Genomic analysis of response to bacillus Calmette-Guérin (BCG) treatment in high-grade stage 1 bladder cancer patients.

BACKGROUND: Intravesical bacillus Calmette-Guérin (BCG) therapy is standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) but overall efficacy is low, and no reliable predictive biomarkers currently exist to refine patient selection. We performed genomic analysis on high-grade (HG) T1 NMIBCs to determine if response to therapy is predicted by certain mutational and/or expressional changes. METHODS: Patients with HG T1 NMIBC treated with induction BCG were stratified by response into durable and non-durable responders. Baseline tumor samples were subjected to targeted DNA sequencing and whole-exome RNAseq. Genomic variants differing significantly between response groups were analyzed using Ingenuity Pathway Analysis (IPA) software. Variant selection was refined to target potential biomarker candidates for responsiveness to BCG. RESULTS: Among 42 patients, the median follow-up was 51.7 months and 40.5% (n=17) were durable BCG responders. Deleterious mutations in the RNA sequence of JCHAIN, S100A7, CLEC2B, and ANXA10 were more common in non-durable responders. Mutations in MCL1 and MSH6 detected on targeted sequencing were more commonly found in durable responders. Of all deleterious DNA and RNA mutations identified, only MCL1 was significantly associated with longer recurrence free survival (RFS) (P=0.031). CONCLUSIONS: Differences in the genomic profiles of HG T1 NMIBC tumors exist between those who show durable response to BCG and those who do not. Using pathway analysis, those differences imply upregulation of several interconnected inflammatory pathways among responders. Specific variants identified here, namely MCL1, are candidates for further study and, if clinically validated, may serve as useful biomarkers in the future.

Ophelimus mediterraneus sp. n. (Hymenoptera, Eulophidae): a new Eucalyptus gall wasp in the Mediterranean region.

We report here for the first time the presence of Ophelimus mediterraneus sp. n. in Mediterranean Europe. This species appears to be closely related to Ophelimus maskelli, a well-known invasive pest of Eucalyptus. Based on molecular (cytochrome oxidase I, 28S), morphological (multivariate ratio analysis) and bio-ecological investigations, our study gives unambiguous relevant criteria that allow the discrimination between these two species. A full description of O. mediterraneus sp. n. is also provided. The geographic distribution of O. mediterraneus sp. n. as well as its impact on Eucalyptus species needs to be more widely assessed since its presence may have been confused with O. maskelli in their sympatric introduced areas. Further investigations of potential parasitoids in the native area may thus be welcomed to evaluate classical biological control achievability.

A Rare Presentation of Stage IV Large Cell Neuroendocrine Carcinoma of the Cervix with Metastasis to the Cranium.

Neuroendocrine tumors (NETs) are aggressive diseases developing from neuroendocrine cells that most frequently involve the gastro-entero-pancreatic tract and the lung, but more rarely are found in almost all body tissues. Limited biological and clinical data are currently available for NETs in uncommon sites, such as female genital tract. NETs represent 0.9% to 1.5% of the tumors of the uterine cervix. This case is reported on a 75-year-old Caucasian woman, presenting with dental and generalized pain for two weeks. Later during her admission, facial droop and diplopia were noticed. Radiological findings ruled out cerebrovascular accident but revealed multiple bone marrow lesions involving the left and the right clivus, right Meckel's cave, and posterior margin of the right cavernous sinus. Findings also included pulmonary nodules and adenopathy supporting diagnosis of likely stage IV metastatic carcinoma. Further imaging revealed homogeneous enhancement of the uterus suggestive of diffusely infiltrative carcinoma; pathology results confirmed large cell neuroendocrine carcinoma of the uterine cervix (LCNEC) giving her a 1.5-month median survival range.

Subforaminal bridges in Hymenoptera (Insecta), with a focus on Chalcidoidea.

Variation in structures of the posterior surface of the head in Hymenoptera is compared and interpreted according to theories of head capsule evolution, with focus on understanding previously baffling conditions in the superfamily Chalcidoidea. Features are investigated separately without first classifying subforaminal bridges into subcategories. In Proctotrupomorpha (including Chalcidoidea), Ceraphronoidea and some Ichneumonoidea, there are multiple posterior pits associated with the tentorium. In most examined Hymenoptera with a subforaminal bridge, there was a differentiated median area, typically with highly variable microtrichia. This area is elevated in Cephoidea and Pamphilioidea, but is not elevated in other Hymenoptera. Subforaminal bridges in Apocrita previously classified as hypostomal bridges are discussed in the context of A.P. Rasnitsyn's hypothesis that relative importance of adult feeding drives subforaminal bridge evolution.

