Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response.

BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.

Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).

Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed. Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002). Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.

Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results: Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions: Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

High-resolution HLA allele and haplotype frequencies in majority and minority populations of Costa Rica and Nicaragua: Differential admixture proportions in neighboring countries.

The HLA system shows the most extensive polymorphism in the human genome. Allelic and haplotypic frequencies of HLA genes vary dramatically across human populations. Due to a complex history of migration, populations in Latin America show a broad variety of admixture proportions, usually varying not only between countries, but also within countries. Knowledge of HLA allele and haplotype frequencies is essential for medical fields such as transplantation, but also serves as a means to assess genetic diversity and ancestry in human populations. Here, we have determined high-resolution HLA-A, -B, -C, and -DRB1 allele and haplotype frequencies in a sample of 713 healthy subjects from three Mestizo populations, one population of African descent, and Amerindians of five different groups from Costa Rica and Nicaragua and compared their profiles to a large set of indigenous populations from Iberia, Sub-Saharan Africa, and the Americas. Our results show a great degree of allelic and haplotypic diversity within and across these populations, with most extended haplotypes being private. Mestizo populations show alleles and haplotypes of putative European, Amerindian, and Sub-Saharan African origin, albeit with differential proportions. Despite some degree of gene flow, Amerindians and Afro-descendants show great similarity to other Amerindian and West African populations, respectively. This is the first comprehensive study reporting high-resolution HLA diversity in Central America, and its results will shed light into the genetic history of this region while also supporting the development of medical programs for organ and stem cell transplantation.

Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma.

BACKGROUND: The potential for surgical resection of primary hepatoblastoma tumours was assessed at diagnosis, and after two and four cycles of neoadjuvant chemotherapy. METHODS: Available radiographic images for patients with stage III and IV hepatoblastoma diagnosed between 1991 and 2008 were reviewed. The extent of disease was determined at diagnosis using the PRETEXT staging system, and after two and four cycles of therapy by POST-TEXT staging. Tumour resectability based on radiographic studies was assessed independently by two surgeons with expertise in hepatic surgery who were blinded to treatment and clinical outcome. RESULTS: Radiographic images from 20 patients with hepatoblastoma were reviewed. Six of 20 tumours were downstaged after two cycles, and three additional tumours were downstaged following four cycles. All PRETEXT stage III and IV tumours were determined to be surgically unresectable at diagnosis. The number of tumours considered unresectable decreased from 16 of 20 at diagnosis to seven of 20 after two cycles, and to four of 20 after four cycles. Five of the seven tumours that were unresectable after two cycles, and all four tumours that were unresectable after four cycles would have qualified for liver transplant based on radiographic studies. CONCLUSION: The majority of stage III and IV hepatoblastomas achieved radiographic resectability after two cycles of chemotherapy. There may be an opportunity for earlier surgical intervention and potential for a reduction in chemotherapy in a considerable number of patients.

The impact of changing neonatal respiratory management on extracorporeal membrane oxygenation utilization.

BACKGROUND: The introduction of inhaled nitric oxide (INO) and high-frequency oscillatory ventilation (HFV) has had a profound effect on the use of extracorporeal membrane oxygenation (ECMO) for respiratory failure in neonates without congenital diaphragmatic hernia (CDH). The purpose of this study was to evaluate the changes in the demographics and outcome of non-CDH neonates who underwent ECMO for hypoxemic respiratory failure. METHODS: All neonates (non-CDH and noncardiac) who underwent ECMO between January 1, 1989 and January 1, 2001 were reviewed. Patients were separated into 3, 4-year periods for comparison (period A, 1989 through 1992; B, 1993 through 1996; C, 1997 through 2000). Data were examined by analysis of variance and contingency table analysis. RESULTS: There was a progressive decline in the total number of neonates requiring ECMO over time (period A, 172; B, 114; C, 56; P <.01). The utilization of pre-ECMO alternate respiratory therapies such as INO (period A, 0%; B, 23%; C, 98%; P <.01) and HFV (period A, 9%; B, 61%; C, 89%; P <.01) have increased significantly associated with an increase in the age of ECMO initiation (Period A, 40.5 hours; B, 58.3 hours; C, 68.5 hours; P <.01). The length of ECMO run also has increased (period A, 154.7 hours; B, 193.0 hours; C, 174.5 hours; P <.01), but the overall mortality rate has remained unchanged. CONCLUSIONS: With the increasing use of INO and HFO, the absolute number of non-CDH, noncardiac neonates with hypoxemic respiratory failure requiring ECMO has decreased. Initiation of ECMO has become progressively later likely because of the use of these rescue therapies, but the overall mortality rate remains unchanged despite this delay.

