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BackgroundImmune checkpoint inhibitors are now standard of care treatment for many cancers. Treatment failure in metastatic melanoma is often due to tumor heterogeneity, which is not easily captured by conventional CT or tumor biopsy. The aim of this prospective study was to investigate early microstructural and functional changes within melanoma metastases following immune checkpoint blockade using multiparametric MRI.MethodsFifteen treatment-naïve metastatic melanoma patients (total 27 measurable target lesions) were imaged at baseline and following 3 and 12 weeks of treatment on immune checkpoint inhibitors using: T2-weighted imaging, diffusion kurtosis imaging, and dynamic contrast-enhanced MRI. Treatment timepoint changes in tumor cellularity, vascularity, and heterogeneity within individual metastases were evaluated and correlated to the clinical outcome in each patient based on Response Evaluation Criteria in Solid Tumors V.1.1 at 1 year.ResultsDifferential tumor growth kinetics in response to immune checkpoint blockade were measured in individual metastases within the same patient, demonstrating significant intertumoral heterogeneity in some patients. Early detection of tumor cell death or cell loss measured by a significant increase in the apparent diffusivity (Dapp) (papp), was consistently higher in the pseudoprogressive and true progressive lesions, compared with the responding lesions throughout the first 12 weeks of treatment. These preceded tumor regression and significant tumor vascularity changes (Ktrans, ve, and vp) detected after 12 weeks of immunotherapy (pConclusionsMultiparametric MRI demonstrated potential for early detection of successful response to immune checkpoint inhibitors in metastatic melanoma.

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy., Metastatic melanoma is associated with a poor prognosis and understanding the genetic features of metastases may enable better treatment strategies. Here, the authors analyse multiple metastases from individual patients finding high levels of heterogeneity in metastases from different organs.

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal that metastatic cells may depart the primary tumour very early in the disease course and follow a branched pattern of evolution. Truncal UV-induced mutations that often swamp downstream analyses of heterogeneity, were found to be replaced by APOBEC-associated mutations in the branches of the evolutionary tree. Multi-sample analyses from a further 7 patients confirmed that branched evolution was pervasive, representing an important mode of melanoma dissemination. Our analyses illustrate that combining cancer cell fraction estimates across multiple metastases provides higher resolution phylogenetic reconstructions relative to single sample analyses and highlights the limitations of accurately inferring inter-tumoural heterogeneity from a single biopsy.

We analyzed our initial 100-case experience with the 3.5 cm artificial urinary sphincter cuff to identify risk factors for cuff erosion.We reviewed the records of a single surgeon, consecutive series of patients treated with 3.5 cm artificial urinary sphincter cuff placement from September 2009 to August 2013. Each patient underwent single perineal cuff placement via standardized technique. Preoperative characteristics, technical considerations and postoperative outcomes were analyzed and compared to those in a cohort of patients in whom a larger (4.0 cm or greater) artificial urinary sphincter cuff was placed during the same period. We identified clinical factors associated with an increased risk of 3.5 cm artificial urinary sphincter cuff erosion.Of the 176 men who met study inclusion criteria during the 4-year period 100 (57%) received the 3.5 cm artificial urinary sphincter cuff and 76 (43%) received a larger cuff (4.0 cm or greater). The continence rate (83% vs 80%, p = 0.65) and mean followup (32 vs 25 months, p = 0.14) were similar in the 2 groups. Erosion developed in 16 of the 176 patients (9%) during the study period, of whom 13 had the 3.5 cm cuff. Of the 100 patients with the 3.5 cm cuff 52 (52%) had a history of radiation, including 11 (21%) with erosion. Cuff erosion developed only rarely in nonirradiated men (2 of 48 or 4%, p = 0.01). A history of radiation was the only significant risk factor associated with 3.5 cm cuff erosion (OR 6.2, 95% CI 1.3-29.5).Men with a history of radiation who underwent placement of a 3.5 cm artificial urinary sphincter cuff experienced an increased (21%) risk of cuff erosion.

For ventral buccal mucosa graft onlay during bulbar urethroplasty, spongioplasty with advancement and closure of the corpus spongiosum is ordinarily performed to stabilize the graft. In the pendulous and distal bulbar urethra the spongiosum is often too thin to allow complete graft coverage. We describe the results of what to our knowledge is a novel technique for ventral graft coverage using periurethral vascularized tissue. We compared these results to those of conventional spongioplasty.We retrospectively reviewed all urethroplasties performed by 2 surgeons at separate tertiary care facilities from July 2007 to July 2012. One-stage urethroplasties involving ventral buccal mucosa graft placement were selected for analysis. Conventional spongioplasty was performed when possible. When spongiosal tissue was inadequate for graft coverage, periurethral tissue flaps were mobilized bilaterally and sutured together in the midline as pseudospongioplasty to provide coverage. We compared the outcomes of the 2 techniques.Of 637 urethroplasties performed during the 5-year study period 102 (16%) with a buccal mucosa graft onlay met study inclusion criteria. Pseudospongioplasty was performed in 46 of 102 cases (45%), predominantly in the pendulous urethra (34 of 46 or 74%), with success in 37 of 46 (80%) at a mean followup of 41 months. Conventional spongioplasty had a similar 84% success rate (47 of 56 cases) at a mean followup of 39 months (p = 0.645). For conventional spongioplasty mean stricture length was 4.7 cm compared to 5.8 cm for pseudospongioplasty (p = 0.028).Ventral buccal mucosa grafts can be applied reliably to various locations throughout the anterior urethra. For distal grafts, flaps of periurethral tissue provide a suitable host bed for revascularization with results equivalent to those of conventional spongioplasty.