Incidence and epidemiology of spinal cord injury within a closed American population: the United States military (2000-2009).

STUDY DESIGN: Cohort study. OBJECTIVES: The objective of this study was to characterize the incidence of spinal cord injury (SCI) within the population of the United States military from 2000-2009. This investigation also sought to define potential risk factors for the development of SCI. SETTING: The population of the United States military from 2000-2009. METHODS: The Defense Medical Epidemiology Database was queried for the years 2000-2009 using the International Classification of Diseases, Ninth Revision, Clinical Modification codes for SCI (806.0, 806.1, 806.2, 806.3, 806.4, 806.5, 806.8, 806.9, 952.0, 952.1, 952.2, 952.8, 952.9). The raw incidence of SCI was calculated and unadjusted incidence rates were generated for the risk factors of age, sex, race, military rank and branch of service. Adjusted incidence rate ratios were subsequently determined via multivariate Poisson regression analysis that controlled for other factors in the model and identified significant independent risk factors for SCI. RESULTS: Between 2000 and 2009, there were 5928 cases of SCI among a population at-risk of 13,813,333. The raw incidence of SCI within the population was 429 per million person-years. Male sex, white race, enlisted personnel and service in the Army, Navy or Marine Corps were found to be significant independent risk factors for SCI. The age groups 20-24, 25-29 and >40 were also found to be at significantly greater risk of developing the condition. CONCLUSIONS: This study is one of the few investigations to characterize the incidence, epidemiology and risk factors for SCI within the United States. Results presented here may represent the best-available evidence for risk factors of SCI in a large and diverse American cohort.

Effects of serial anesthesia using ketamine or ketamine/medetomidine on hematology and serum biochemistry values in rhesus macaques (Macaca mulatta).

BACKGROUND: This study aimed at determining the cumulative effect of daily anesthesia, using two drug regimens, over hematological and biochemical parameters. METHODS: Blood samples were obtained from rhesus monkeys 20 minutes after intramuscular administration of ketamine or ketamine/medetomidine combination for three consecutive days and results were evaluated to determine their effect on hematological and serum biochemistry values. Statistical significance of drug, day, and interaction of these two variables were evaluated. RESULTS: Drug effect resulted in a dramatic increase of aspartate aminotransferase and creatine kinase values. Day effect resulted in decreases of RBC, HCT, Hgb, and alkaline phosphatase but an increase of other biochemical parameters evaluated. The drug/day interaction effect was found to be -significant for RBC, platelets, aspartate aminotransferase, alanine aminotransferase, and creatine kinase values. CONCLUSION: The results of our study suggest a cumulative effect of serial anesthesia and should be an important consideration when interpreting hematology and serum biochemistry in rhesus macaques.

Strategies in the management of renal tumors amenable to partial nephrectomy.

PURPOSE: The laparoscopic approach to radical and partial nephrectomy is becoming the standard of care for treating patients with renal tumors. Hand-assisted laparoscopic partial nephrectomy (HALPN) provides some advantages over the pure laparoscopic approach which include manual manipulation of the kidney, tactile feedback, and timely specimen removal. MATERIALS AND METHODS: We describe our technique for HALPN and emphasize the implementation of an in-room pathologist to examine gross margins during the period of renal arterial occlusion. Between 2004 and 2007, 46 patients underwent HALPN performed by the same surgeons. Mean patient age was 59.5 years and mean tumor size was 2.55 cm. Twelve of these patients underwent significant concomitant procedures. RESULTS: Our mean operating time was 173.26 min (range 90-306 min) and our mean warm ischemic time was 28.32 min (range 14-54 min). Average estimated blood loss was 116.82 ml (range 10-1000 ml) with no transfusions. Thirty-six (78%) tumors were renal cell carcinoma, seven (15%) were oncocytomas, and three (7%) were angiomyolipomas. The average length of stay was 5.17 days (range 3-9 days) and there were no positive margins. There was one postoperative bleed (2%) and two postoperative urine leaks (4.3%). DISCUSSION: In our institution, the hand-assist approach to laparoscopic partial nephrectomy has resulted in favorable perioperative outcomes. The use of an in-room pathologist to provide real-time assessment of gross tumor margins has allowed us to achieve a 0% positive final margin rate. We believe that the use of an in-room pathologist during the timely extraction of the specimen made possible by the hand-assisted approach provides a great advantage over pure laparoscopic partial nephrectomy. This low positive margin rate is also the result of maintaining a bloodless field of resection with temporary renal arterial occlusion as well as the avoidance of visual tissue distortion with cold, sharp scissor dissection.