Influence of life-history parameters on organochlorine concentrations in free-ranging killer whales (Orcinus orca) from Prince William Sound, AK.

Certain populations of killer whales (Orcinus orca) have been extensively studied over the past 30 years, including populations that use Puget Sound, WA, the inside waters of British Columbia, Southeastern Alaska and Kenai Fjords/Prince William Sound, Alaska. Two eco-types of killer whales, 'transient' and 'resident', occur in all of these regions. These eco-types are genetically distinct and differ in various aspects of morphology, vocalization patterns, diet and habitat use. Various genetic and photo-identification studies of eastern North Pacific killer whales have provided information on the male-female composition of most of these resident pods and transient groups, as well as the approximate ages, reproductive status and putative recruitment order (birth order) of the individual whales. Biopsy blubber samples of free-ranging resident and transient killer whales from the Kenai Fjords/Prince William Sound, AK region were acquired during the 1994-1999 field seasons and analyzed for selected organochlorines (OCs), including dioxin-like CB congeners and DDTs. Concentrations of OCs in transient killer whales (marine mammal-eating) were much higher than those found in resident animals (fish-eating) apparently due to differences in diets of these two killer whale eco-types. Certain life-history parameters such as sex, age and reproductive status also influenced the concentrations of OCs in the Alaskan killer whales. Reproductive female whales contained much lower levels of OCs than sexually immature whales or mature male animals in the same age class likely due to transfer of OCs from the female to her offspring during gestation and lactation. Recruitment order also influenced the concentrations of OCs in the Alaskan killer whales. In adult male residents, first-recruited whales contained much higher OC concentrations than those measured in non-first-recruited (e.g. second recruited, third recruited) resident animals in the same age group. This study provides baseline OC data for free ranging Alaskan killer whales for which there is little contaminant information.

Technical advances in pediatric laparoscopy have had a beneficial impact on splenectomy.

PURPOSE: The aim of this study was to demonstrate the effects of recent technical advances on the safety and benefits of pediatric laparoscopic splenectomy. METHODS: A retrospective review was conducted of patients undergoing laparoscopic splenectomy from January 1998 to January 2000. Technical advances utilized during this period included the harmonic scalpel, a specialized flexible hilar retractor, a larger, wire-rimmed specimen bag, and lateral patient positioning. RESULTS: Laparoscopic splenectomy was performed successfully on 18 patients aged 3 to 17 years (median, 9). The indications were hereditary spherocytosis (n = 10), idiopathic thrombocytopenic purpura (n = 5), and other (n = 3). Eight patients had concomitant procedures including cholecystectomy (n = 3), resection of an accessory spleen (n = 3), and other (n = 2). The median operating time, including the concomitant procedures, was 125 minutes (range, 70 to 235). Patients tolerated a regular diet on median postoperative day 1 (range, 1 to 3), and 16 were discharged home on or before postoperative day 2. None of the patients required blood product transfusion or conversion to an open technique. There were no complications, and all patients had returned to usual activity by 2 weeks. CONCLUSION: With recent technological advances, the laparoscopic approach has become easy to perform, safe, and should be considered the procedure of choice for pediatric splenectomy.

Respiratory failure in postpneumonectomy syndrome complicated by thoracic lordoscoliosis: treatment with prosthetic implants, partial vertebrectomies, and spinal fusion.

STUDY DESIGN: This study investigated the case of a 17-year-old girl with postpneumonectomy syndrome, complicated by a thoracic lordoscoliosis, who was successfully treated with prosthetic implants, partial vertebrectomies, and anteroposterior spinal fusion. OBJECTIVE: To report a unique case and describe the authors' method of treatment. SUMMARY OF BACKGROUND DATA: Postpneumonectomy syndrome is an uncommon complication of pneumonectomy. Many case reports describe successful treatment with insertion of prosthetic implants into the empty hemithorax to shift the mediastinum to its original position. Thoracic lordoscoliosis reportedly has contributed to pulmonary compromise, but no cases have shown its occurrence in the setting of postpneumonectomy syndrome. METHODS: The patient was observed at the National Children's Hospital in Tokyo, referred to Children's Hospital in Los Angeles, California for surgical correction, and followed in Tokyo for the next year. RESULTS: Two prosthetic implants with an injection port for further expansion were positioned in the right hemithorax to restore the mediastinum to its normal position. Anterior discectomies, partial vertebrectomies, and fusion of T5-T10 was performed concurrently. Then 5 days later, posterior spinal fusion of T1-T12 with instrumentation and bone graft were performed to correct the thoracic lordoscoliosis and increase the chest cavity space. At 1 month after the surgery, the patient was extubated after being ventilator dependent for 5 months. At the time of operation, the girl was ventilator dependent and nonambulatory, but 1 year later could participate in all activities of daily living without any oxygen supplementation. CONCLUSIONS: Postpneumonectomy syndrome can be treated successfully with prosthetic implants to restore the normal position of the mediastinum. Thoracic lordoscoliosis can complicate the syndrome and may be corrected to help restore normal pulmonary function.