We recently demonstrated that radiotherapy induced urethral strictures can be successfully managed with urethroplasty. We increased size and followup in our multi-institutional cohort, and evaluated excision and primary anastomosis as treatment for radiotherapy induced urethral strictures.A retrospective review was performed of 72 patients from 3 academic institutions treated for radiotherapy induced bulbomembranous strictures. Outcome parameters of successful repair included recurrence, incontinence and erectile dysfunction.Among the 72 men treated for radiotherapy induced strictures 66 (91.7%) underwent excision and primary anastomosis. Mean followup was 3.5 years (median 3.1, range 0.8 to 11.2). Prostate cancer was the most common reason for radiotherapy (in 64 of 66, 96.9%). External beam radiotherapy and brachytherapy were performed in 28 of 66 men (42.4%) each, and a combination of both was performed in 9 (13.6%). Mean time from radiation to excision and primary anastomosis was 6.4 years (range 1 to 20) and mean stricture length was 2.3 cm (range 1 to 6). Successful reconstruction was achieved in 46 men (69.7%). Mean time to recurrence was 10.2 months (range 1 to 64) with new onset of incontinence observed in 12 men (18.5%). This was associated with stricture length greater than 2 cm (p = 0.013) and treatment center (p0.001). The rate of erectile dysfunction remained stable (preoperative 45.6%, postoperative 50.9%, p = 0.71). Radiotherapy type did not affect stricture length (p = 0.41), recurrence risk (p = 0.91), postoperative incontinence (p = 0.88) or erectile dysfunction (p = 0.53).Radiotherapy induced bulbomembranous urethral strictures can be successfully managed with excision and primary anastomosis. Substitution urethroplasty with graft or flap is needed infrequently. Patients should be counseled on the potential risks of urinary incontinence and erectile dysfunction.

Objective To evaluate our 5-year experience with deep lateral transurethral incisions of bladder neck contracture (TUIBNC), identify risk factors associated with failure of procedure, and assess outcomes of men subsequently treated for concomitant or de novo stress urinary incontinence (SUI). Materials and Methods We reviewed 50 consecutive patients who underwent TUIBNC between June 2007 and January 2012. TUIBNC was standardized to include initial dilation followed by deep transurethral incisions. All patients were evaluated cystoscopically after a 2-month interval; those with recurrent bladder neck contracture (RBNC) underwent a second TUIBNC. For patients with concomitant SUI, we assessed the timing between TUIBNC and subsequent artificial urinary sphincter (AUS) placement and its outcome. Perioperative characteristics were reviewed to identify factors associated with failure. Results Of the 50 patients analyzed, most were refractory, 78% having failed previous TUIBNC. After TUIBNC, 72% required no further surgery for obstruction at a mean follow-up of 12.9 months. Of the 14 who failed initial TUIBNC, 7 underwent repeat TUIBNC with success, representing an overall success rate of 86% after 2 procedures. Significant factors associated with treatment failure were >10 pack/year smoking history (P = .039) and ≥2 previous endoscopic BNC procedures (P = .03). Of 39 men (78%) with concomitant SUI, two-thirds underwent AUS placement after an average of 2.9 months after TUIBNC. Only 2 of 26 (8%) patients required repeat transurethral procedures after AUS placement for RBNC. Conclusion Deep lateral TUIBNC alone is a highly effective treatment modality for RBNC. Smokers and those having 2 or more previous transurethral procedures appear to have greater risk for failure. Subsequent AUS placement can be safely performed with >90% long-term urethral patency.

