Mice with Dab1 or Vldlr insufficiency exhibit abnormal neonatal vocalization patterns.

Genetic and epigenetic changes in components of the Reelin-signaling pathway (RELN, DAB1) are associated with autism spectrum disorder (ASD) risk. Social communication deficits are a key component of the ASD diagnostic criteria, but the underlying neurogenetic mechanisms remain unknown. Reln insufficient mice exhibit ASD-like behavioral phenotypes including altered neonatal vocalization patterns. Reelin affects multiple pathways including through the receptors, Very low-density lipoprotein receptor (Vldlr), Apolipoprotein receptor 2 (Apoer2), and intracellular signaling molecule Disabled-1 (Dab1). As Vldlr was previously implicated in avian vocalization, here we investigate vocalizations of neonatal mice with a reduction or absence of these components of the Reelin-signaling pathway. Mice with low or no Dab1 expression exhibited reduced calling rates, altered call-type usage, and differential vocal development trajectories. Mice lacking Vldlr expression also had altered call repertoires, and this effect was exacerbated by deficiency in Apoer2. Together with previous findings, these observations 1) solidify a role for Reelin in vocal communication of multiple species, 2) point to the canonical Reelin-signaling pathway as critical for development of normal neonatal calling patterns in mice, and 3) suggest that mutants in this pathway could be used as murine models for Reelin-associated vocal deficits in humans.

The effect of moderate levels of simulated altitude on sustained cognitive performance.

Previous work has documented cognitive deficits at high altitudes (15,000-25,000 ft), but there is controversy for lower altitudes. This study looked at the effects of moderate altitudes--12,500 ft and 15,000 ft--on short-term memory in comparison to 2,000 ft. Seventy-two student pilots and instructors were first administered the Vocabulary, Digit Span, and Digit Symbol subtests from the Wechsler Adult Intelligence Scale-Revised, the Vandenberg Mental Rotation Test, and the near-contrast sensitivity portion of the Vistech VCTS 6000 chart. Participants then spent 1 1/2 hr at their designated altitude for cognitive testing. Participants performed a 30 min vigilance task while listening to an audiotape with instructions to recall radio calls prefaced by their assigned call sign. Half of the radio calls were high memory loads (at least 4 pieces of information), and half were low memory loads (no more than 2 pieces of information). No effects of altitude were found in performance on the Vigilance task. However, for readbacks of high memory load, significant deficits in recall were observed at 12,500 ft and 15,000 ft, whereas no effect of altitude was observed on recall of readbacks with low memory loads. These results indicate that, at altitude, short-term memory was exceeded for the readbacks requiring a larger amount of information to be recalled, and that cognitive deficits are found at lower altitudes than previously observed.

Adequacy of chemotherapy prior to cytoreductive surgery in testicular carcinoma.

Removal of residual masses after cisplatin-based chemotherapy (cytoreductive surgery) for inoperable or metastatic testicular carcinoma has demonstrated that many partial regressions are defects without malignant cells. Such negative results allow a clarification of complete regression. Failure to achieve complete regression requires intensive salvage chemotherapy or bone marrow transplant. Extended initial chemotherapy could reduce these failures. Cytoreductive surgery was performed on 44 patients with inoperable stage II or stage III testicular cancer with residual defects following chemotherapy. The patients were evaluated according to whether (a) adequate treatment was given based on attaining normal markers followed by two additional courses of therapy, (b) normal markers were achieved but two additional courses were not administered, or (c) normal markers were never attained. These were subdivided into those receiving five or more courses of chemotherapy or fewer than five courses. Patients receiving two additional courses of chemotherapy after markers became normal had a low death rate (15.4%) and highest median follow-up. Fewer patients died if they had five or more courses of chemotherapy (11.8%). Of all those who attained normal markers with at least five or more courses of therapy, 10% are dead. The presence of residual malignant cells in those receiving five or more courses of therapy was 18.2% in contrast to 50% in those receiving fewer courses. Adequate chemotherapy and attainment of normal markers followed by two more courses of therapy results in fewer patients with residual malignant cells, a greater potential of cure, and less need for intensive salvage regimens.

