Utilising a modified accelerated Delphi process to develop a national multidisciplinary consensus on peri-operative optimisation of patients with obesity undergoing non-bariatric surgery.

BACKGROUND: In the last three decades, the worldwide prevalence of obesity has increased by threefold. Using a modified Delphi consensus technique, the Irish Surgical Research Collaborative (ISRC) aimed to formulate consensus guidelines on the peri-operative optimisation of patients with obesity undergoing non-bariatric surgery. METHODS: Subgroups within the ISRC were established to formulate consensus statements using a nominal group technique (NGT) to address the three domains of pre-operative, intra-operative and post-operative care. Three Delphi rounds were circulated nationally to multidisciplinary members of the peri-operative team via electronic survey. Consensus was considered achieved for any statement with >80 % agreement. Data was analysed using Microsoft Excel (Microsoft Corp, Redmond, WA). RESULTS: Following three Delphi rounds, a total of 94 statements centred around optimising peri-operative care for patients with obesity undergoing non-bariatric surgery reached consensus. Pre-operatively, access to prehabilitation, use of pre-operative risk stratification tools and strategies to reduce obesity-related co-morbidities were all deemed important along with nomination of a hospital obesity lead. Intra-operatively, the prioritised domains were involvement of consultant anaesthetist and surgeon for safe and considered patient positioning, utilisation of minimally invasive surgical techniques, adherence to venous thromboembolism prophylaxis and surgical site infection prevention strategies as well as adoption of multimodal analgesia. Appropriate analgesia prescription, nutritional support, enhanced recovery after surgery and the role of physiotherapy were all deemed essential elements of post-operative care. CONCLUSION: As a multidisciplinary peri-operative group, through Delphi consensus, we report agreed perioperative standards to optimise the perioperative care of patients with obesity undergoing non-bariatric surgery. This consensus can be utilised to standardise clinical practice and identify areas for quality improvement.

The protective role of phosphodiesterase inhibitors in preventing colorectal cancer and advanced colorectal polyps: a systematic review and meta-analysis.

AIM: Inflammatory cells within the tumour microenvironment are the driving forces behind colorectal cancer (CRC) tumourigenesis. Understanding the different pathways involved in CRC carcinogenesis paves the way for effective repurposing of drugs for cancer prevention. Emerging data from preclinical and clinical studies suggest that, due to their antiproliferative and anti-inflammatory properties, phosphodiesterase-5 inhibitors (PDE5i) might have an anticancer effect. The aim of this study was to clarify through systematic review and meta-analysis of published peer-reviewed studies whether an association exists between PDE5i use and CRC risk. METHOD: This study was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Prospective registration was performed on PROSPERO (CRD42022372925). A systematic review was performed for studies reporting CRC and advanced colorectal polyp incidence in PDE5i 'ever-users' and PDE5i 'never-users'. Meta-analysis was performed using RevMan version 5. RESULTS: Four observational cohort studies and two case-control studies, comprising 995 242 patients were included in the final analysis, of whom 347 126 were PDE5i ever-users. Patients who were PDE5i ever-users had a significantly lower incidence of CRC or advanced colorectal polyps than never-users (OR 0.88, CI 0.79-0.98, p = 0.02). To examine the primary preventative role of PDE5i, subgroup analysis of four studies including patients without a previous history of CRC found that use of PDE5i was associated with a lower incidence of CRC (OR 0.85, CI 0.75-0.95, p = 0.005, I2 = 64%). There was no significant temporal relationship found between PDE5i use and CRC risk as both current users and previous users had a significantly lower incidence of CRC than never-users. CONCLUSION: Our study found a significant anticancer effect of PDE5i, as shown by a reduced risk of CRC in the context of both primary and secondary CRC prevention.

The association between breast density and breast cancer pathological response to neoadjuvant chemotherapy.