Forty-two cell lines recapitulating mammary carcinoma heterogeneity were profiled for all-trans retinoic acid (ATRA) sensitivity. Luminal and ER(+) (estrogen-receptor-positive) cell lines are generally sensitive to ATRA, while refractoriness/low sensitivity is associated with a Basal phenotype and HER2 positivity. Indeed, only 2 Basal cell lines (MDA-MB157 and HCC-1599) are highly sensitive to the retinoid. Sensitivity of HCC-1599 cells is confirmed in xenotransplanted mice. Short-term tissue-slice cultures of surgical samples validate the cell-line results and support the concept that a high proportion of Luminal/ER(+) carcinomas are ATRA sensitive, while triple-negative (Basal) and HER2-positive tumors tend to be retinoid resistant. Pathway-oriented analysis of the constitutive gene-expression profiles in the cell lines identifies RARα as the member of the retinoid pathway directly associated with a Luminal phenotype, estrogen positivity and ATRA sensitivity. RARα3 is the major transcript in ATRA-sensitive cells and tumors. Studies in selected cell lines with agonists/antagonists confirm that RARα is the principal mediator of ATRA responsiveness. RARα over-expression sensitizes retinoid-resistant MDA-MB453 cells to ATRA anti-proliferative action. Conversely, silencing of RARα in retinoid-sensitive SKBR3 cells abrogates ATRA responsiveness. All this is paralleled by similar effects on ATRA-dependent inhibition of cell motility, indicating that RARα may mediate also ATRA anti-metastatic effects. We define gene sets of predictive potential which are associated with ATRA sensitivity in breast cancer cell lines and validate them in short-term tissue cultures of Luminal/ER(+) and triple-negative tumors. In these last models, we determine the perturbations in the transcriptomic profiles afforded by ATRA. The study provides fundamental information for the development of retinoid-based therapeutic strategies aimed at the stratified treatment of breast cancer subtypes.

Objective To present our updated experience and patient-reported outcomes of high submuscular (HSM) placement of urologic prosthetic balloons and reservoirs (UPBRs). Methods A retrospective review was performed of patients who underwent inflatable penile prosthesis and/or artificial urinary sphincter placement between 2011 and 2013. UPBRs were placed in an HSM location between the transversalis fascia and the rectus abdominis muscle by blunt dissection through the external inguinal ring via a trans-scrotal approach. Patient demographics, perioperative outcomes, and patient-reported outcomes were reviewed. Results During the study period, 146 patients received 158 HSM implants: inflatable penile prosthesis reservoirs (n = 93) or artificial urinary sphincter balloons (n = 65). Patients completed a standardized survey at a mean of 3.2 months (range, 1.1-23.4 months) after surgery and were last followed up at a mean of 5.5 months (range, 1.1-28.7 months). Overall, 94% (n = 149) of UPBRs caused no bother, and patients were satisfied with 96% (n = 151) of implants. Patients were unable to palpate 80% (n = 126) of UPBRs and minimally palpate 16% (n = 26). The primary surgeon was unable to palpate 72% (n = 115) of UPBRs and minimally palpate 20% (n = 31). Type of UPBR, body mass index, reservoir volume, and reservoir manufacturer were not associated with patient or surgeon palpability. Of the 158 UPBRs placed, only 2 (1.3%) were revised due to bothersome patient palpability. No bowel, bladder, ureteral, or vascular injuries occurred. Conclusion HSM placement of UPBR is safe and feasible, well tolerated, and avoids deep retropubic dissection. Patient-reported outcomes support low palpability, low bother, and high patient satisfaction.

Objective To compare the safety and efficacy of patients undergoing dorsal penile plication with patients undergoing ventral and lateral plication. Methods A retrospective review was performed of all patients who underwent penile plication between 2007 and 2013. Plication was performed through a 2-cm longitudinal incision in the proximal or midpenile shaft without degloving. Plication sutures were placed in parallel opposite the angle of greatest curvature. Dorsal plication was performed with minimal displacement of the neurovascular bundle. Patient demographics, perioperative outcomes, and patient-reported outcomes were analyzed. Results Of 215 patients who underwent penile plication, complete operative and patient-reported outcomes data were available for 118 (55%). Patients were grouped by location of plication: dorsal (n = 17 [14%]), ventral (n = 65 [55%]), and lateral (n = 36 [31%]). Mean age (52-58 years; P = .51) and preoperative curvature (36-51°; P = .78) were similar among the 3 groups. Each group required a similar number of sutures (8-9; P = .18) to achieve similar correction (37-45°; P = .33). Patients completed a satisfaction survey at a mean of 15 months (range, 1-41 months) after surgery. All groups reported equally high rates of satisfaction for penile curvature ( P = .64), penile rigidity ( P = .64), strength of erection ( P = .98), and overall satisfaction ( P = .75). Although each group reported subjective decrease in penile length ( P = .10), objective length loss occurred on a small scale (mean length loss for all groups, 0.3-0.8 cm; P = .24). Conclusion Penile plication is a safe and effective technique for correcting all directions of curvature. Dorsal plication without degloving produces favorable objective and subjective results comparable to ventral and lateral plication.