Optimal number of chemotherapy courses in advanced nonseminomatous testicular carcinoma.

BACKGROUND: Nonseminomatous germ cell tumors (NSGCT) (testicular carcinoma) are a curable disease. Stages I and II are nearly 100% curable. Stage III has had remarkable progress in attaining complete regression, but a substantial number fail to be cured. Using platinum-based regimens such as vinblastine, bleomycin, and cisplatin (VBP), or using etoposide instead of vinblastine (BEP), or without bleomycin (EP), four courses of chemotherapy have become a national standard. Based on our prior experience with mithramycin (plicamycin), which used six courses, six courses of VBP chemotherapy were utilized as our treatment goal. This report challenges the concept that "standard therapy" for stage III testicular carcinoma is four courses. METHOD: From 1976 to 1990, 74 patients with advanced NSGCT were treated with standard doses of plantinum-based chemotherapies. Five or more courses were delivered to 41 patients and fewer than five courses to 33 patients. The intent of therapy was to attain as close to six courses as possible. Because of physician preference, patient adherence, or toxicity, some patients did not reach that goal. RESULTS: Of 33 patients receiving less than five courses, there were 28 (85%) complete responders, and 26 (78.8%) are alive. Of 41 patients receiving five or more courses, 38 (92.7%) had complete responses, and 34 (83%) are alive. One person in each group is living with nonresectable teratoma present. In the group receiving 5+ courses, two died from causes unrelated to testis cancer and had no testis cancer present. As a result of the initial treatment, there was no evidence of cancer in 24 (72.8%) in the group receiving less than five courses and 35 (85.4%) had no cancer after five or more courses. In considering only patients with advanced level of stage III disease in contrast to minimal or moderate stage III disease, there were fewer complete regressions with less than five courses (64.3%) than with five or more courses (88.0%). CONCLUSIONS: For minimal stage III disease, four courses of chemotherapy may be adequate. For advanced stage III disease, more chemotherapy provides fewer treatment failures. Once a complete response is achieved without restriction to an arbitrary number of courses, two additional courses may constitute a more curative regimen.

Epidermal growth factor receptor and transforming growth factor alpha expression in papillary and nonpapillary renal cell carcinoma: correlation with metastatic behavior and prognosis.

Papillary renal carcinomas are a cytogenetically unique subset of renal carcinomas that have been reported to be clinically less aggressive. We have examined 19 papillary tumors for immunohistochemical expression of the epidermal growth factor receptor (EGF-R) and its ligand, transforming growth factor alpha (TGF-alpha). EGF-R and TGF-alpha expression was also studied in 149 nonpapillary tumors and 7 mixed papillary/solid tumors. EGF-R and TGF-alpha expression were compared to histology, stage, metastatic behavior, and survival. Formalin-fixed, paraffin-embedded nephrectomy specimens collected between 1977 and 1986 were stained with antibodies to EGF-R and TGF-alpha. Patients with papillary tumors were found to present with earlier stage disease and had significantly longer survival. Papillary tumors had a significantly lower rate of EGF-R positivity than solid pattern tumors (21% versus 73%, P < 0.001). Intermediate or strong cell membrane immunoreactivity for EGF-R was associated with high tumor grade and poor disease-specific survival. EGF-R positivity in the primary tumor was associated with the presence of metastatic disease and with metastatic spread to lung versus bone. Tumor parenchymal TGF-alpha staining was present in 50% of the cases and was not associated with stage or grade. Unrelated to tumor parenchymal TGF staining, tumor vessels stained for TGF-alpha in 56% of the cases. Vessel TGF-alpha staining was absent in papillary tumors (P < 0.001). The improved clinical behavior of papillary tumors as compared to nonpapillary renal tumors may be related, in part, to their relatively lower levels of EGF-R expression.

Association of immunohistochemical staining for p53 with metastatic progression and poor survival in patients with renal cell carcinoma.