Comparison of elements in bottlenose dolphins stranded on the beaches of Texas and Florida in the Gulf of Mexico over a one-year period.

We analyzed tissue samples from bottlenose dolphins (Tursiops truncatus) that had stranded on beaches in Texas and Florida over a 1-year period starting in September 1991. The concentrations of 10 elements plus methyl mercury (MeHg) were determined in brain, kidney, and liver, and we examined these results for differences based upon age, site, sex, and tissue type. A strong inverse relationship between total mercury (Hg) and the percentage that was MeHg was found in liver, kidney, and brain tissue, presumably due to demethylation of MeHg. A threshold concentration was found for total Hg in brain tissue, indicating that most Hg was present as MeHg up to about 8 years of age. Increases in total Hg after this age were accompanied by an increase in the ratio of total Hg to MeHg, indicating demethylation. Strong relationships were found between total Hg in liver and age and between total Hg and selenium in liver, which have been observed before in many fish- and squid-eating marine mammals. The only difference based on sex of the animals was observed for MeHg, which was higher in females and contrary to the pattern often observed for organic contaminants. Several elements (copper, Hg, lead, zinc) exhibited intersite differences, which were not consistent. Bottlenose dolphin from Florida exhibited the highest levels of MeHg and total Hg, while animals from Texas exhibited the highest levels of lead, copper, and zinc. The essential elements copper and zinc were expected to be the same for the Texas and Florida animals; however, observed differences may indicate population differences in basic physiological levels, dietary intake, or health status.

Complete cDNA sequence of the Ki-ras proto-oncogene in the liver of wild English sole (Pleuronectes vetulus) and mutation analysis of hepatic neoplasms and other toxicopathic liver lesions.

A complete copy of Ki-ras b cDNA from English sole (Pleuronectes vetulus), a benthic marine flatfish, was cloned and sequenced. The percent identity between the predicted amino acid sequence of English sole and human Ki-ras b was 97%, whereas the percent identity between the English sole gene and rainbow trout or Rivulus Ki-ras b was 98%. Areas of amino-acid sequence conservation included codons 12, 13, and 61, the positions in which mutations are observed in ras cellular oncogenes in other species. The 5' untranslated region (UTR), consisting of 217 nt, was not highly GC rich but contained four ATG start codons upstream of the major open reading frame. The 3' UTR, containing 26 nt, was AU rich. Analysis of Ki-ras mutations was performed on a variety of necrotic, preneoplastic, and neoplastic lesions in livers from 13 English sole collected from contaminated waterways in Puget Sound, WA. Despite reports of Ki-ras mutations in hepatic tumors from other fish, no mutations in codons 12, 13, or 61 were found in hepatic lesions from English sole by direct DNA sequencing of polymerase chain reaction-amplified genomic DNA. Although mutations could exist at levels below the detection limits of this analysis, the results suggest that Ki-ras has a role in liver carcinogenesis that varies according to the fish species or carcinogen. Furthermore, future studies of the etiology of chemically induced cancer in feral English sole should consider mutations in other cancer-related genes, such a5p53, Ha-ras, and N-ras.

Molecular epizootiology of genotoxic events in marine fish: linking contaminant exposure, DNA damage, and tissue-level alterations.