Twenty to thirty percent of patients with Peyronie's disease (PD) have erectile dysfunction (ED) refractory to medical therapy and may benefit from a combined procedure addressing both conditions.The aim of this study was to show the efficacy of inflatable penile prosthesis (IPP) insertion and synchronous penile plication for correcting penile curvature and ED in patients with PD.A retrospective review was performed of all patients who underwent IPP insertion with synchronous penile plication at our tertiary care center between 2010 and 2013. All patients received an intraoperative saline intracorporal injection to induce an artificial erection. After the tunica albuginea was exposed via a standard transverse scrotal incision over the proximal penile shaft, the incision was retracted distally and/or laterally as needed for plication suture placement. Plication sutures were placed in parallel opposite the angle of greatest curvature. The incision was returned proximally to the standard penoscrotal junction for IPP insertion. Demographic and surgical data were collected from the patients' medical records. Patient satisfaction was assessed postoperatively using a nonvalidated questionnaire.The focus of this study was surgical outcomes, both technical and patient-reported satisfaction.Eighteen patients with a mean age of 63 years underwent IPP insertion with synchronous penile plication. Patients presented with dorsal (n = 11), lateral (n = 2), and biplanar curvature (n = 5). Mean preoperative curvature was 39 degrees (range 30-60) and was corrected on average to5 degrees (range5-12) using a median of four plication sutures (range 3-6). Among 15 patients completing a postoperative satisfaction survey at a mean of 11 months, all reported improvement in their overall condition and penile curvature; one with biplanar deformity reported minor residual curvature. None reported continued pain or required suture release.IPP insertion with synchronous penile plication for the correction of ED and PD is effective and results in high patient satisfaction.

METHODS: At eight centers a total of fifteen patients with locally positive, but no systemic signs and symptoms of wound / IPP infection were reviewed. If the patient had systemic / septic symptoms, immediate surgical treatment was performed. Basic patient demographics and post-operative data were acquired. All patients were carefully and frequently followed on one to two oral antibiotics. RESULTS: Fifteen patients were retrospectively reviewed. Demographics reveal age of 47 to 70 (mean 59.4), 7 of 15 (47%) being diabetic, 12 Titans / 1 700 / 1 Genesis / 1 Ambicor [has no infection retardant coating] and 11 (73%) were primary implantation with 3 (20%) being replacements and 1 (6.7%) into previous infected IPP scarred corporal bodies. Time to local wound / IPP infection after implantation was 7 to 40 days (mean 20.4 days), 14 (93 %) had incisional wound drainage with some described as large quality of fluid, 3 (20%) had significant swelling, 1 (6.7%) had device skin fixation and 4 (27%) of the 15 patients had significant increase in IPP pain / tenderness. 9 different bacteria isolates were cultured out of the incisional drainage of 7 patients with 3 Staph Epi, 2 pseudomonas, 1 enterococcus, 2 E. coli, 1 staph aurerus, 1 alpha streptococcus and 1 proteus growths. Time to total resolution of symptoms was 21 to 141 (mean 76.2) days with 13 patients having total resolution of symptoms and two currently under observation. CONCLUSIONS: Observation maybe an option for patients with local signs / symptoms of IPP infection, even with incisional drainage of culture positive bacteria, that traditionally indicated immediate surgical intervention. The authors strongly feel that from a medical legal issue this information is important to get into the literature.

INTRODUCTION AND OBJECTIVES: The true reoperation rate of penile prosthetic surgery is unknown due limited data from retrospective, single institution studies. This study aims to evaluate the reoperation rate after virgin penile prosthetic surgery using a large population database METHODS: A longitudinal analysis of California Office of Statewide Health Planning and Development database from 1995 to 2010 was performed. Inclusion criteria were men who underwent their first penile prosthetic surgery. Patients were excluded if they had an explant of a prior prosthesis at the time of their first recorded surgery. Primary outcome was reoperation, specified as the removal or replacement of the prosthesis. Censoring events included penile amputation, surgeries of the genitalia or pelvis, and cancer involving the genitourinary organs. Statistical analysis was performed via KaplanMeier plot, hazard curve, and multivariate analysis adjusting for age, race, gender, comorbidities, insurance status, hospital volume and teaching status RESULTS: 7,666 patients (40,932 patient years) were included in the study. The 5 and 10-year cumulative reoperation rates were 11.2% (CI: 10.5-12.0%) and 15.7% (CI: 14.7-16.8%) respectively. Malfunction and infection accounted for 57% and 27% of reoperations. Reoperation rate was highest at 1 year post-operatively (3.4% per year), and steadily declined until 2 years post-operatively, after which it remained at roughly 1.25% per year. Multivariate analysis showed higher rates of reoperation among younger patients (HR1⁄41.51, CI: 1.122.05 for 75yo), African American patients (HR1⁄41.30, CI: 1.05-1.62), and Hispanic patients (HR1⁄41.32, CI: 1.121.57). 22.9% of the reoperations were performed at a hospital different from the initial implantation CONCLUSIONS: Reoperation rate for penile prosthetic surgery is highest in the first year postoperatively. The patients with highest risk for reoperation are African American, Hispanics, and younger age for unclear reasons that warrant further study. Nearly a quarter of reoperations occur at a hospital different from the initial surgery, suggesting that existing literature does not reflect the true prevalence of penile prosthetic complications