BACKGROUND: Mutations of the p53 gene have been found in many types of human tumors. In some tumors, p53 gene mutations are associated with advanced disease and poor prognosis. There is wide variation in the reported incidence of p53 mutation in renal cell carcinoma, and its prognostic significance for this tumor is unknown. PURPOSE: This retrospective immunohistochemical study was designed to examine associations between p53 immunostaining and histologic type, tumor grade, clinical behavior, and survival. METHODS: Paraffin-embedded nephrectomy specimens collected from 1978 through 1986 from 175 patients were immunostained for p53 using the D07 monoclonal antibody. Positive staining for p53 has been linked to the accumulation of mutant p53 protein. Thirteen specimens of concurrent metastatic lesions were available from 11 primary cases. Clinical follow-up information was available on 164 patients. RESULTS: Immunostaining for p53 suggested the presence of p53 mutation in 49 (28%) of 175 renal tumors studied. Staining was associated with high tumor grade and stage but not with cell type or histologic pattern. Eleven (85%) of 13 metastatic lesions stained positively for p53, versus only four (36%) of the 11 paired primary tumors. Immunostaining for p53 was strongly associated with poor survival among patients without distant metastases at presentation. In this group, 10-year disease-specific survival was 78% for patients with nonstaining tumors versus 48% for those with p53-positive tumors (P < or = .003). There was an 87% 10-year disease-specific survival rate for patients with nonstaining Robson stage 1 tumors versus a 62% 10-year survival rate for patients with p53-positive Robson stage 1 tumors (P < .01). Multivariate analysis showed p53 immunoreactivity to be an independent predictor of survival for patients with nonmetastatic renal cell carcinoma, whereas tumor grade was not. CONCLUSIONS: Positive p53 immunostaining in renal cell carcinoma is associated with metastatic disease and poor survival in patients with early-stage disease. IMPLICATIONS: In renal cell carcinoma, mutations of the p53 gene may allow or contribute to the acquisition of metastatic potential.

Adjuvant chemotherapy for stage II nonseminomatous germ cell cancer of the testis.

BACKGROUND: The success of chemotherapy for Stage III testicular carcinoma warranted its use as an adjuvant therapy for Stage II cancer. The current report reflects the adjuvant program begun at the University of Minnesota using four courses of vinblastine, bleomycin, and cisplatin (VBP) before the onset of the Testicular Cancer Intergroup Study using two courses of chemotherapies. METHODS: A review of 78 patients with Stage II nonseminomatous germ cell tumors treated between 1972 and 1986 defined three groups: 19 patients treated between 1972 and 1979 with various adjuvant chemotherapies (termed "other"), 37 patients treated from 1975 to 1986 with VBP adjuvant chemotherapy, and 21 patients who received no therapy during the same era of VBP. The latter group was not offered adjuvant chemotherapy at other institutions or declined therapy. RESULTS: Nineteen patients received adjuvant chemotherapy before the cisplatin era. Their survival rate was 42%, including two patients treated with cisplatin-based chemotherapy for recurrence. In the group of 21 patients who did not receive adjuvant therapy, 14 (66.7%) survived. Of these, five had no recurrence and nine were treated for recurrence. In a third group, adjuvant VBP therapy was given to 37 patients, 32 of whom received four full courses. There have been no recurrences, and 36 (97.3%) remain alive; one obese patient with hypertension died of a ruptured aortic aneurysm 12.9 years after the retroperitoneal lymph node dissection. Nodal involvement was more extensive in the VBP group. CONCLUSION: Four courses of VBP adjuvant chemotherapy for pathologic Stage II testicular cancer resulted in a 100% cure rate, all patients having been followed up for more than 6 years. Whether two courses are as adequate remains to be determined when long-term follow-up is reported.

Computerized tomography in the diagnosis of appendicovesical fistula.

Appendicitis and its complications are among the causes of an enterovesical fistula, with approximately 100 such cases reported. This condition is seldom diagnosed preoperatively and surgery is often delayed. We report 2 cases of an appendicovesical fistula that were diagnosed preoperatively by computerized tomography (CT). We describe a CT finding consistent with the diagnosis, namely calcification in the thickened bladder wall adjacent to the cecum on noncontrast CT, which is a fecalith in the lumen of the fistula.

Extragonadal abdominal germ cell cancers.