Molecular epizootiological studies are increasingly being used to investigate environmental effects of genotoxic contaminants. The assessment of damage to DNA and linking the damage to subsequent molecular, cellular, or tissue-level alterations is a central component of such studies. Our research has focused on the refinement of the 32P-postlabeling assay for measuring covalent DNA-xenobiotic adducts arising from exposure to polycyclic aromatic compounds, using DNA adducts as molecular dosimeters of genotoxic contaminant exposure in biomonitoring studies, and investigating the relationship of DNA adduct formation to toxicopathic liver disease, including neoplastic lesions. A combination of field and laboratory studies using the 32P-postlabeling assay has shown that DNA adducts in marine fish are effective molecular dosimeters of genotoxic contaminant exposure. Investigations of the relationship of DNA adduct formation to neoplastic liver disease have shown that elevated levels of DNA adducts in certain fish species from contaminated coastal sites are associated with increased prevalences of toxicopathic hepatic lesions, including neoplasms, and that the ability to assess DNA damage has helped to explain, in part, species differences in lesion prevalence. Moreover, in a study of a site in Puget Sound contaminated with polycyclic aromatic compounds, we have shown, for the first time, that elevated levels of hepatic DNA adducts are a significant risk factor for certain degenerative and preneoplastic lesions occurring early in the histogenesis of hepatic neoplasms in feral English sole (Pleuronectes vetulus). These latter findings coupled with our current studies of mutational events in the K-ras proto-oncogene should provide further mechanistic substantiation that mutagenic events resulting from exposure to complex mixtures of genotoxic polycyclic aromatic compounds are involved in the etiology of hepatic neoplasia in English sole.

The cost benefit of changing protocols in the management of intussusception.

BACKGROUND: At a time when pressure is being applied to healthcare systems to reduce costs and improve efficiency, both the medical and financial implications of changing practices need to be documented. METHODS: A review was undertaken of 703 patients with intussusception, treated during a 10-year period from 1983. RESULTS: This review showed that changes to the protocol for the management of intussusception have not only benefited the patient by reducing the morbidity and the operative rate, but also have led to a reduction in the length of hospital stay, providing significant cost savings to the health system. The reduction in the operative rate accounts for an estimated annual saving at the Royal Children's Hospital of $139,000. CONCLUSIONS: Improvements in the management of intussusception have resulted in significant reductions in the costs of treatments. The recent diagnosis-related group casemix funding arrangements mean, however, that the Royal Children's Hospital benefits more financially from inappropriate operative management of intussusception, than from non-operative management. Funding arrangements should not discourage optimal treatment.

Organochlorine contaminants in blubber of four seal species: integrating biomonitoring and specimen banking.

Blubber samples from four Alaska seal species (bearded seal, Erignathus barbatus, harbor seal, Phoca vitulina, northern fur seal, Callorhinus ursinus, ringed seal, P. hispida) were collected for inclusion in the US National Biomonitoring Specimen Bank, as well as for immediate analysis as part of the contaminant monitoring component of the US National Marine Fisheries Service's Marine Mammal Health and Stranding Response Program. The blubber samples were analyzed for organochlorine (OC) contaminants (e.g., PCB congeners, pesticides, DDTs). Results for bearded and ringed seals from the Alaska Arctic revealed low blubber concentrations of OC contaminants. Harbor seals from Prince William Sound. Gulf of Alaska, had somewhat higher blubber concentrations of OC contaminants. In contrast, northern fur seals sampled from the Pribilof Islands had blubber concentrations of certain OC contaminants that were about an order of magnitude higher than those found in the other seal species. Differences in contaminant concentrations among the Alaska seals may be explained by differences in feeding habits and migratory patterns, age or gender did not appear to account for the differences observed. The highest concentrations of OCs were found in harbor seals stranded along the northwestern US mainland, which is consistent with higher concentrations of anthropogenic contaminants being found in urban coastal areas than in more remote Arctic environments. The integration of real-time contaminant monitoring with specimen banking provides important baseline data that can be used to plan and manage banking activities. This includes identifying appropriate specimens that are useful in assessing temporal trends and increasing the utility of the banked samples in assessing chemical contaminant accumulation and relationships to biological effects.

Chemical contaminants in harbor porpoise (Phocoena phocoena) from the north Atlantic coast: tissue concentrations and intra- and inter-organ distribution.

Concentrations of chlorinated hydrocarbons (CHs), such as polychlorinated biphenyls (PCBs), were measured in subsamples taken from different anatomical locations of blubber and liver of three apparently healthy harbor porpoises (Phocoena phocoena) incidentally caught in a gill-net fishery along the northwest Atlantic coast; selected elements (e.g., mercury) were measured in subsamples of liver. The vertical distribution (skin to muscle) of contaminants within blubber was also determined. Additionally, the concentrations of CHs and elements were determined in individual samples of brain, lung, kidney, and testis to assess how the disposition of toxic chemicals may be dependent on the physiological characteristics of a specific organ. Statistical analyses of the results showed that the anatomical location of the blubber or liver sample had no significant effect on concentrations of either CHs in blubber and liver, or of selected elements in liver. However, there were statistical differences between strata of blubber (skin to muscle) for the concentrations of CHs. As expected, the results showed that the CH concentrations, based on wet weight, were considerably higher in the blubber than in the other tissues; however, the concentrations of CHs in the different tissues were more comparable when values were based on total lipid weight with the exception of the brain where lipid normalized concentrations were lower than in all other tissues: This low relative accumulation of lipophilic contaminants in the brain tissue may be due to the presence of the blood-brain barrier, or due to a lower proportion of neutral lipids, such as triglycerides, as analysis for percent lipid and for the proportion of specific lipid classes showed.

