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Phyllodes tumors of the breast are diagnostically and managerially enigmatic, as their malignant potential is difficult to predict based on the standard morphologic criteria. Thus, there is a need for additional markers of biologic potential. Although a number of ancillary tests have been reported, consensus in the literature is lacking. We studied 38 cellular fibroadenomas and phyllodes tumors of various grade (World Health Organization benign, borderline, and malignant) with a panel of immunohistochemical stains (p53, CD117, phospho-Histone3, mdm2, cdk4) and screened 26 of the tumors for mutations across 30 cancer-related genes using PCR and mass-spectrometry based methods. p53 and phospho-Histone3 (mitotic marker) showed increased staining in higher grade phyllodes tumors. CD117, mdm2, and cdk4 showed no difference in expression across different grades of phyllodes tumors. Mutational analysis revealed an S8R substitution in FBX4 (an E3 ubiquitin ligase) in 3 cases: 1 benign and 2 borderline. The S8R substitution seems to be more common in phyllodes tumors (11.5%) as compared with other cancers. FBX4 S8R cases had high cyclin D1 expression, but this finding was not specific. Our data support earlier studies showing that p53 has potential use in pathologic assessment of phyllodes tumors, and we newly characterized phospho-Histone3 for this application. Further studies are needed to characterize the molecular pathogenesis of the phyllodes tumors, as we were unable to identify activating mutations despite screening for a large panel of activating hotspot mutations. The significance of the FBX4 substitution deserves further investigation.

Papillary lesions of the breast have an uncertain relationship to the histogenesis of breast carcinoma, and are thus diagnostically and managerially challenging. Molecular genetic studies have provided evidence that ductal carcinoma in situ and even atypical ductal hyperplasia are precursors of invasive carcinoma. However, papillary lesions have been seldom studied. We screened papillary breast neoplasms for activating point mutations in PIK3CA, AKT1, and RAS protein-family members, which are common in invasive ductal carcinomas. DNA extracts were prepared from sections of 89 papillary lesions, including 61 benign papillomas (28 without significant hyperplasia; 33 with moderate to florid hyperplasia), 11 papillomas with atypical ductal hyperplasia, 7 papillomas with carcinoma in situ, and 10 papillary carcinomas. Extracts were screened for PIK3CA and AKT1 mutations using mass spectrometry; cases that were negative were further screened for mutations in AKT2, BRAF, CDK, EGFR, ERBB2, KRAS, NRAS, and HRAS. Mutations were confirmed by sequencing or HPLC assay. A total of 55 of 89 papillary neoplasms harbored mutations (62%), predominantly in AKT1 (E17K, 27 cases) and PIK3CA (exon 20 >exon 9, 27 cases). Papillomas had more mutations in AKT1 (54%) than in PIK3CA (21%), whereas papillomas with hyperplasia had more PIK3CA (42%) than AKT1 (15%) mutations, as did papillomas with atypical ductal hyperplasia (PIK3CA 45%, AKT1 27%, and NRAS 9%). Among seven papillomas with carcinoma in situ, three had AKT1 mutations. The 10 papillary carcinomas showed an overall lower frequency of mutations, including 1 with an AKT1 mutation (in a tumor arising from a papilloma), 1 with an NRAS gene mutation (Q61H), and 2 with PIK3CA mutations (1 overlapping with the NRAS Q61H). These findings indicate that approximately two-thirds of papillomas are driven by mutations in the PI3CA/AKT pathway. Some papillary carcinomas may arise from these lesions, but others may have different molecular origins.

There is an immediate and critical need for a rapid, broad-based genotyping method that can evaluate multiple mutations simultaneously in clinical cancer specimens and identify patients most likely to benefit from targeted agents now in use or in late-stage clinical development. We have implemented a prospective genotyping approach to characterize the frequency and spectrum of mutations amenable to drug targeting present in urothelial, colorectal, endometrioid, and thyroid carcinomas and in melanoma. Cancer patients were enrolled in a Personalized Cancer Medicine Registry that houses both clinical information and genotyping data, and mutation screening was performed using a multiplexed assay panel with mass spectrometry–based analysis to detect 390 mutations across 30 cancer genes. Formalin fixed, paraffin-embedded specimens were evaluated from 820 Registry patients. The genes most frequently mutated across multiple cancer types were BRAF, PIK3CA, KRAS, and NRAS. Less common mutations were also observed in AKT1, CTNNB1, FGFR2, FGFR3, GNAQ, HRAS, and MAP2K1. Notably, 48 of 77 PIK3CA-mutant cases (62%) harbored at least one additional mutation in another gene, most often KRAS. Among melanomas, only 54 of 73 BRAF mutations (74%) were the V600E substitution. These findings demonstrate the diversity and complexity of mutations in druggable targets among the different cancer types and underscore the need for a broad-spectrum, prospective genotyping approach to personalized cancer medicine.