The charts of eleven patients with abdominal germ cell tumors were reviewed; one had a seminoma. They all had normal testes by physical examination. Therapy consisted of cisplatin-based chemotherapy and, in some cases, surgical debulking. A complete clinical response occurred in seven patients (63%). Two patients relapsed after achieving pathology complete responses and died of progressive disease despite second-line chemotherapy. All patients that failed to achieve a complete clinical response died of progressive disease. Five patients (45%) are long-term disease-free survivors, having no recurrence 4-10 years from the time of the diagnosis (median 6 years). The outcome for this group of patients did not differ significantly from that for patients with mediastinal germ cell tumors in this institution. They do not fare as well as patients with testicular cancer.

Total bladder replacement using detubularized sigmoid colon: technique and results.

We performed total bladder replacement with a detubularized segment of sigmoid colon in patients after cystoprostatectomy. The surgical technique and long-term results in 27 patients are reported. This neobladder configuration compared favorably with other neobladder types regarding ease of construction. The surgical complications were acceptable. Initial reservoir function was good but improved further with time. After 1 year the capacity averaged 600 cc, pressures during filling and at capacity were low (average 12 and 16 cm. water) and emptying was satisfactory (residual urine 4 to 80 cc). All patients were continent during the day and 67% were continent at night without excessive voiding habits. Nighttime incontinence was further resolved in 2 patients by using the AMS 800 artificial sphincter around the bulbous urethra. The detubularized sigmoid is an excellent neobladder configuration after cystoprostatectomy.

Epidermoid cyst (monodermal teratoma) of the testis.

We report 14 patients with epidermoid cyst of the testis (monodermal teratoma). In 7 patients (5 treated within the last 5 years) the mass was excised and adjacent testicular tissue was biopsied. Seven patients underwent radical inguinal orchiectomy. Carcinoma in situ was not detected in any testicular tissue examined. There was no evidence of tumour recurrence in any patient after a mean follow-up of 10 years. Ultrasonographic appearance was not specific for a diagnosis of epidermoid cyst and exploratory surgery was required in all cases. Excision of the tumour and biopsy of adjacent testicular tissue to determine the presence or absence of carcinoma in situ is adequate treatment for this rare testicular neoplasm.

The role of ilioinguinal lymphadenectomy and significance of histological differentiation in treatment of carcinoma of the penis.

We reviewed retrospectively the medical records of 58 patients treated for squamous cell carcinoma of the penis who were followed for more than 3 years or until they died. Tissue sections from all patients were reviewed. Of 15 patients with stage I disease 11 underwent partial penectomy, and 4 underwent partial penectomy and immediate ilioinguinal lymphadenectomy; none died of cancer. Nine patients with stage II and 9 with stage III disease underwent partial or total penectomy and immediate ilioinguinal lymphadenectomy, and 5-year survival was 100 and 75%, respectively. Of 20 patients with clinical stage II disease who did not undergo immediate ilioinguinal lymphadenectomy 18 had metastasis to the groin. Of these 18 patients 12 underwent delayed ilioinguinal lymphadenectomy but only 1 survived more than 5 years. We evaluated the possible significance of the degree of histological differentiation of the primary tumor to the course of the disease. Of the 23 cases of carcinoma in situ or well differentiated disease only 1 became metastatic, while of the 35 cases of moderately to poorly differentiated disease 31 metastasized to the groin. Vascular invasion of cancer cells in the primary tumor was another indicator for poor prognosis.

Intratubular germ cell neoplasia in testicular teratomas and epidermoid cysts. Correlation with prognosis and possible biologic significance.

The clinicopathologic features of 4 testicular teratomas in infants, 13 testicular epidermoid cysts in adults, and 8 pure teratomas in adults were compared. Intratubular germ cell neoplasia (ITGCN, carcinoma in situ) was observed in 88% of the teratomas in adults; 63% of the patients in this group had metastases and 37% died. No ITGCN was observed in infant testes with teratomas or adult testes with epidermoid cysts; all of the neoplasms in the latter two groups behaved as benign tumors. ITGCN is associated with malignant potential (P = 0.0004; Fisher's exact test). These tumors comprise a spectrum of clinicopathologic entities that probably reflect differences in pathogenesis.