PURPOSE: Mammographic Density (MD) refers to the amount of fibroglandular breast tissue present in the breast and is an established risk factor for developing breast cancer. The ability to evaluate treatment response dynamically renders neoadjuvant chemotherapy (NACT) the preferred treatment option in many clinical scenarios. Previous studies have suggested that MD can predict patients likely to achieve a pathological complete response (pCR) to NACT. We aimed to determine whether there is a causal relationship between BI-RADS breast composition categories for breast density at diagnosis and the pCR rate and residual cancer burden score (RCB) by performing a retrospective review on consecutive breast cancer patients who received NACT in a tertiary referral centre from 2015 to 2021. METHODS: The Mann-Whitney U Test was used to test for differences between two independent groups (i.e. those who achieved pCR and those who did not). A binary logistic regression model was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for an association between the independent variables of molecular subtype, MD, histological grade and FNA positivity and the dependant variable of pCR. Statistical analysis was conducted with SPSS (IBM SPSS for Mac, Version 26.0; IBM Corp). RESULTS: 292 patients were included in the current study. There were 124, 155 and 13 patients in the BI-RADS MD category b, c and d, respectively. There were no patients in the BI-RADS MD category a. The patients with less dense breast composition (MD category b) were significantly older than patients with denser breast composition (MD category c, d) (p = 0.001) and patients who had a denser breast composition (MD category d) were more likely to have ER+ tumours. There was no significant difference in PgR status, HER2 status, pathological complete response (pCR), FNA positivity, or RCB class dependent upon the three MD categories. A binary logistic regression revealed that patients with HER2-enriched breast cancer and triple-negative breast cancer are more likely to achieve pCR with an OR of 3.630 (95% CI 1.360-9.691, p = 0.010) and 2.445 (95% CI 1.131-5.288, p = 0.023), respectively. CONCLUSION: Whilst dense MD was associated with ER positivity and these women were less likely to achieve a pCR, MD did not appear to independently predict pCR post-NACT.

Urogenital function following robotic and laparoscopic rectal cancer surgery: meta-analysis.

BACKGROUND: Mixed results are reported on clinical and cancer outcomes in laparoscopic rectal cancer surgery (LRCS) compared with robotic rectal cancer surgery (RRCS). However, more favourable functional outcomes are reported following RRCS. This study compared urinary and sexual function following RRCS and LRCS in male and female patients. METHODS: A systematic review and meta-analysis of urinary and sexual function after RRCS and LRCS was performed following PRISMA and MOOSE guidelines, and registered prospectively with PROSPERO (ID:CRD42020164285). The functional outcome reporting tools most commonly included: the International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF) and Female Sexual Function Index (FSFI). Mean scores and changes in mean scores from baseline were analysed using RevMan version 5.3. RESULTS: Ten studies were included reporting on 1286 patients. Some 672 patients underwent LRCS, of whom 380 (56.5 per cent) were men and 116 (17.3 per cent) were women (gender not specified in 176 patients, 26.2 per cent). A total of 614 patients underwent RRCS, of whom 356 (58.0 per cent) were men and 83 (13.5 per cent) were women (gender not specified in 175 patients, 28.5 per cent). Regarding urinary function in men at 6 months after surgery, IPSS scores were significantly better in the RRCS group than in the LRCS group (mean difference (MD) -1.36, 95 per cent c.i. -2.31 to -0.40; P = 0.005), a trend that persisted at 12 months (MD -1.08, -1.85 to -0.30; P = 0.007). ΔIIEF scores significantly favoured RRCS at 6 months [MD -3.11 (95%CI -5.77, -0.44) P <0.021] and 12 months [MD -2.76 (95%CI -3.63, -1.88) P <0.001] post-operatively. Mixed urinary and sexual function outcomes were reported for women. CONCLUSION: This meta-analysis identified more favourable urinary and erectile function in men who undergo robotic compared with conventional laparoscopic surgery for rectal cancer. Outcomes in women did not identify a consistently more favourable outcome in either group. As robotic rectal cancer surgery may offer more favourable functional outcomes it should be considered and discussed with patients.

Risk of colorectal cancer associated with BRCA1 and/or BRCA2 mutation carriers: systematic review and meta-analysis.

