Jak3 deficiency blocks innate lymphoid cell development.

Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1tm1Ven/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC precursor and the pre-NK cell progenitor. We further demonstrate that the pan-JAK inhibitor tofacitinib and the specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis. Both tofacitinib and PF-06651600 are currently in clinical trials for several other immune-mediated conditions. Our data suggest that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy.

Innate lymphoid cells and the MHC.

Innate lymphoid cells (ILCs) are a new class of immune cells that include natural killer (NK) cells and appear to be the innate counterparts to CD4(+) helper T cells and CD8(+) cytotoxic T cells based on developmental and functional similarities. Like T cells, both NK cells and other ILCs also show connections to the major histocompatibility complex (MHC). In human and mouse, NK cells recognize and respond to classical and nonclassical MHC I molecules as well as structural homologues, whereas mouse ILCs have recently been shown to express MHC II. We describe the history of MHC I recognition by NK cells and discuss emerging roles for MHC II expression by ILC subsets, making comparisons between both mouse and human when possible.

Salvage radical prostatectomy following primary high intensity focused ultrasound for treatment of prostate cancer.

PURPOSE: High intensity focused ultrasound for the treatment of primary prostate cancer is increasing in a subset of men seeking definitive treatment with reduced morbidity. We review outcomes in men undergoing salvage radical prostatectomy after failed whole gland high intensity focused ultrasound. MATERIALS AND METHODS: Prospective data were collected for men presenting with an increasing prostate specific antigen and biopsy proven prostate cancer after high intensity focused ultrasound from 2007 to 2010 who underwent salvage open radical prostatectomy with a 22-month median followup, including prostate specific antigen, prostate volume, pathology results, continence and erectile function. RESULTS: Data for 15 men were available, including median age 64 years (IQR 55-69), Gleason score before high intensity focused ultrasound of 6 (8), Gleason score 7 (7), median cores positive 39% (IQR 17%-63%) and median prostate specific antigen 7 ng/ml (IQR 5-8). Whole gland high intensity focused ultrasound achieved median nadir prostate specific antigen 1.1 ng/ml (IQR 0.5-3.1). Biopsy after high intensity focused ultrasound demonstrated Gleason score 6 (in 3 patients), 7 (9) and 8/9 (3), and 42% (IQR 25%-50%) cores positive and a median time from high intensity focused ultrasound to radical prostatectomy of 22 months (IQR 7-26). Perioperative morbidity was limited to 1 transfusion in a patient with a rectal injury. Pathologically extensive periprostatic fibrosis was found with persistent prostate cancer, as pT3 disease (in 9 of 14), Gleason scores 6 (2), 7 (9) and 8 of 9 (4), with focally positive margins in 3 of 11 (pT3a). Postoperative prostate specific antigen was unrecordable in 14 of 15 patients with further treatment in 2. Postoperative continence (more than 12 months of followup) yielded no pad use in 6 of 10 men with universally poor erectile function. CONCLUSIONS: Radical prostatectomy as salvage is feasible for men in whom high intensity focused ultrasound failed, but with a higher morbidity than for primary surgery. Pathology results are alarming given the number of cases with extraprostatic extension yet early followup data suggest acceptable oncologic control. These results should be factored in when counseling men who wish to undergo primary high intensity focused ultrasound.

The natural history of small renal masses.