Pseudoinfiltrative tubal metaplasia of the endocervix: a potential form of in utero diethylstilbestrol exposure-related adenosis simulating minimal deviation adenocarcinoma.

We report three cases of unusual tubal-type endocervical glandular proliferations simulating minimal deviation adenocarcinoma in women with a history of in utero diethylstilbestrol (DES) exposure. The lesions were characterized by haphazard glandular proliferations extending from 3.4 to 6.1 mm into the endocervical stroma and to the margins of excision in all cases. Most of the glands were small to medium-sized and round; some exhibited a moderate degree of cystic dilatation, and occasional glands had curvilinear profiles. The glandular epithelium displayed extensive tubal-type differentiation in all cases. In two cases, the glands lacked cytologic atypia and mitotic activity, and in one case, there was mild to moderate nuclear atypia with occasional mitotic activity. Immunohistochemical studies showed diffuse expression of estrogen and progesterone receptors and essentially no expression of p16 in two cases tested; there was no expression of CD10 in one case that was tested. The Ki-67 proliferation index was zero in one case and 25% in another. Human papillomavirus DNA was not detected by in situ hybridization in one case that was tested. The proliferations lacked features of mucinous and tubo-endometrioid types of minimal deviation adenocarcinoma. The clinicopathologic findings suggest the lesions are benign, and the association with in utero DES exposure raises the possibility that these could be a form of DES-related adenosis.

Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study.

PURPOSE: To determine whether the addition of paclitaxel to doxorubicin plus cisplatin improves overall survival (OS) in women with advanced or recurrent endometrial carcinoma. Secondary comparisons included progression-free survival (PFS), response rate (RR), and toxicities. PATIENTS AND METHODS: Eligible, consenting patients received doxorubicin 60 mg/m(2) and cisplatin 50 mg/m(2) (AP), or doxorubicin 45 mg/m(2) and cisplatin 50 mg/m(2) (day 1), followed by paclitaxel 160 mg/m(2) (day 2) with filgrastim support (TAP). The initial doxorubicin dose in the AP arm was reduced to 45 mg/m(2) in patients with prior pelvic radiotherapy and those older than 65 years. Both regimens were repeated every 3 weeks to a maximum of seven cycles. Patients completed a neurotoxicity questionnaire before each cycle. RESULTS: Two hundred seventy-three women (10 ineligible) were registered. Objective response (57% v 34%; P <.01), PFS (median, 8.3 v 5.3 months; P <.01), and OS (median, 15.3 v 12.3 months; P =.037) were improved with TAP. Treatment was hematologically well tolerated, with only 2% of patients receiving AP, and 3% of patients receiving TAP experiencing neutropenic fever. Neurologic toxicity was worse for those receiving TAP, with 12% grade 3, and 27% grade 2 peripheral neuropathy, compared with 1% and 4%, respectively, in those receiving AP. Patient-reported neurotoxicity was significantly higher in the TAP arm following two cycles of therapy. CONCLUSION: TAP significantly improves RR, PFS, and OS compared with AP. Evaluation of this regimen in the high-risk adjuvant setting is warranted, but close attention should be paid to the increased risk of peripheral neuropathy.

A prospective evaluation of untreated acute grade III acromioclavicular separations.