BACKGROUND: Carriers of the BRCA1 and/or BRCA2 mutation incur a lifetime risk of up to 85 per cent for breast cancer, and between 20 and 40 per cent for ovarian cancer. Efforts to estimate the lifetime risk of developing colorectal cancer for BRCA mutation carriers have produced conflicting results. Consequently, there are no formal guidelines regarding the need for bowel screening for individuals with BRCA1 and/or BRCA2 mutations. This systematic review and meta-analysis determined the risk of colorectal cancer associated with BRCA carrier mutations. METHODS: The primary outcome was incidence of colorectal cancer in BRCA mutation carriers. Secondary outcomes were the incidence in BRCA1 and BRCA2 carriers, Ashkenazi Jews, and age- and sex-matched cohorts. RESULTS: Eleven studies were included in the review, with an overall population of 14 252 and 4831 colorectal cancers identified. Nine studies were included in the meta-analysis. There was no increase in colorectal cancer among patients carrying a BRCA mutation (odds ratio 1·03, 95 per cent c.i. 0·80 to 1·32; P = 0·82). After adjustment for Ashkenazi heritage, and age and sex estimates, there was no increased odds of developing colorectal cancer (with no heterogeneity, I2  = 0 per cent). CONCLUSION: BRCA1 and/or BRCA2 mutation carriers are not at a higher risk of colorectal cancer.

ANTECEDENTES: Las portadoras de la mutación BRCA1 y/o BRCA2 presentan un riesgo a lo largo de la vida de hasta un 85% para presentar un cáncer de mama y entre 20-40% para el cáncer de ovario. Los esfuerzos para estimar el riesgo de desarrollar cáncer colorrectal (colorectal cancer, CCR) a lo largo de la vida en portadoras de mutaciones BRCA han dado resultados contradictorios. En consecuencia, no existen pautas formales con respecto a la necesidad de realizar el cribado de CRC en personas portadoras de mutaciones BRCA1 y/o BRCA2. Esta revisión sistemática y metaanálisis analiza el riesgo de CRC asociado en pacientes portadoras de mutaciones BRCA. MÉTODOS: Se incluyeron nueve estudios en el metaanálisis. La población general del estudio fue de 18.839 pacientes, con 4.978 con CRC identificado. La variable principal fue la incidencia de cáncer colorrectal en portadoras de mutaciones BRCA. Las variables secundarias incluyeron el análisis de la incidencia de subgrupos en BRCA 1, BRCA 2, etnia judía Ashkenazi y cohortes emparejadas por edad y sexo. RESULTADOS: No hubo un aumento de CRC en pacientes con una mutación BRCA (razón de oportunidades, odds ratio, OR 1,03; i.c. del 95% 0,80-1,32; P = 0,82). Cuando se ajustó de acuerdo con la ascendencia Ashkenazi y las estimaciones de edad y sexo, no hubo mayores probabilidades de desarrollar cáncer colorrectal (sin heterogeneidad en los estudios (I2 = 0)). CONCLUSIÓN: Este metaanálisis concluye que el riesgo de cáncer colorrectal no fue significativamente mayor en las portadoras de mutaciones BRCA1 y/o BRCA2. Sin embargo, se requiere más evidencia antes de no recomendar la colonoscopia de cribado a las portadoras de la mutación BRCA1/2. Las pruebas de inmunoquímica fecal pueden ser una alternativa apropiada en esta población.

Invasive lobular carcinoma of the breast; clinicopathologic profile and response to neoadjuvant chemotherapy over a 15-year period.

INTRODUCTION: Invasive lobular carcinoma (ILC) accounts for 5-15% of invasive breast cancers. Typical ILC is oestrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative. Atypical biomarker profiles (ER- and HER2+, ER+ and HER2+ or triple negative) appear to differ from typical ILCs. This study compared subtypes of ILC in terms of clinical and pathological parameters, and response to neoadjuvant chemotherapy (NACT) according to biomarker profile. METHODS: All patients with ILC treated in a single centre from January 2005 to December 2020 were identified from a prospectively maintained database. Clinicopathologic and outcome data was collected and analysed according to tumour biomarker profile. RESULTS: A total of 582 patients with ILC were treated. Typical ILC was observed in 89.2% (n = 519) and atypical in 10.8% (n = 63). Atypical ILCs were of a higher grade (35% grade 3 vs 9.6% grade 3, p < 0.001). A larger proportion of atypical ILC received NACT (31.7% vs 6.9% p < 0.001). Atypical ILCs showed a greater response to NACT (mean RCB (Residual Cancer Burden Score) 2.46 vs mean RCB 3.41, p = 0.0365), and higher pathological complete response rates (15% vs 0% p = 0.017). Despite this, overall 5-year disease-free survival (DFS) was higher in patients with typical ILC (91% vs 83%, p = 0.001). CONCLUSIONS: Atypical ILCs have distinct characteristics. They are more frequently of a higher grade and demonstrate a superior response to NACT. Despite the latter, atypical ILCs have a worse 5-year DFS which should be taken into consideration in terms of prognostication and may assist patient selection for NACT.