PURPOSE: Ultrasound, computerized tomography and magnetic resonance imaging are widely available. Incidentally discovered small renal masses are reported more frequently. Most of these masses are low stage renal cell carcinomas. To understand better the natural history of these lesions and offer appropriate management, we followed prospectively a series of patients with this type of lesion. MATERIALS AND METHODS: A total of 13 patients with radiologically detected solitary small renal masses who were unfit for or refused surgery were followed with abdominal imaging for a median of 42 months. Median patient age was 69 years and mean lesion volume at diagnosis was 13.6 cm.3 or 2.95 cm. in diameter. Growth rate was calculated based on tumor volume rather than bi-dimensional diameter. Individual slopes of tumor size in time were calculated. RESULTS: Of the 13 patients 5 underwent surgery following a period of surveillance because of apparent tumor enlargement or new onset of symptoms. Pathological evaluation revealed renal cell carcinoma in all 5. No patient had metastases. Only 2 tumors were fast growing and these were the only 2 cases in which symptoms developed. When these patients were excluded from analysis, average growth rate was 1.32 cm.3 per year (p = 0.5, 95% confidence interval -3.00 to 5.76 cm.3 per year), which was not statistically significantly different from 0 slope or no growth. CONCLUSIONS: These results demonstrate that the growth rate of small renal tumors is variable, tumors that are destined to grow and possibly metastasize do so early and most small tumors grow at a low rate or not at all.

Auditory brainstem response and magnetic resonance imaging for acoustic neuromas: costs by prevalence.

OBJECTIVE: To compare hypothetical costs for identification of acoustic tumors when using magnetic resonance imaging with gadolinium Gd 64 (MRI-(64)Gd) as a sole diagnostic test and when using auditory brainstem response (ABR) testing followed by MRI-( 64)Gd (ABR + MRI-(64)Gd) for those with positive ABR findings. PATIENTS AND METHODS: Retrospective review of the medical records of 75 patients having surgically confirmed acoustic neuromas to categorize them into 3 subgroups relative to their risk of having a cerebellopontine angle tumor based on history, symptoms, and routine pure-tone and speech audiometric findings. Hypothetical costs associated with identification of patients with acoustic neuroma in each subgroup were calculated for MRI-(64)Gd alone and ABR + MRI-( 64)Gd. Auditory brainstem response sensitivity and specificity data for the 75 patients with acoustic neuroma and 75 patients without a tumor matched for hearing loss were applied to the hypothetical subgroups. Tumor size was considered also. SETTING: Tertiary care center. MAIN OUTCOME MEASURE: Comparison of costs for MRI-(64)Gd and ABR + MRI-(64)Gd. RESULTS: Fouteen patients with acoustic neuroma were assigned to the high-risk category (30% probability); 45 were in the intermediate-risk category (5% probability); and 16 were in the low-risk category (1% probability). Auditory brainstem response testing correctly identified 100% of the large tumors (>2.0 cm), 93% of the medium-sized tumors (1.1-2.0 cm), and 82% of the small tumors (<1.0 cm). The hypothetical costs for identifying 14 patients with acoustic neuroma among 47 patients in the high-risk category using MRI-(64)Gd would be $70,500; ABR + MRI-(64)Gd costs for the 13 patients identified by ABR would be $39,600. Hypothetically 900 patients would be tested to identify the 45 acoustic neuromas in the intermediate-risk category. Magnetic resonance imaging with (64)Gd screening would reach $1.35 million for this sample. Auditory brainstem response testing and MRI-(64)Gd would be $486,000, but 4 acoustic neuromas would be missed. For the low-risk subgroup MRI-6(4)Gd screening of 1600 patients to identify 16 acoustic neuromas would total $2.4 million; ABR + MRI-(64)Gd to identify 15 of them would be $787,500. In this sample of 75 acoustic neuromas, large tumors were more prevalent in the low-risk subgroup than in the high- or intermediate-risk subgroups. CONCLUSIONS: Decisions regarding assessment of patients at risk for acoustic neuromas must be made on a case-by-case basis. Use of ABR + MRI-( 64)Gd allows considerable savings when patients are in the intermediate- or low-risk subgroups. New MRI and ABR testing techniques offer promise for reducing costs.

Factors influencing long-term primary cadaveric kidney transplantation--importance of functional renal mass versus avoidance of acute rejections--the Toronto Hospital experience 1985-1997.