We prospectively studied the natural history of untreated acute grade III acromioclavicular separations. Twenty-five patients were treated nonoperatively with a sling for comfort through progressive early range of motion as tolerated. Ten additional uninjured subjects underwent strength testing to evaluate the difference between the dominant and nondominant sides so that patient data could be standardized. The patients were examined at intervals of 6, 12, 24, 36, and 52 weeks after injury, at which time they completed a subjective questionnaire and underwent isometric dynamometer testing as well as military press and bench press strength testing. One patient underwent a surgical procedure at 2 weeks after injury because of cosmetic concerns. Twenty of the 25 patients completed the 1-year evaluation and strength-testing protocol. Subjectively, 4 of the 20 patients (20%) thought that their long-term outcome was suboptimal, although for 3 of them it was not enough to warrant surgery. Objective examination and strength testing of the 20 patients revealed no limitation of shoulder motion in the injured extremity and no difference between sides in rotational shoulder muscle strength. The bench press was the only strength test that showed a significant short-term difference, with the injured extremity being an average of 17% weaker. This study documents the natural history of patients with an untreated acute grade III acromioclavicular separation and provides a reference with which to judge all other proposed methods of treatment.

The influence of tendon length and fit on the strength of a tendon-bone tunnel complex. A biomechanical and histologic study in the dog.

Using a dog model, we examined the influence of tendon length and fit within a bone tunnel on the pull-out strength of a tendon-bone tunnel complex at 6 weeks after fixation. Fourteen adult mongrel dogs (weight, 25 to 30 kg) underwent bilateral hindlimb surgery in which the extensor digitorum longus tendon was transplanted into an extraarticular metaphyseal bone tunnel. Our findings demonstrated that pull-out strength at 6 weeks was enhanced by increasing the length of tendon within the tunnel. The average load to failure with 1 cm of tendon within the tunnel was 153.7 +/- 78.6 N, compared with 265.5 +/- 93.3 N for the specimens with 2 cm of tendon in the tunnel. Tendon fit within the tunnel was also found to be important. The average load to failure when a tendon was placed in a 4.2-mm diameter tunnel was 301 +/- 61 N at 6 weeks. The average load to failure when the tendon was placed within a 6-mm diameter tunnel was 228 +/- 65 N. These differences were statistically different. Histologically, the interface between the tendon and bone appeared to be most mature when there was intimate bone-to-tendon contact. These data suggest that maximizing tendon length within a bone tunnel and minimizing tendon-tunnel diameter mismatch will maximize the strength of a tendon-bone tunnel complex at 6 weeks.

Axillary nerve temperatures during radiofrequency capsulorrhaphy of the shoulder.

PURPOSE: The purpose of this study was to determine the temperatures along the course of the axillary nerve during radiofrequency (RF) capsulorrhaphy of the shoulder in a cadaver model. The hypothesis of this project was that temperatures capable of damaging neural tissue would be recorded during simulated RF capsulorrhaphy. TYPE OF STUDY: Basic science evaluation. METHODS: This study used 9 fresh-frozen cadaver shoulder capsules removed en bloc along with the underlying axillary nerve and soft tissue. The axillary nerve was instrumented with 4 thermocouples placed along the course of the nerve (2 thermocouples anterior and 2 posterior to the 6 o'clock position, spaced 7 mm apart). Each of the specimens underwent RF thermal capsulorrhaphy during which the temperature at each of the thermocouple positions was continuously recorded. RESULTS: The average of the maximum temperature at each of the 4 positions measured along the course of the axillary nerve were 52.2 +/- 18.0 degrees C at the most anterior place probed, 45.8 +/- 5.44 degrees C (mid anterior), 44.5 +/- 8.7 degrees C (mid posterior), and 42.8 +/- 10.1 degrees C at the most posteriorly positioned probe. Two specimens had a maximum temperature greater than the 67 degrees C set point of the device, and 7 specimens had a maximum temperature greater than 45 degrees C in at least 1 thermocouple position. CONCLUSIONS: This study shows that heating of the axillary nerve can occur during RF capsular shrinkage of the shoulder and may potentially reach levels that can damage neural tissue.

Obtaining intra-articular bone grafts arthroscopically for intra-articular grafting.

Autogenous bone graft is frequently necessary for arthroscopic procedures and even small open procedures that involve cruciate revision, osteochondritis dissecans repair, and fracture reduction and internal fixation. Currently used sites to obtain bone graft are the iliac crest and Gerdy's tubercle. This article describes an arthroscopic technique for harvest of small amounts of bone graft from the distal femur. This avoids the morbidity of the extra-articular harvest. Tube harvesters frequently used for osteochondral autografts are the primary tool required for this technique. However, as described, the obtaining of bone graft is much less technically exacting than when procuring osteochondral bone plugs. This provides a safe, simple way to obtain extra autogenous bone at minimal additional operative morbidity.

