Multidisciplinary Surgical Approach to Increase Survival for Advanced Ovarian Cancer in a Tertiary Gynaecological Oncology Centre.

PURPOSE: The purpose of this paper is to report on changes in overall survival, progression-free survival, and complete cytoreduction rates in the 5-year period after the implementation of a multidisciplinary surgical team (MDT). METHODS: Two cohorts were used. Cohort A was a retrospectively collated cohort from 2006 to 2015. Cohort B was a prospectively collated cohort of patients from January 2017 to September 2021. RESULTS: This study included 146 patients in cohort A (2006-2015) and 174 patients in cohort B (2017-2021) with FIGO stage III/IV ovarian cancer. Median follow-up in cohort A was 60 months and 48 months in cohort B. The rate of primary cytoreductive surgery increased from 38% (55/146) in cohort A to 46.5% (81/174) in cohort B. Complete macroscopic resection increased from 58.9% (86/146) in cohort A to 78.7% (137/174) in cohort B (p < 0.001). At 3 years, 75% (109/144) patients had disease progression in cohort A compared with 48.8% (85/174) in cohort B (log-rank, p < 0.001). Also at 3 years, 64.5% (93/144) of patients had died in cohort A compared with 24% (42/174) of cohort B (log-rank, p < 0.001). Cox multivariate analysis demonstrated that MDT input, residual disease, and age were independent predictors of overall (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.203-0.437, p < 0.001) and progression-free survival (HR 0.31, 95% CI 0.21-0.43, p < 0.001). Major morbidity remained stable throughout both study periods (2006-2021). CONCLUSIONS: Our data demonstrate that the implementation of multidisciplinary-team, intraoperative approach allowed for a change in surgical philosophy and has resulted in a significant improvement in overall survival, progression-free survival, and complete resection rates.

Unveiling the epigenomic mechanisms of acquired platinum-resistance in high-grade serous ovarian cancer.

Resistance to platinum-based chemotherapy is the major cause of death from high-grade serous ovarian cancer (HGSOC). We hypothesise that detection of specific DNA methylation changes may predict platinum resistance in HGSOC. Using a publicly available "discovery" dataset we examined epigenomic and transcriptomic alterations between primary platinum-sensitive (n = 32) and recurrent acquired drug resistant HGSOC (n = 28) and identified several genes involved in immune and chemoresistance-related pathways. Validation via high-resolution melt analysis of these findings, in cell lines and HGSOC tumours, demonstrated the most consistent changes were observed in three of the genes: APOBEC3A, NKAPL and PDCD1. Plasma samples from an independent HGSOC cohort (n = 17) were analysed using droplet digital PCR. Hypermethylation of NKAPL was detected in 46% and hypomethylation of APOBEC3A in 69% of plasma samples taken from women with relapsed HGSOC (n = 13), with no alterations identified in disease-free patients (n = 4). Following these results, and using a CRISPR-Cas9 approach, we were also able to demonstrate that in vitro NKAPL promoter demethylation increased platinum sensitivity by 15%. Overall, this study demonstrates the importance of aberrant methylation, especially of the NKAPL gene, in acquired platinum resistance in HGSOC.

Investigating the role of the IGF axis as a predictor of biochemical recurrence in prostate cancer patients post-surgery.

BACKGROUND: Between 20% and 35% of prostate cancer (PCa) patients who undergo treatment with curative intent (ie, surgery or radiation therapy) for localized disease will experience biochemical recurrence (BCR). Alterations in the insulin-like growth factor (IGF) axis and PTEN expression have been implicated in the development and progression of several human tumors including PCa. We examined the expression of the insulin receptor (INSR), IGF-1 receptor (IGF-1R), PTEN, and AKT in radical prostatectomy tissue of patients who developed BCR post-surgery. METHODS: Tissue microarrays (TMA) of 130 patients post-radical prostatectomy (65 = BCR, 65 = non-BCR) were stained by immunohistochemistry for INSR, IGF-1R, PTEN, and AKT using optimized antibody protocols. INSR, IGF1-R, PTEN, and AKT expression between benign and cancerous tissue, and different Gleason grades was assessed. Kaplan-Meier survival curves were used to examine the relationship between proteins expression and BCR. RESULTS: INSR (P < 0.001), IGF-1R (P < 0.001), and AKT (P < 0.05) expression was significantly increased and PTEN (P < 0.001) was significantly decreased in cancerous versus benign tissue. There was no significant difference in INSR, IGF-1R, or AKT expression in the cancerous tissue of non-BCR versus BCR patients (P = 0.149, P = 0.990, P = 0.399, respectively). There was a significant decrease in PTEN expression in the malignant tissue of BCR versus non-BCR patients (P = 0.011). Combinational analysis of the tissue proteins identified a combination of decreased PTEN and increased AKT or increased INSR was associated with worst outcome. We found that in each case, our hypothesized worst group was most likely to experience BCR and this was significant for combinations of PTEN+INSR and PTEN+AKT but not PTEN+IGF-1R (P = 0.023, P = 0.028, P = 0.078, respectively). CONCLUSIONS: Low PTEN is associated with BCR and this association is strongly modified by high INSR and high AKT expression. Measurement of these proteins could help inform appropriate patient selection for postoperative adjuvant therapy and prevent BCR.

Smoking-Related Interstitial Fibrosis: Evidence of Radiologic Regression with Advancing Age and Smoking Cessation.