We compare stricture outcomes in patients with artificial urinary sphincter cuff erosion managed with and without synchronous urethral repair.Records of patients who underwent artificial urinary sphincter removal for cuff erosion from 2007 to 2013 were retrospectively reviewed. Two cohorts of patients were evaluated, with those in group 1 treated with in situ urethroplasty and those in group 2 treated with a Foley catheter only. We compared demographic, clinical and radiological data to assess resultant stricture disease, and compared operative times between the cohorts.Of the 26 artificial urinary sphincter cuff erosion cases identified 13 underwent in situ urethroplasty while 13 did not. Mean patient age was 73 years (range 61 to 83) with a mean followup of 24 months (range 8 to 69). The rate of urethral stricture formation after artificial urinary sphincter explantation was significantly reduced among patients treated with in situ urethroplasty (5 of 13, 38%) compared to those treated with Foley catheter only (11 of 13, 85%; p=0.047). Mean operative times were similar at 78 minutes (50 to 133) for the in situ urethroplasty group vs 70 minutes (51 to 92) for the Foley catheter only group (p=0.39). Those treated with in situ urethroplasty underwent significantly fewer procedures per patient before artificial urinary sphincter replacement (0.4 vs 1.1, p=0.004) and had a much higher rate of eventually undergoing secondary artificial urinary sphincter implantation (7 of 13, 54% vs 2 of 13, 15%, p=0.04) compared to those with cuff erosion treated with Foley catheter only.Urethral repair at the time of artificial urinary sphincter explantation for cuff erosion appears to prevent stricture development, thus facilitating successful artificial urinary sphincter replacement.

INTRODUCTION AND OBJECTIVES: Current standard management of Peyronie’s disease with erectile dysfunction involves penile prosthesis placement with manual modeling. We report an alternative technique utilizing synchronous penile plication and inflatable penile prosthesis (IPP) placement. METHODS: An artificial erection is induced with injectable saline and a penile tourniquet to identify the nature of the penile curvature. A 2 cm penoscrotal incision is made and mobilized over the convex aspect of the penile curvature. The dissection is carried down through dartos and Buck’s fascia. The incision is then mobilized distally along the shaft to allow placement of multiple parallel plicating sutures (braided, nonabsorbable polyester) in the tunica albuginea until the curvature is completely corrected. IPP placement is then immediately performed through the same incision in a standard fashion. Patients were administered a postoperative survey to identify functional outcomes and patient satisfaction. RESULTS: Sixteen patients have undergone synchronous penile plication with IPP placement. Preoperative penile curvature was a mean of 43 degrees compared with 4 degrees post-procedure. We achieved approximately 8 degrees of correction with each plication suture. Of the 10 patients who completed the survey, 90% described their penile curvature as much better and 10% as slightly better. No patients have had infection or have required reoperation. CONCLUSIONS: Penile plication with concomitant IPP placement is an effective, safe, and controlled method for treatment of Peyronie’s disease with erectile dysfunction.

surgeons prospectively enrolled urethral stricture patients in a multiinstitutional, IRB approved study. The approved protocol included performing a cystoscopy at 3 and 12 months after reconstruction. Failure was defined as the inability to pass a flexible cystoscope past the area of reconstruction without force. Patients with voiding complaints at time of cystoscopy were considered “symptomatic.” For this study, men not compliant with the protocol were called and asked 1) “Is your urination better than before surgery” and 2) “Has your urethra been instrumented since surgery with answers of yes/no respectively representing a success. We reported 3 success rates for the cohort 1) Cystoscopy with no recurrence 2) Cystoscopy or phone call with no recurrence 3) Cystoscopy/phone call or lost to follow-up at one-year (with presumed success). RESULTS: Included were 190 single-stage bulbar urethroplasties performed by 7 surgeons (mean 27). Compliance with protocol follow-up cystoscopy was 79% at 3 mo and 55% at 12 mo which did not differ significantly by surgeon. Success rates are shown in the figure. Of the 16 recurrences found by cystoscopy, 12 (75%) were symptomatic at the time of the procedure. CONCLUSIONS: 1-year success rates after bulbar urethroplasty of those compliant with our standardized follow-up protocol were 89% and 76% for excisional and buccal urethroplasty respectively. When less stringent definitions of failure are used, which are the most commonly used in the current literature, success rates increased significantly. Of recurrences found by cystoscopy, 25% were asymptomatic at time of failure, implying that a significant percentage of men may have asymptomatic recurrences. Institution of this cystoscopic protocol was difficult despite the prospective nature of the study, as compliance was a challenge with all 7 surgeon cohorts.

N VIEW of the interest in allergic as well as physiologic phenomena, the question of colonic absorption is important. This report presents data obtained in a study of that question. The products of protein digestion in vitro differ from the original protein by being slightly diffusible. For some time it was assumed that only diffusible protein was absorbed and hence that peptonization was essential. Schloss and Worthen,l however, demonstrated by precipitin and anaphylactic tests, that foreign protein might be absorbed. in an undigested or partially digested state. This has been more recently confirmed by Walzer2 by application of the local passive transfer phenomenon described by Prausnitz and Ktistner.3 Walzer showed that, in adults, oral administration of the antigen gave results quite comparable with those obtained by injection in the local sensitized skin areas. In a previous study4 me have reported similar results in new’born infants. There has remained, however, the question as to the site of this absorption in the intestinal tract. The opinion in many textbooks is that. absorption takes place above the cecum and that only water a.nd crystalloids are absorbed from the large bowel. The contrary evidence of Voit? has apparently been overlooked. Following rectal a.dministration of egg white and salt solution, they found an increase in urinary nitrogen. Since it was, known that practically no peptonization took place in the colon and since the effect of enzymes could be ruled out, absorption probably accounted for their findings. Egg white represents a nonassimilable type of protein in colztrast with its acid albumin fraction. Introduced in the blood stream the former substance is excreted by the kidney. Schloss and Worthenl demonstrated the presenee of egg white in the urine following oral administration. They emphasized the greater absorption from upset or abnormal intestinal t.racts. Colonic absorption is suggested from their findings since with increased peristalsis the chance of absorption from the upper intestinal tract is 1es.s. Yet it has been shown by previous passive transfer studies4 that the majority of healthy yoang infants will absorb egg white antigen after oral administration. The f olloming experiments were designed to see if application of local passive trans