Girls with Turner's syndrome are born short, grow slowly, and usually fail to enter puberty spontaneously and to undergo a pubertal growth spurt. The goal of estrogen therapy is to correct estrogen deficiency in a manner that optimizes height potential, permits attainment of normal bone mass, and provides appropriate feminization with minimal risk of adverse effects. The issues to be resolved include the age at which treatment should be begun, the preparation, route of administration, and dosage to be given, the effect on concurrent growth hormone administration, the rate of dose increase during treatment, the timing and nature of progestin administration, and the total duration of treatment. The available data suggest that treatment should be initiated between the ages of 12 and 14 years. The dose-response relationship between growth rate and estrogen dose is biphasic. Optimal growth stimulation for ethinyl estradiol occurs at approximately 100 ng/kg body weight per day, which is below the dose that produces full feminization. Although suboptimal doses of estrogen and growth hormone appear to have additive effects, estrogen causes only a minor increase in the short-term growth response to an optimal dose of growth hormone. The long-term effects of estrogen combined with growth hormone are unknown. In the absence of data concerning the outcome of different dose schedules, we treated for 2 years at 100 ng/kg/day of ethinyl estradiol, then double the dose annually until menstruation, at which time cyclic monthly progestin therapy is added (medroxyprogesterone acetate 10 mg daily from days 16 to 25). The importance of estrogen in maintaining normal bone mass suggests that treatment should be lifelong. Current research in our clinic is assessing the long-term effect on adult height of ultra-low-dose treatment (25 to 50 ng/kg/day of ethinyl estradiol) during the childhood years (ages 5 to 11), alone or in conjunction with supplemental growth hormone.

Developmental changes in plasma dehydropiandrosterone (DHA) and in adrenal histology were studied in several marmoset species (Callithrix jacchus and Saguinus labiatus, nigricollis, and fuscicollis) to evaluate these primates as experimental models for the study of fetal adrenal zone regression. Newborn marmosets had a prominent fetal adrenal zone, plasma DHA levels above 1000 ng/dl, and plasma DHA sulfate (DHAS) levels of 140 micrograms/dl. The fetal zone regressed dramatically during the first week of life, paralleled by a marked decline in plasma DHA, the plasma DHA to cortisol ratio, and plasma DHAS. The adult marmoset, however, had no adrenal reticular zone and no evidence of adrenal DHA secretion; DHA levels in castrate adults were undetectable (less than 25 ng/dl). Thus, the marmoset represents the first example of a primate that has a regressing, DHA- and DHAS-secreting fetal adrenal zone but that does not subsequently develop a DHA-secreting adrenal reticular zone.

Two experiments were accomplished which involved time‐intensity trades on a lateralization task. In the first experiment, subjects adjusted interaural time differences between binaural stimuli to compensate for interaural intensity disparities. In the second, the same listeners adjusted the interaural intensity relationship to offset interaural time differences. Three pure tones (250, 500, and 1000 Hz) were employed as binaural stimuli. The two experiments yielded substantially different time‐intensity trading ratios for large values of interaural time differences and intensity disparities. This finding supplies evidence of a new type that the time‐intensity trading ratio does not accurately reflect the central auditory processes that are involved with interaural time and intensity on a lateralization task.

A REACTIVE ARTHRITIS may occur following intestinal infection with Yersinia, I Shigella, ~ and Salmonella. ~ The clinical events that precede the arthritis are subtle and frequently overlooked. We report a case of arthritis following Salmonella gastroenteritis to highlight the features of this entity. CASE REPORT A 14-year-old white boy was admitted for evaluation of fever and polyarticular arthritis. He had been well until two weeks prior to admission when he developed anorexia, abdominal cramping, diarrhea, and fatigue. The diarrhea occurred three to four times a day and was described as watery, but without blood or mucus. He had no fever, rash, coryza, vomiting, or joint pain. The patient's 17-year-old sibling had experienced similar symptoms one week earlier, which cleared without treatment. The patient's symptoms resolved over a period of five days and he resumed normal activity. One week prior to admission the patient developed painful swelling of the feet and ankles; walking became difficult and anorexia and malaise were present. Over the next five days painful swelling developed in both knees, the left wrist, and the proximal interphalangeal and distal interphalangeal joints of the right index finger. The patient also developed late afternoon fevers to 38.5~ He lost 10 pounds during the two weeks. At admission he denied rash, headache, eye discharge, sore throat, stiff neck, cough, abdominal pain, back pain, dysuria, urinary frequency, or urethral discharge. His bowel movements were now normal, with one formed stool per day. Past medical history and family history were noncontributory. No family