Twenty four-hour helpline access to expert management advice for food-allergy-triggered anaphylaxis in infants, children and young people: a pragmatic, randomized controlled trial.

BACKGROUND: Anaphylaxis is a life-threatening emergency. If promptly administered, adrenaline is potentially life-saving. Many food-allergic-children/carers are unsure when to use their adrenaline autoinjectors, contributing to a low quality of life and worse outcomes in the setting of an acute allergic reaction. OBJECTIVES: The aim of this study was to assess the effectiveness of 24-hour telephone access to specialist clinical advice on disease-specific quality of life. METHODS: A pragmatic two-arm, parallel-group randomized control trial was conducted. Children/carers (<16 years) with food allergy, trained in adrenaline auto-injector use, were recruited from a hospital-based paediatric allergy clinic. Baseline disease-specific quality of life was ascertained using the validated Food-Allergy-Related Quality-of-Life Questionnaire (FAQLQ), either Parent Form, Child Form or Teenager Form depending on child's age. Participants were then centrally randomized for a 6-month period to 24-hour telephone specialist support line or to usual care. The primary outcome measure was a change in FAQL scores, at one and 6 months postrandomization, compared with baseline. The minimum clinically important difference (MCID) in score is 0.5. RESULTS: Fifty two children/carers were recruited. FAQL scores remained static in the control group across the three time points. Scores gradually improved in the intervention group, with a significant difference seen at 6 months (T1-T3 Mean difference = -1.5, (CI 0.87-2.25) P < 0.005] Follow-up questionnaires, 6 months after the intervention was removed, T4, showed sustained significant difference between the groups (control M = 3.0; intervention M = 1.1[t = -4.113, P < 0.05]). CONCLUSION: The 24-hour helpline improved food-allergy-specific quality of life in children. Six-month intervention support resulted in sustained benefits for at least a further 6 months.

Longitudinal validity and responsiveness of the Food Allergy Quality of Life Questionnaire - Parent Form in children 0-12 years following positive and negative food challenges.

BACKGROUND: There are no published studies of longitudinal health-related quality of life (HRQL) assessments of food-allergic children using a disease-specific measure. OBJECTIVE: This study assessed the longitudinal measurement properties of the Food Allergy Quality of Life Questionnaire - Parent Form (FAQLQ-PF) in a sample of children undergoing food challenge. METHODS: Parents of children 0-12 years completed the FAQLQ-PF and the Food Allergy Independent Measure (FAIM) pre-challenge and at 2 and 6 months post food challenge. In order to evaluate longitudinal validity, differences between Group A (positive challenge) and Group B (negative challenge) were expected over time. We computed correlation coefficients between change scores in the FAQLQ-PF and change scores in the FAIM. To determine the minimally important difference (MID), we used distributional criterion and effect size approaches. A logistic regression model profiled those children falling below this point. RESULTS: Eighty-two children underwent a challenge (42 positive; 40 negative). Domains and total score improved significantly at pos-challenge time-points for both groups (all P<0.05). Sensitivity was demonstrated by significant differences between positive and negative groups at 6 months [F(2, 59)=6.221, P<0.003] and by differing improvement on relevant subscales (P<0.05). MID was 0.45 on a seven-point response scale. Poorer quality of life at baseline increased the odds by over 2.0 of no improvement in HRQL scores 6-month time-point. General maternal health (OR 1.252), number of foods avoided (OR 1.369) and children >9 years (OR 1.173) were also predictors. The model correctly identified 84% of cases below MID. CONCLUSION: The FAQLQ-PF is sensitive to change, and has excellent longitudinal reliability and validity in a food-allergic patient population. The standard error of measurement value of 0.5 points as a threshold for meaningful change in HRQL questionnaires was confirmed. The FAQLQ-PF may be used to identify problems in children, to assess the effectiveness of clinical trials or interventions, and to guide the development of regulatory policies.