Summary Determinations of the concentration of certain lipoprotein molecules (S f 10–20 class) are reported for forty-six juveniles with diabetes mellitus. Diabetic girls and diabetic boys have higher levels than their normal counterparts. The values for the girls were higher than those for boys. No close correlation was found in this age group between the level of S f 10–20 lipoprotein molecules in the sera and (1) the duration of the diabetic state, (2) the degree of control, (3) the severity of the disease, (4) the analytic serum cholesterol levels, or (5) the dietary intake of fat per unit of body weight.

On intracutaneous injection, the serums from certain infants with eczema give an immediate wheal formation. In about 30 patients with eczema, studied by passive transfer, 10, or over 30 per cent, showed this phenomenon. This toxicity is not related to enteral absorption of offending allergens nor to alteration of the colloidal properties by heat or cold. It resembles the effect of the theoretical "histamine-like" substance described by Lewis in studying the response of the skin to trauma, but other conditions in which there was extensive skin injury failed to show similar toxicity in the serum.

T HE observation of infants and children would seem to offer an opportunity to study the nature of certain diseases in relatively pure or uncomplicated st,ates. The cumulative results from diverse insults to the human organism, which confuse t,he adult picture, usually are absent in the young. Hereditary factors, on the other hand, are more obvious and the usual home relations afford information more accurate with regard to familp history and less subjcctivc with regard to symptomatology. Hence,, it has been expected that in the field of juvenile allergy etiologic factors and prevent,ive measures could be discovered more readily. The problem of etiology and prcvcntion is not, however, easily solved. The marked la.bility of infants as a group affords no gauge for t)he reactions which may bc seen in older children or adults. All too frequently natural processes, or at least factors beyond the knowledge and intent of medical treatmcni! will alter the nature and severity of the later manifestations considerably. (Nervous and psychogenic fact)ors may complie:lte the adolescent period.) The defense mechanisms with which allergy is somewhat allied are poorly established in infants. In early infant)there may be protection from some diseases because of transmission of maternal immunit,y, but this is of short duration. The inherent immune bodies (judged by precipitins, etc.) are developed with age. Although exireme variability in the acquisition of immunity may be noted, time is an element of great import. The most recent discussions of the relationship of immunity and allergy are those of Schick,l who in contrast wit,h Rich and his coworkers2 would emphasize the similarity of the mechanism in allergy and immunity. The skin of the young infant must undergo changes before it affords adequate protect,ion. Early the skin is extremely sensitive to tho physical agents, light, heat, cold and trauma, just as it is poorly rcsistant to infectious organisms. It would seem that a condition analogous to ‘ ‘ st,reet immunit!’ ’ might be concerned with some allergies. But regardless of that possibility, the skin, from which we frequently expect information concerning specific allergic tests, is notably unre

Treating the serum from patients giving positive skin tests with saturated ammonium sulphate, the essential antibody fraction is precipitated with the globulins. The albumin fraction is without sensitizing power, as judged by passive transfer, while the precipitated globulins when dialyzed and redissolved are potent. While passive transfer offers a poor means of estimating the titer of this antibody, it is apparently possible to concentrate the substance. It is found associated with the pseudoglobulin, ∗ ∗We use the term "associated with pseudoglobulin" feeling that the exact chemical nature of antibodies is still a matter of discussion. not with the euglobulin, and the nonessential lipoidal substances may be eliminated by prolonged cold-storage of the serum before treatment with ammonium sulphate. In many respects the antibody substance behaves like the antitoxin of diphtheria, save in its relative heat lability.

1.1. The skin of younger children and infants gives a greater response to trauma than does that of older individuals. This may be due to liberation of a toxic substance in the skin cells. 2.2. Clinically this finding may interfere with the interpretation of specific allergy tests, particularly when the intracutaneous method is used. 3.3. Specific skin reactions dependent on an antibody presence (reagin of Coca) are rare in infants under four months, regardless of sensitivity or contact with allergen. With increasing age, the antibody likewise increases, apparently following a general immunologic law. 4.4. Skin tests may become negative following these conditions: 4.1.(a) Severe allergic reactions. 4.2.(b) Graded therapy. 4.3.(c) Freedom from contact. 4.4.(d) Epinephrin administration. Skin reaction may also fail because of faulty preparations of the test substances (allergens) or because of inability of the individual to form the skin test antibody, even though he is clinically sensitive.