Axillary nerve injury after thermal capsular shrinkage of the shoulder.

The purpose of this study was to evaluate 4 cases in which axillary nerve injury was observed after radiofrequency capsular shrinkage of the shoulder. These cases were used to evaluate the clinical circumstances under which axillary nerve injury occurred, the time frame over which these injuries recovered, and the ultimate outcome observed in these patients. The case histories of each of these 4 patients were carefully evaluated. In 2 of the 4 cases, purely sensory findings were found, and in 2 cases both sensory and motor injuries occurred. In each case the inferior axillary recess was treated using the Oratech Interventions Tac-S probe. The authors conclude that injury to the axillary nerve during this procedure is possible and postulate that heat penetration through the capsule to the nerve is the most likely cause of injury.

Pitfalls associated with fixation of osteochondritis dissecans fragments using bioabsorbable screws.

The purpose of this study was to evaluate 2 cases in which bioabsorbable screw fixation for an osteochondritis dissecans lesion of the femoral condyle resulted in complications necessitating the need for secondary surgery. We reviewed the case history of these patients and described the circumstances under which the bioabsorbable screws were used, the events leading to the need for secondary surgery, and the ultimate outcome. In the 2 cases presented, these implants were found to retain their mechanical stiffness for many months. This resulted in articular damage in 1 case after the treated lesion failed to heal. In the second case, screw breakage 8 months after implantation resulted in it becoming a loose body, which required removal during a second arthroscopic procedure. We conclude that these implants retain their mechanical properties for many months and cannot be relied on to degrade quickly. If a treated lesion fails to heal, these implants can cause mechanical problems due to their retained structural properties.

Pathology residents' use of a Web-based tutorial to improve Gleason grading of prostate carcinoma on needle biopsies.

Little is known about pathology residents' ability to Gleason grade or their ability to learn surgical pathology using Internet-based technology. A free Web-based program (available at www.pathology. jhu.edu/prostate) was developed that consisted of 20 pretutorial images for grading, 24 tutorial images, and the same 20 posttutorial images for Gleason grading. The grading images were selected from cases that had a consensus Gleason grade from 10 uropathology experts. In 2.5 months, 255 residents visited the website, and 151 (59%) completed it. Of those who completed the website, their year in training was known in 85 (56%): 1st year, 25.8%; 2nd year, 20%; 3rd year, 22.3%; 4th year, 14.1%; 5th year, 15.3%; and 6th year, 2.4%. Eighty percent learned Gleason grading in residency versus being self-taught, and 66% were male. In a multivariate analysis, higher pretutorial scores were associated with both their year in training (P = .001) and their hospital size (P = .003). Improvements in grading posttutorial were not related to the residents' year in training. Overall, the website significantly improved grading in 11 of 20 images and had no effect in 9 of 20 images. Improvements were noted in 1 of 1 Gleason score 4; 2 of 7 Gleason score 5 to 6; 2 of 6 Gleason score 7; and 6 of 6 Gleason score above 7 tumors. In summary, a Web-based tutorial improved Gleason grading accuracy by pathology residents to an equal extent regardless of their year in training. It is more difficult to teach residents to grade Gleason scores 5 to 7 tumors, and additional training should be concentrated in this area.

The effect of reconstruction of the medial patellofemoral ligament on patellar tracking.

We evaluated patellar tracking in six cadaveric knees with the medial restraints intact and then sectioned to determine their contribution to lateral translation of the patella with and without a lateral force on the patella. The medial patellofemoral ligament was then reconstructed with a gracilis tendon graft and patellar tracking was again evaluated. The knees were extended using a materials testing machine, and patellar tracking was measured with a position sensing system. With no lateral force applied to the patella, patellar tracking was unaffected by the presence or absence of the medial restraints or by reconstruction of the medial patellofemoral ligament. With a lateral force applied to the patella, patellar tracking was changed significantly by the loss of the medial restraints. Normal patellar tracking was substantially restored by reconstruction of the medial patellofemoral ligament.