Formaldehyde activation of mitoxantrone yields CpG and CpA specific DNA adducts.

Recently we have found that mitoxantrone, like Adria-mycin, can be activated by formaldehyde and subsequently form adducts which stabilise double-stranded DNA in vitro. This activation by formaldehyde may be biologically relevant since formaldehyde levels are elevated in those tumours in which mitoxan-trone is most cytotoxic. In vitro transcription analysis revealed that these adducts block the progression of RNA polymerase during transcription and cause truncated RNA transcripts. There was an absolute requirement for both mitoxantrone and formaldehyde in transcriptional blockage formation and the activated complex was found to exhibit site specificity, with blockage occurring prior to CpG and CpA sites in the DNA (non-template strand). The stability of the adduct at 37 degrees C was site dependent. The half-lives ranged from 45 min to approximately 5 h and this was dependent on both the central 2 bp blockage site as well as flanking sequences. The CpG specificity of mitoxantrone adduct sites was also confirmed independently by a lambda exonuclease digestion assay.

Interstrand cross-linking by adriamycin in nuclear and mitochondrial DNA of MCF-7 cells.

Activation of Adriamycin by formaldehyde leads to the formation of drug-DNA adducts in vitro and these adducts stabilise the DNA to such a degree that they function as virtual interstrand cross-links. The formation of these virtual interstrand cross-links by Adriamycin was investigated in MCF-7 cells using a gene-specific interstrand cross-linking assay. Cross-linking was measured in both the nuclear-encoded DHFR gene and in mitochondrial DNA (mtDNA). Cross-link formation increased linearly with Adriamycin concentration following a 4 h exposure to the drug. The rate of formation of Adriamycin cross-links in each of the genomes was similar, reaching maximal levels of 0.55 and 0.4 cross-links/10 kb in the DHFR gene and mtDNA respectively, following exposure to 20 micro M Adriamycin for 8 h. The interstrand cross-link was short lived in both DNA compartments, with a half-life of 4.5 and 3.3 h in the DHFR gene and mtDNA respectively. The kinetics of total Adriamycin adduct formation, detected using [(14)C]Adriamycin, was similar to that of cross-link formation. Maximal adduct levels (30 lesions/10 kb) were observed following incubation at 20 micro M drug for 8 h. The formation of such high levels of adducts and cross-links could therefore be expected to contribute to the mechanism of action of Adriamycin.

DNA interstrand cross-links induced by psoralen are not repaired in mammalian mitochondria.

Although it is generally known that mitochondria are defective in DNA damage processing, little is known about the DNA repair pathways and mechanisms that exist in these vital organelles. Certain lesions that are removed by base excision repair are efficiently removed in mitochondria, whereas some bulky lesions that are removed by nucleotide excision repair are not repaired in these organelles. There has been much interest in whether mitochondria possess activities for recombination repair, and some previous studies have reported such activities, whereas others have not. We have taken the approach of studying the formation and removal of interstrand cross-links (ICLs) in DNA. These lesions are thought to be repaired by a repair mechanism that involves nucleotide excision and recombinational repair. The formation and repair of DNA ICLs by 4'-hydroxymethyl-4,5',8-trimethylpsoralen was investigated in both the nuclear and mitochondrial genomes in hamster cells. Seven-fold-higher levels of ICLs were generated in mtDNA than in the dihydrofolate reductase gene, clearly indicating that the mitochondrial genome is a preferential target of 4'-hydroxymethyl-4,5',8-trimethylpsoralen damage. ICLs were removed efficiently from the dihydrofolate reductase gene, but no repair was observed in mtDNA. Our observations support previous work showing efficient gene-specific repair of these lesions in the nucleus but suggest that repair of this type of ICL does not exist in the mitochondria. The preferential damage of mtDNA and the absence of cross-link repair further suggests that mtDNA may be a biologically important target for psoralen.

Comprehensive genetic and histopathologic study reveals three types of neuroblastoma tumors.