Although considerable attention has been given to the occurrence and significance of acidosis, it is only recently that changes of body neutrality to the alkaline side have received much notice. 1 REVIEW OF THE LITERATURE Wilson and his co-workers 2 were among the first to consider alkalosis as a possible cause of tetany. They found, following parathyroidectomy, that there was a slight increase in the p H or alkalinity of the blood, a change in the hemoglobin dissociation curve and a rise in alveolar carbon dioxide tension. Accompanying these changes there was found also an increase in urinary p H (alkalinity) with diminished ammonia and acid excretion. It was further assumed that with the onset of tetany, the acid products of muscular contraction were sufficient to change this primary increased alkalinity to a normal or more acid reaction. In 1918, McCann 3 reported chemical analyses of the blood following parathyroidectomy

n/a

Summary Determinations of the concentration of certain lipoprotein molecules (S f 10–20 class) are reported for 147 normal children ranging in age from birth to 15 years. These molecules previously have been shown to be associated with atherosclerosis. Similarity of values was found for normal male and female children. Boys had significantly lower values than those previously determined for normal male adults, but the levels for girls approximate the range for young normal female adults. No correlation was present between the concentrations of these lipoproteins in the sera of newborn infants and their mothers. No significant correlation was noted between the total serum cholesterol and the level of the S f 10–20 class. The data presented would indicate that children can tolerate a much higher intake of fat per unit of body weight than adults without showing comparable increases in concentration of the S f 10–20 molecules.

Presentation of Patient (March 18, 1942): Mrs. D. (Case No. U81,690), a divorcee, aged 49, was referred to the clinic on Feb. 24, 1942, because of menorrhagia and metrorrhagia of four months' duration. In 1934, following thyroidectomy for Graves' disease at a local hospital, she had a convulsion and was found to have tetania parathyreopriva. She was satisfactorily treated with parathormone (0.5 c.c. every other day), calcium, vitamin D, and thyroid substance. Although she had occasional paresthesias, no further convulsions or cramps occurred. She entered this hospital three weeks ago on the Gynecological Service, where uterine fibroids were discovered and a'diagnostic curettage was done. The pathologic report has not yet been issued. In order to produce an artificial menopause 1,500 millicuries of radium were inserted. When Dr. Brainerd saw the patient in consultation, he noted coarseness of hair, dryness of skin, and bilateral 2 + Chvostek and Trousseau signs. The patient had hypochromic anemia, with hem...

Summary In some children having severe hypothyroidism resembling that of the true cretins, many of the epiphyses develop abnormally and have the following characteristics: There are multiple loci of calcification; the calcification is slow; abnormal epiphyses occur in many parts of the skeleton; the distribution usually is bilateral; the process occurs generally in the capital epiphyses; and there may never be normal structure without treatment. When thyroid extract is used normal epiphyses develop in as short a time as six to twelve months. Dysgenesis is frequently mistaken for the chondrodystrophy of Calve-Legg-Perthes disease.

INTRODUCTION Reviewing the literature on blood studies one is struck by the comparatively few extensive investigations which have been carried on with the blood of the new-born. The morpohologic variations in hemoglobin and cells have received more consideration than any other phase of the problem. The chemistry of the blood of the new-born has been given little attention. Sedgwick's1findings stand out as the most extensive and illuminating, and Slemon's2investigations on maternal and fetal blood are fundamental, furnishing conclusive evidence of the mechanistic function of the placenta. Coagulation has been given little real attention and except for isolated studies on individual cases of hemorrhages of the new-born few, beside Rodda,3have attempted to analyze the factors entering into this problem. We have, therefore, attempted to bring together all these phases—morphology, chemistry, coagulation and pigment metabolism—into a combined study of the blood of the normal new-born

Two patients are described who present typical histories and physical findings of allergic sensitization. The significance of the symptomatology and correlated laboratory findings are discussed. Of the greater importance is a discussion regarding the adequate handling of the severe episodes and the necessity of carrying therapeutic and prophylactic programs to the home. Inspection of the home environment and interpretation of the program in that environment are most essential for good results.

THE following case reports and comment are presented to call attention to a possible new syndrome with the hope that further observations and interest will clarify the present uncertainty of its nature. REPORT OF CASES Case1.—S. W., a 5 month old girl, was admitted to the University of California Hospital in April 1938. Both parents and a sibling were in good health. The patient had been born at term with a normal delivery and weighed 6 pounds 14 ounces (3,120 Gm.). She had been given feedings of evaporated milk formulas, with orange juice and cod liver oil in addition. There had been no previous illnesses, but she was said to have fallen from her crib at 2 months of age. Six weeks prior to admission to this hospital she became extremely irritable, especially when handled about the face or given the bottle. She was able to take feedings once