Laparoscopy for diagnosis and treatment of recurrent abdominal pain in children.

Extensive radiographic evaluation of children with recurrent abdominal pain (RAP) is rarely diagnostic or cost-effective. The authors sought to define the role of laparoscopy in the evaluation of children with RAP. Fifteen children underwent laparoscopy for RAP in a 2-year period. Their mean age was 12 years (range, 6 to 16 years), 13 (87%) were female, and the mean duration of symptoms was 11 months (range, 2 to 60 months). Thirty-eight imaging studies (excluding plain films) had been obtained before laparoscopy, including 19 abdominal sonograms, 9 upper gastrointestinal series, four abdominal computed tomography scans, 3 barium enemas, 2 isotope scans, and 1 magnetic resonance examination of the head. Only two (5%) of these studies provided an accurate diagnosis. Eleven of the 15 children (73%) had positive findings diagnosed and treated laparoscopically. These included eight appendiceal abnormalities (in six patients), three Meckel's diverticula, one inguinal hernia, one urachal cyst, one para-fallopian tube cyst, and one adhesion to an appendectomy stump. Eight of 11 (73%) children with positive findings had immediate resolution of symptoms after laparoscopic treatment. Three children with pathological findings at the time of laparoscopy had persistent symptoms, which resolved completely within 4 months of the laparoscopy. Laparoscopy is an accurate technique for the evaluation and treatment of children with RAP. Its early application could provide economic benefit by eliminating many low-yield imaging studies and minimizing lost time from school.

Barriers to timely mammography.

A survey of 399 women between 50 and 59 years of age was conducted to learn how we could improve their compliance with mammography screening guidelines. Our results showed that 78% of the women surveyed believed their physician would tell them if they needed a mammogram. Women who had not had a mammogram were more likely to be misinformed about indications for mammography than women who had had a mammogram. Women who had not had a mammogram were less likely to visit a health center than were women who had had a mammogram. A multifaceted approach including patient education to correct misinformation, reminder systems for women not seen regularly in health centers, and physician reminders may have the most impact.

Butyltin contamination of sediments and benthic fish from the East, Gulf and Pacific coasts of the United States.

Butyltin concentrations were determined in sediments, tissues and stomach contents of fish collected in 41 embayments on the East, Gulf and Pacific coasts of the U.S.A. between 1986 and 1991 as part of the National Oceanic and Atmospheric Administration's (NOAA) National Benthic Surveillance Project (NBSP). A total of 99 sediments, 108 fish liver samples from 11 fish species, and 10 composites of fish stomach contents were analyzed for tetrabutylin, tributylin, dibutylin and monobutylin. Tributyltin (TBT) was detected (i.e. > 10 ng/g) in 38 of the sediments samples analyzed and was generally the predominant bulytin present; concentrations of total butyltins ranged from 15 to 1600 ng/g wet weight. The highest concentrations were found in sediments from urban sites, especially sites on the West coast. Many of the fish liver and stomach contents samples also contained butyltins. Tributyltin represented 83 (7.1)% [mean (SEM); n=15], 64 (6.6)% (n=12) and 36 (7.8)% (n=12) of the total butyltins in livers from white croaker, winter flounder and Atlantic croaker, respectively, suggesting possible species differences in biotransformation of TBT. The concentrations of butyltins in stomach contents indicated that diet can be a significant route of exposure of fish to butyltins. Between 1986 and 1991 butyltin concentrations in sediments and fish generally appeared to be declining; however, no statistically significant temporal trends were observed at individual sites or for the sites overall.

Laparoscopic bipolar strip-tease appendicectomy. A new endosurgical technique.

Since its conception, several techniques have been described for laparoscopic appendicectomy. We describe a technique which utilizes a 5-mm bipolar forceps designed to coagulate and cut tissues at the same time; 50 pediatric patients underwent laparoscopic appendicectomy for acute appendicitis using this "stripping and teasing" technique. No bleeding complications occurred. There were only two postoperative abscesses in the series. We believe that the bipolar laparoscopic striptease appendicectomy technique as developed by the senior author is safe, quick, and effective, even for severe appendicitis.