PURPOSE: To determine the relationship between multiple genetic features, tumor morphology, and prognosis in neuroblastoma. PATIENTS AND METHODS: The genetic alterations and morphologic features that underpin three histopathologic risk classifications were analyzed in 108 neuroblastoma patients. Tumors were subdivided into four groups based on the three most frequent and prognostically significant genetic alterations (17q gain, 1p deletion, and MYCN amplification), and all other genetic, morphologic, and clinical data were analyzed with respect to these groups. RESULTS: Our analyses identify three nonoverlapping tumor types with distinct genetic and morphologic features, defined here as types 1, 2, and 3. Type 1 tumors show none of the three significant genetic alterations and have good prognosis. Both type 2 (17q gain only or 17q gain and 1p del) and type 3 (17q gain, 1p del, and MYCN amplification) tumors progress. However, these tumor types are distinguished clinically by having significantly different median age at diagnosis and median progression-free survival (PFS). Multivariate analysis indicates that 17q gain is the only independent prognostic factor among all genetic, histopathologic, and clinical factors analyzed. Among histopathologic risk systems, the International Neuroblastoma Pathology Classification was the best predictor of PFS. CONCLUSION: Our results indicate that specific combinations of genetic changes in neuroblastoma tumors contribute to distinct morphologic and clinical features. Furthermore, the identification of two genetically and morphologically distinct types of progressing tumors suggests that possibilities for different therapeutic regimens should be investigated.

The DNA sequence specificity of cyanomorpholinoadriamycin.

Cyanomorpholinoadriamycin (1 microM) was reacted in a transcription buffer with DNA of an initiated transcription complex. Subsequent elongation of the initiated complex revealed permanent transcriptional blockages at 16 sites after only 5 min of drug-DNA reaction time. The most dominant sites were immediately prior to 5'-CC (six) and 5'-GG (six) sequences of the non-template strand, consistent with the presence of intrastrand crosslinking between adjacent guanine residues. Minor levels of blockage were at 5'-GC and 5'-CG sequences and may reflect low levels of interstrand crosslinking.

DNA sequence-specific adducts of adriamycin and mitomycin C.

Adriamycin and mitomycin C were reduced by xanthine oxidase/NADH in the presence of a DNA template comprising a stable initiated ternary transcription complex derived from the lac UV5 promoter. Subsequent elongation of the transcription complex treated with mitomycin C revealed high levels of terminated transcripts one nucleotide prior to G residues on the coding strand (i.e. at X of XpC sequences of the non-coding strand). Lower levels of termination occurred with adriamycin, and these were also one nucleotide prior to G residues of the coding strand, but with greater sequence specificity since they were observed mainly at G of GpC sequences of the non-coding strand. The same sites were also observed with adriamycin in the absence of reducing conditions and the level of termination at these sites was enhanced up to 10-fold by Fe2+ and Fe3+, but not by Cu2+, Zn2+, Co2+ or Ni2+. These results suggest that an iron-adriamycin complex with DNA is highly sequence-specific and results in adducts, similar to those of mitomycin C, which can terminate the transcription process. Such a mechanism offers new insights into the possible mode of action of anthracyclines.

EWS-FLI1 fusion transcripts identified in patients with typical neuroblastoma.

The t(11.22)(q24.q12) results in expression of a chimeric RNA product, EWS-FLI1. This RNA product is expressed in over 85% of tumours belonging to the Ewing's family, and is increasingly used as a definitive characteristic of these tumours. In this study, we evaluated reverse transcriptase-polymerase chain (RT-PCR) for EWS-FLI1 fusion transcripts in 18 neurally derived small round cell tumours. These included six Ewing's family tumours and 12 neuroblastomas. EWS-FLI1 fusion transcripts were identified in all six Ewing's tumours, but also in two of the 12 neuroblastomas. One neuroblastoma contained the classic type 1 fusion transcript, and the second a type 1 transcript containing a 66 bp (base pair) insert that was not derived from the EWS or FLI1 gene. The presence of EWS-FLI1 fusion products in RNA extracted from primary neuroblastoma suggests the identification of EWS-FLI1 fusion transcripts is not pathognomonic for tumours of the Ewing's family. The clinical significance of these fusion transcripts in neuroblastoma is not known.

Primary hepatic malignant tumor with rhabdoid features. A histological, immunocytochemical, and electron microscopic study of four cases and a review of the literature.