1. The 5-year actuarial graft, patient and functional graft survival rates were analyzed in 743 consecutive primary cadaveric kidney transplants from The Toronto Hospital between January 1985-December 1997. 2. Recipient age > or = 55 years, male recipient sex, recipient diabetes mellitus, CIT > 36 hours and delayed graft function were found to significantly decrease patient survival. 3. Recipient age > or = 55 years, sensitization to HLA antigens (peak PRA > 50%), donor/recipient HLA antigen mismatches, CIT > 36 hours, delayed graft, function and 6-month SCr > 200 mumol/L were found to significantly decrease graft survival. 4. Acute rejection episodes had no significant impact on overall 5-year patient or graft survival. 5. The observation that serum creatinine > 200 mumol/L had a major adverse influence on long-term outcome reflects the importance of functional renal mass on graft survival.

Nonsurgical factors predictive of postoperative hearing for patients with vestibular schwannoma.

OBJECTIVE: The purposes of the study were to determine whether preoperative cochlear reserve as measured by evoked otoacoustic emissions (EOAE) as well as other hearing variables often associated with hearing preservation are correlated with hearing preservation after tumor removal and to determine whether any hearing variables are independent of tumor size as a predictor of hearing preservation. STUDY DESIGN: Preoperative audiologic data for 104 patients having vestibular nerve schwannomas removed via a retrosigmoid surgical approach were reviewed and subjected to factor analysis. SETTING: All patients were seen at the Mayo Clinic, Rochester, Minnesota. PATIENTS: The patient sample was divided into two groups based on hearing thresholds after surgery. Group I consisted of 73 ears without hearing preservation. The remaining 31 ears, group II, had preserved hearing (defined as average postoperative pure-tone thresholds < or = 85-dB HL for 0.5, 1, 2, and 3 kHz). MAIN OUTCOME MEASURES: Variables not predictive of hearing preservation were age, gender, tumor laterality, and cochlear reserve (EOAE). Variables predictive of hearing preservation were small tumor size, pure-tone hearing sensitivity, speech reception thresholds, word recognition scores, integrity of cochlear nerve (acoustic reflex thresholds, and auditory brain stem response [ABR] waveforms). RESULTS: A multivariate logistic regression analysis showed that only word recognition scores at 40-dB sensation level were independent of tumor size as a predictor of hearing preservation.

Effect of temperature elevation on rabbit cochlear function as measured by distortion-product otoacoustic emissions.

Low-intensity laser stapedotomy has been shown to produce temperature elevations of 3 degrees to 4 degrees C within the cochlea. This study investigates the effect of temperature elevations in this range on cochlear outer hair cell function by use of distortion-product otoacoustic emissions in rabbits. Using esophageal temperature monitoring, we compared 2f1-f2 distortion-product otoacoustic emissions over a range of frequencies (1806 to 8691 Hz) at rabbit normothermia, normothermia plus 3 degrees C, and normothermia after passive cooling. Cochlear temperature was found to exceed changes in esophageal temperature by as much as 1.2 degrees C. We found that a maximum of 3 degrees C elevation in esophageal temperature did not permanently impair outer hair cell function in the rabbit cochlea. Results of this study suggest that moderate changes in cochlear temperature, such as those produced by low-intensity CO2 and holmium-yttrium aluminum garnet lasers, may not produce irreversible thermal damage to the cochlear outer hair cells.

Impact of pathologic extraprostatic disease on local and systemic progression following radical prostatectomy.

Fifty patients underwent radical prostatectomy for localized prostate cancer (Stages A2, B) between 1977 and 1982. Surgical specimens were examined for tumor grade and extraprostatic extension of the disease. Forty-one of the 50 patients had capsular involvement (82%), 26 (52%) positive margins and 14 (28%) seminal vesicular involvement. Six patients progressed locally, six systematically and three both. Eight patients progressed at five years and an additional seven at ten years. In all 15 progressors tumor involved the capsule yet four patients with capsular involvement alone progressed. Eleven of the 26 patients (42%) with positive margins progressed. Five of the 14 patients (37%) with seminal vesicle involvement progressed, all five had positive margins as well. None of the patients with disease confined within the capsule progressed. Gleason score for non-progressors ranged between three and nine with a median of six while for progressors it ranged between five and nine with a median of seven. Long rank test and Cox Proportional Hazard Model statistical analysis were employed among all the factors: capsular involvement, positive margins, positive seminal vesicles and grade of tumor. Positive margins was the only statistically significant factor affecting local progression of the disease in both univariate and multivariate analysis at a 95% confidence (p=0.04). All factors were statistically insignificant in affecting systemic progression (p>0.5).