Since the introduction of chemically acidified milk by Marriott, 1 numerous suggestions and modifications have been made regarding its use, but evaporated milk acidified with lactic acid has stood the test of repeated trials. There is still some skepticism, however, regarding the role of the acid. Marriott considered acid milk valuable because of further alteration of the milk curd and improved gastric digestion when the buffer salts of the milk are neutralized by acidification. Brennemann 2 reported his gradual adoption of Marriott's formula for acid milk after a clinical trial in the Children's Memorial Hospital in Chicago and his conclusion was: "The result was all that has been claimed and all that could be hoped for, and again such as I had never seen before with any other food." As to the theoretical role of the acid, he believed that the effectiveness of the formula was due to the finer

As one of a series of integrated reports regarding the role of thyroid in growth and metabolism of normal and I131thyroid-ablated infant rhesus monkeys,1this communication presents quantitative aspects of iodine metabolism. Earlier reports of thyroid function in rhesus monkeys are limited to observations on thyroidectomized mature animals,2except in the study of Fleischmann and (Footnotes continued on next page) co-workers,2awhere two 8-month-old animals were also observed. Of the reported studies,2none have dealt with iodine metabolism per se, nor have they been concerned with the role of thyroid in growth and development. In all cases, thyroidectomy was achieved either by prolonged administration of thiouracil3or by surgical means—the latter frequently being complicated by severe and often fatal hypoparathyroidism.4When thiouracil was used, large doses (0.8 gm. per day) were found necessary to produce hypothyroidism and thyroid hyperplasia in adult animals

To the Editor:— For the record, while I am opposed to the use of eponyms and while "priorities" are of low significance, I cannot refrain from calling your attention to a statement in an editorial ofThe Journal(175:495 [Feb. 11] 1961) that the condition known as cortical hyperostosis was first described by Dr. Caffey. It is true that the report by Caffey and Silverman was published in theAmerican Journal of Roentgenologyfor July, 1945. The report by Smyth, Potter, and Silverman was published in theA.M.A. Journal of Diseases of Childrenfor April, 1946. What is overlooked is that Silverman was at the University of California prior to joining the Department of Pediatrics at Columbia with Caffey, and that a footnote to Caffey's article states that the report was read in summary before the New York Academy of Medicine on March 8, 1945. In similar fashion, the

IT IS THE purpose of this paper to integrate roentgenologic features of skeletal growth and development in normal and athyroid infant rhesus monkeys with previously reported studies of growth and metabolism in the same animals. 1 In the present study, skeletal growth and maturation were evaluated by serial roentgenograms. The roentgenologic features of thyroid deficiency in humans are well described. 2 These features, however, have not previously been investigated in subhuman primates. METHODS AND MATERIALS Animals. —Six infant rhesus monkeys whose lineage was carefully recorded were obtained for our studies from the indoor macaque colony of Dr. van Wagenen at Yale University. 1a Animals D-766 and C-794 were used as controls throughout the study, while Animal B-767 was used as a third normal control until the age of 162 days at which time it received a thyroid-ablating dose of 1.5 mc. of I 131.1b Animal B-767 was thereafter included in

There have been many excellent reports on the demineralization of bone in association with chronic diffuse nephritis (renal rickets), but the condition is still imperfectly understood. To quote Hunter,1"the theory that phosphate retention, due to the renal defect, is primarily responsible for the changes in the bones is clearly unsatisfactory." The dwarfing, polyuria and polydipsia, which are not infrequent and which strongly suggest an endocrine factor, are likewise unexplained. A lemon yellow tint to the skin, anemia and weakness of the musculature are commonly associated with chronic nephritis, but these conditions are also found in hyperparathyroidism. The case summarized in the following report is of interest because of the opportunity it afforded to study some of the metabolic and pathologic factors in detail. REPORT OF A CASE History.—D. R., a boy aged 14 years, was referred to the pediatric service in April 1932 with the following history

To the Editor:— I am delighted to read of the interest and support which the American Medical Association is giving to the "People to People" program between the United States and other countries, but I cannot refrain from voicing some apprehension with regard to the form which this support is taking. I refer to the use of the hospital ship Consolation as a sort of floating medical center and hospital visiting "Southeast Asia." To outfit and run the ship for one year will require $3,500,000. This amount of money would go far in equipping a permanent medical school, in underwriting visiting teams going over to stay at the medical schools, and in giving advanced training to potential faculty from the foreign country. While perhaps not as dramatic and spectacular, I believe the latter style of educational program would have more lasting effect and in many ways be more acceptable as

To the Editor:— I note with interest the letter from Dr. Merl G. Colvin in The Journal, February 21, in which he proposes the establishment of an International School of Medicine. The problem of our responsibility and opportunity in meeting the needs of the foreign countries interest me greatly. The role of medicine and the health sciences is an extremely important one in the concept of present world affairs. The war has left us with a responsibility and an opportunity formerly expected of Europe, and, as Dr. Colvin's letter implies, this small world's health vitally affects our own health and economy. Too often in the past, however, foreign students whose countries present a different economic and social picture from ours have been sent to our schools, which of necessity educate and train men for situations as they exist in this country. Many have returned to their own countries, where they