controls and the Hematoxylin and Eosin stained slides. Areas of extreme necrosis or where metal debris was present demonstrated sites of nonspecific reactivity. Areas of necrosis have a high nonspecific affinity for antibodies and these areas of necrosis can be demonstrated on the Hematoxylin and Eosin sections, and were avoided in determining the amount of specific cellular reactivity. The results of this study strongly suggest that the aforementioned factors must be carefully controlled in determining true cellular responses that causes resorption of bone and eventually implant failure.

Immunofluorescent examination of the skin of rabies-infected animals as a means of early detection of rabies virus antigen.

Correlations were made on immunofluorescence positivity to antirabies conjugate between cranium-derived nerve fibers in skin and traditional samplings of brain tissue from several species and illness categories of animals with naturally acquired rabies. The overall correlation of results from all categories was about 98% (n, 104) for those that were brain positive and 100% (n, 99) for those that were brain negative. Some animals that ultimately developed rabies were found to have immunofluorescence-positive results 2 or more days before the onset of clinical signs in both natural and experimental infections. The percentage of those with positive skin immunofluorescence results increased as the onset of symptoms approached. From the midcourse period of illness to death, the correlation between skin and brain approached 100%. Different vaccines, commonly given to prevent rabies and other diseases of dogs and cats, were administered to groups of mice and were found to not produce false-positive results when their skin was examined by immunofluorescence for rabies virus antigen. These data suggest that examination of surgical biopsy specimens by immunofluorescence for rabies virus antigen is a useful and reliable diagnostic tool to evaluate the rabies status of biting dogs or cats, or to confirm a clinical diagnosis of rabies in the species tested. The biopsy evaluation of any other species as a means of assessing bite risk is not suggested by these data.

The arthroscopic evaluation and characteristics of severe polyethylene wear in total knee arthroplasty.

Four hundred eighty-seven porous-coated anatomic (PCA) total arthroplasties were performed by the same surgeon between January 1982 and December 1989. Forty-three patients developed an effusion, pain, or decreased range of motion after a period of pain-free function. Average time to onset of symptoms was 4.5 years. Joint fluid aspirations were sterile and revealed the presence of high-density polyethylene crystals, best seen under a polarizing microscope. Thirty-three of these patients were arthroscopically evaluated. Extensive polyethylene wear and delamination were identified. Wear was most extensive on the medial tibial plateau. Patellar polyethylene wear was also identified. Substantial femoral component abrasions were present in areas where exposure of the tibial and patellar base plates had occurred. Diffuse granulomatous synovial tissue revealed an extensive foreign-body giant-cell reaction to polyethylene particles. In all patients, temporary symptomatic relief was obtained after arthroscopy. Thirty-two patients have, subsequently, had revision surgery. Intraoperative findings and biopsies at the time of revision confirmed the arthroscopic observations. Arthroscopy allowed the accurate diagnosis of polyethylene wear, provided temporary symptomatic relief, and facilitated preoperative revision planning. Polyethylene wear in PCA total knee replacements was related to patient characteristics (larger, younger, more active patients), nonconforming femotibial articular surfaces, thin polyethylene, heat-pressed polyethylene, and nonrigid mechanical attachment of polyethylene to metal base plate. Younger, more active, larger patients with total knee arthroplasties should be observed closely for evidence of polyethylene wear.

Cellular responses to various levels of sustained delivery of testosterone in the ventral prostate.

The objective of this study was to evaluate the effect of various dosages of testosterone (T) delivered in a sustained manner by means of tricalcium phosphate-lysine (TCPL) delivery system on morphological changes of prostatic tissue using adult male rats as a model. In this experiment, adult male rats (250-300 g BW) were randomly divided into five equal groups (n = 8). Rats in group I, II, and III were castrated and implanted subcutaneously with TCPL loaded with three different dosages (10, 100 and 200 mg T, respectively) of T. Rats in group IV were castrated and implanted with sharm TCPL capsules, and rats in group V served as intact unimplanted controls. Surgical aseptic techniques were performed according to standard laboratory procedures. At the end of 4 and 12 weeks post implantation, four animals from each group were sacrificed and the prostate tissues were collected, weighted, and embedded for histo-pathological evaluations. Data collected from this study have shown that exogenous intake of T delivered in a sustained manner for twelve weeks induced several pathophysiological conditions in ventral prostatic tissue in comparison to the control and sham operated groups. This phenomenon was found to be directly proportional to the dose or the level of sustained delivery. The results demonstrated that the use of 10 mg filled TCPL implants decreased the total mass weight of ventral prostate. Light microscopic evaluation of this group (Group I) revealed a cellular adaptation through an atrophy in the epithelium component. Cytopathological observations such as low cuboidal and thin glands, pleomorphism, and occasional presence of connective tissue stroma were detected. In contrast, ventral prostate collected from animals implanted with TCPL filled with 200 mg T (Group III) showed a significant increase in weights of the wet prostatic tissues in comparison to all groups. Histopathological evaluations demonstrated the following. (i) prostatic hypertrophy alone, or in conjunction with hyperplasia of the epithelial cells, (ii) less connective tissue stroma in comparison to the control group, (iii) occasional involvement of mitotic figures, and (iv) increased angiogenesis. No significant change was observed in those animals implanted with TCPL capsules containing 100 mg T compared to the intact control animals.