Sarcomas of the retroperitoneum and genitourinary tract.

A total of 62 patients with retroperitoneal or genitourinary sarcoma was treated at our institutions during the last 46 years. Of the patients 51 were followed for at least 5 years or until they died (median followup 11 years); 5 patients were lost to followup. The most common site was the retroperitoneum. Liposarcoma, leiomyosarcoma and malignant fibrous histiocytoma were the most common tumors (74 per cent). Tumors were completely resected in 42 patients (68 per cent) and incompletely resected in 11, while a biopsy only was performed in 9. Some patients also received adjuvant radiation therapy and/or chemotherapy. There were no long-term survivors among patients with unresectable tumors. Over-all 3 and 5-year survival rates were 68 and 39 per cent, respectively. The histological type of the tumor appeared to have prognostic significance. The highest 5-year survivals were for liposarcoma (70 per cent), malignant fibrous histiocytoma (33 per cent) and leiomyosarcoma (13 per cent). The mean survival for patients after adjuvant radiation therapy or chemotherapy was similar to that after a radical operation alone. The primary cause of treatment failure was local recurrence (45 per cent of the patients), which was detected within 3 years of complete resection in most cases (82 per cent). Complete extirpation that provided adequate margins free of tumor was the most effective initial treatment and provided the best chance for cure.

The value of serum prostate specific antigen determinations before and after radical prostatectomy.

We evaluated serum prostate specific antigen before and after radical prostatectomy. In 100 consecutive patients who underwent radical prostatectomy, preoperative prostate specific antigen levels tended to increase with the increasing severity of pathological stage. However, even at levels of greater than 10 ng. per ml. the positive and negative predictive values (78 and 61 per cent, respectively) of prostate specific antigen to predict extracapsular disease were not sufficient to make this test useful alone for staging. In theory, after radical prostatectomy prostate specific antigen should be zero if no remaining prostatic tissue is present. Tests of precision and analytical sensitivity in our laboratory using a commercial prostate specific antigen assay revealed that a value of 0.4 ng. per ml. or more is different from zero at a greater than 95 per cent confidence level. With this guideline we evaluated the meaning of prostate specific antigen levels 3 to 6 months after radical prostatectomy in 59 men. Among men whose prostate specific antigen level was less than 0.4 ng. per ml. only 9 per cent demonstrated recurrence as evidenced by the development of positive bone scan or progressively elevated prostate specific antigen levels within 6 to 50 months. Alternatively, in men whose 3 to 6-month prostate specific antigen level was 0.4 ng per ml. or more there was evidence of recurrence in 100 per cent within 6 to 49 months (p less than 0.0001). Progressively elevated (more than 0.4 ng. per ml.) prostate specific antigen levels preceded recurrence from 12 to 43 months in all 6 patients who had positive bone scans, while increasing prostate specific antigen levels since radical prostatectomy have continued from 9 to 65 months in the 11 patients who have no radiological evidence of recurrent disease to date. Prostatic acid phosphatase serum values after radical prostatectomy were not useful to predict persistent disease. Prostate specific antigen values 3 to 6 months after radical prostatectomy are a sensitive indicator of persistent disease after radical prostatectomy and often precede other evidence of this occurrence by many years. This fact may alter concepts about surgical results, and possibly shorten and sharpen clinical studies involving adjuvant therapy after radical prostatectomy.

Endoscopic treatment of posterior urethral obliteration: long-term followup and comparison with transpubic urethroplasty.

We compare our results with the endoscopic management of posterior urethral obliteration in 8 patients to our previous experience with transpubic urethroplasty in 6 patients. Although most patients who underwent an endoscopic procedure required 2 or 3 followup internal urethrotomies within the first 2 to 10 months after treatment, 6 have remained free of stricture for more than 2 years after this initial period of aggressive endoscopic management. This finding suggests that total obliteration of the posterior urethra can be managed effectively by endoscopic techniques. Comparison of endoscopic treatment with transpubic urethroplasty revealed a decrease in operative time, blood loss and hospital stay with endoscopic management. We recommend that transpubic urethroplasty be reserved for patients in whom urethral continuity cannot be re-established with relatively safe and simple endourological techniques.