Malignant tumors of the liver with rhabdoid features (MTR) are uncommon: Only 14 previous cases are reported in the literature. These tumors are characterised morphologically by sheets of large polygonal cells with abundant eosinophilic cytoplasm containing a periodic acid Schiff's-positive hyaline globular inclusion and vesicular nuclei with a central prominent nucleolus. Immunohistochemically, the inclusions at least show positivity for vimentin and epithelial markers and sometimes for other antigens. Ultrastructurally, the inclusions are composed of whorled intermediate filaments. Despite the superficial resemblance to cells of muscle origin implied in the term rhabdoid, there is no immunohistochemical or ultrastructural evidence to support such a derivation. We describe four additional children with tumors of this type, in three of whom tumor cells showed focal membrane positivity for MIC-2 on immunostaining. Its expression in an hepatic MTR may indicate neuroepithelial differentiation. Hepatic MTR should be considered in the differential diagnosis of an undifferentiated primary liver tumor in an infant in whom the alpha-fetoprotein concentration is normal or only slightly elevated for age.

Fatal pulmonary arterial occlusive vascular disease following chemotherapy in a 9-month-old infant.

Fatal pulmonary hypertension developed in an infant during the 7-month period in which he received, via a central venous catheter, combination chemotherapy for stage IV neuroblastoma as well as intermittent parenteral feeding. In a lung biopsy and at autopsy, small pulmonary arteries showed diffuse medial hypertrophy and peripheral muscularization, very extensive concentric intimal fibrosis, and focal eccentric fibrosis evolving from organizing thrombi. Pulmonary veins were normal. Hypothetically, chemotherapeutic drug therapy (possibly potentiated either by the parenteral nutrition or simply by the vehicular fluids causing volume loading of the pulmonary circulation) could cause occlusive pulmonary arterial disease by several mechanisms, but the association has not been described previously, although use of such drugs has been reported with pulmonary veno-occlusive disease.

Late mediastinal shift after repeated aspiration of postpneumonectomy seroma.

Development of a postoperative seroma is a frequent complication after muscle-sparing thoracotomy. We describe an unusual case of late mediastinal shift in a patient in whom our original plan to perform a limited muscle-sparing thoracotomy was abandoned. The procedure was converted to a standard posterolateral incision to perform a pneumonectomy for a large central carcinoid tumor with extrabronchial extension. Fluid that accumulated in her pneumonectomy space presumably shifted into the dissected tissues of her chest wall, and was then drained repeatedly by her local physician in the time interval between 2 weeks and 3 months after surgery.

Genotypic mapping of HPV and assessment of EBV prevalence in endocervical lesions.

AIMS: To examine the prevalence of human papillomavirus (HPV) and Epstein-Barr virus (EBV) in low grade glandular intraepithelial lesions of the cervix, adenocarcinoma with high grade glandular intraepithelial lesions combined, and adenocarcinomas; and to perform a genotyping mapping analysis of endocervical carcinomas to determine the extent of HPV infections in such lesions. MATERIAL: Archival paraffin wax embeded material from the files of the departments of pathology, National Maternity Hospital, Dublin, and University College Cork, Ireland. METHODS: HPV prevalence was examined using type specific HPV PCR, general primer HPV PCR (pan HPV screen), nonisotopic in situ hybridisation (NISH), and PCR in situ hybridisation (PCR-ISH). In situ hybridisation was performed using fluorescein labelled oligonucleotide cocktail for eber transcripts of EBV. Genotypic analysis was performed, in all cases where possible, using a grid system. RESULTS: HPV 16 and 18 were predominantly identified in low grade glandular intraepithelial lesions, high grade glandular intraepithelial lesions, and adenocarcinomas, with HPV prevalence increasing with grade of dysplasia. EBV was only identified in subepithelial lymphocytes in a minority of cases. No link could be shown between HPV and EBV in endocervical lesions. HPV infection was not clonal in endocervical cancer and coexistent adjacent cervical intraepithelial neoplasia, where present, tended to show a similar HPV type. CONCLUSIONS: The restriction of HPV types 16 and 18 to endocervical lesions suggests that their effect is restricted and specific to endocervical mucosa, but the mechanism of interaction is currently unknown.