An analysis of predictors of long-term cadaveric renal allograft survival.

To determine factors predictive of long-term graft function in patients treated prophylactically with an antilymphocyte antibody, 670 first cadaveric adult renal transplant procedures performed between 1985 and 1991 were reviewed. The actuarial 1- and 5-year patient survival in this group was 95% and 87% respectively, and graft survival was 84% and 70% respectively. The final analysis was based on a study group of 635 patients which excluded 28 patients who lost grafts to early technical failures and 8 patients who were not induced with an antilymphocyte preparation. Multivariate analysis showed that 5-year graft survival was lower in patients with delayed graft function (p = 0.0001), in those who had an acute rejection episode in the first 6 months post-transplant (p = 0.0001), recipients greater than 55 years of age at the time of transplant (p = 0.0001), in patients who were highly sensitized at the time of transplant (p = 0.0331) and, finally, in those who received a graft from an older donor (p = 0.044). The 209 patients with delayed graft function had a 16% lower long-term graft survival than 425 patients with early graft function (62% vs. 78% respectively at 5 years). One or more rejection episodes in the first 6 months post-transplant (329 patients) reduced long-term graft survival by 13% compared to those who did not have a rejection episode (67% vs. 80% respectively at 5 years).(ABSTRACT TRUNCATED AT 250 WORDS)

Otoacoustic emissions in sudden unilateral hearing loss associated with multiple sclerosis.

Sudden unilateral hearing loss may result from etiologies affecting cochlea, eighth nerve, or more central auditory tracts. Two case studies are presented in which the measurement of otoacoustic emissions helped rule out outer hair cell cochlear pathology. In both cases, the final diagnosis was sudden unilateral hearing loss associated with multiple sclerosis (MS). For one case, the sudden hearing loss was the first clinically recognized presenting sign of MS.

Cost Justifications for Multifrequency Tympanometry.

MFT has the potential to become the standard of care when dealing with possible middle ear pathologies. By applying those applications appropriate to the individual practice, and with a reasonable marketing effort, the cost of MFT-capable equipment should be readily recoverable.Finally, and most importantly, MFT is being shown in the current literature to be a better diagnostic tool than traditional tympanometry and to improve the level of care being provided to many clients by the audiologist and the physician. In my mind, this alone justifies the expenditure.

Use of TEOAE, ABR, and Acoustic Reflex Measures to Assess Auditory Function Patients With Acoustic Neuroma.

Cochlear and neural auditory function for a series of 30 patients with acoustic neuroma was assessed pre- and postoperatively by transiently evoked otoacoustic emission (TEOAE), auditory brain stem response (ABR), and acoustic reflex measures. Employing a retrosigmoid surgical approach, physical integrity of the acoustic nerve was preserved for 22 patients. TEOAEs were observed preoperatively for 13 patients and postoperatively for 6 of them. Postoperative neural function remained unchanged or improved following surgery for 7 patients, and cochlear function decreased. TEOAE, ABR, and acoustic reflex measurements were considered valuable in providing information about site of lesion and probable mechanisms of injury associated with tumor removal.

The "cricket bat" flap: a one-stage free forearm flap phalloplasty.

Total and subtotal penile reconstruction represents a major surgical challenge. We present a new method and two illustrative cases using a modified design of the radial forearm free-tissue transfer: the "cricket bat" flap.