More data are needed regarding the radiology, co-morbidities and natural history of smoking-related interstitial fibrosis (SRIF), a common pathological finding, mainly described heretofore in association with lung cancer, where respiratory bronchiolitis (RB) usually co-exists. We prospectively acquired high resolution CT scan data (edge-enhancing lung reconstructions) to detect any radiologic interstitial lung abnormality (ILA) in individuals who ultimately underwent surgical lobectomy for lung cancer (n = 20), for radiologic/pathologic correlation. We also re-examined other smoking-related benign histologic cases: chronic obstructive pulmonary disease (COPD lung explants, n = 20), alpha 1-antitrypsin deficiency (A1AT, explanted lungs n = 20), combined pulmonary fibrosis and emphysema (CPFE, n = 8) and idiopathic pulmonary fibrosis (IPF, n = 10). Finally, we pooled our data with all peer-reviewed published data describing histologic SRIF of known ILA status. SRIF was observed in 40% of cancer lobectomies, mean (±SD) age 65.8 ± 8.7 years, none of whom had ILA. SRIF was observed in other smoking-related benign diseases (COPD 35%, A1AT 20%, CPFE 25%, and IPF 10%). 71.4% of benign SRIF cases had no RB (nearly all ex-smokers) versus 0% of cancer-associated SRIF cases (P = 1.7 × 10-3). Pooled data showed that those SRIF subjects without ILA were 15.05 years older than those with ILA (95% confidence interval 8.99 to 21.11, P = 2.5 × 10-5) and more likely to be former smokers (P = 7.2 × 10-3). SRIF is frequently found without lung cancer, and mostly without RB in former smokers. SRIF is less likely to have ILA in older subjects and with smoking cessation, which could represent RB+/-SRIF regression.

Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression.

Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight junction protein occludin and parallel nuclear accumulation of ß-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin-upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.

The role of multidisciplinary team meeting histopathology review and its impact on revised reports: Analysis of a national quality improvement program.

OBJECTIVES: We conducted the first Irish national study assessing the value of multidisciplinary team meeting review in pathology practice and its impact on error detection before treatment. METHODS: Public and private pathology laboratories across Ireland capture their quality activities using standardized codes and submit their data to a centralized database (National Quality Assurance Intelligence System) overseen by the National Histopathology Quality Improvement (NHQI) program. A total of 1,437,746 histopathology and cytopathology cases submitted to the NHQI program over a 60-month period (January 2017 to December 2021) were included in this study. Cases were analyzed with respect to multidisciplinary team meeting peer review and the presence of a revised report (amended or corrected report), a surrogate marker for error detection before treatment. RESULTS: Across all cases assessed, 13.74% (197,587) underwent multidisciplinary team meeting discussion. Cases discussed at review had a statistically significantly higher rate of revised reports (1.25% [2470]) than cases not discussed at review (0.16% [1959]) (Pearson χ2, 6619.26; P < .0001; odds ratio, 8.00 [95% CI, 7.54-8.49]). Overall, multidisciplinary team meeting review made it 8 times more likely to detect an error before treatment. Cancer resections had the highest rate of review at 55.29% (46,806), reflecting the prioritization of oncology case discussion at review meetings. CONCLUSIONS: The multidisciplinary team meeting review process plays a valuable role in pathology error detection. A pathologist's participation in the review process comes with a clinically significant workload that needs to be recognized for future workforce planning. This study highlighted the positive role pathologists play in enhancing patient safety.

First report of sudden death due to myocarditis caused by adenovirus serotype 3.

Myocarditis is a rare cause of sudden death in childhood. We describe the sudden death of a child from viral myocarditis, which we demonstrate was likely caused by an uncontrolled inflammatory response to a disseminated adenovirus serotype 3 infection originating in the tonsil.

Can a more detailed evaluation of excision margins refine cytologic follow-up of women post-LLETZ for high-grade dysplasia?

The relationship between dysplastic changes in the cervical epithelium and progression to in situ carcinoma and invasive carcinoma has been extensively studied. The removal of dysplastic epithelium through the long loop excision of the transformation zone (LLETZ) in 95% of the cases is curative. About 18% to 37% of LLETZ specimens with dysplasia at the margins have recurrent/residual disease. Earlier small studies suggest that the degree of dysplasia at the margins could predict for recurrence and allow a risk-based stratification of follow-up. We tested this hypothesis in a large group of women post-LLETZ for high-grade dysplasia with follow-up histology and cytology over a 12-year period. The cases were divided according to the excision margin status for dysplasia and if positive, low-grade or high-grade dysplasia. The groups were compared to assess whether the LLETZ specimens' margin status had an impact on the subsequent cytology or histology results. Positive follow-up results were defined as any grade of dysplasia in cytology or histology. Two thousand three hundred twenty-one women had LLETZs containing high-grade dysplasia over the 12-year period. One thousand five hundred thirty-four (66.1%) women had full histology and cytology follow-up available. Eight hundred twenty (53.4%) LLETZ specimens had positive margins and 714 (46.6%) had negative margins. The grade of dysplasia at the margins was available in 796 cases (97%) with 115 (15%) showing low-grade dysplasia and 680 (85%) high-grade dysplasia. One hundred seventy (20.7%) of the specimens with positive margins had positive follow-up results compared with 105 (14.7%) of the specimens with negative margins. The presence of dysplasia at an LLETZ margin is associated with dysplasia on follow-up cytology and histology (P=0.0021); however, the grade of dysplasia at the excision margin is not predictive of recurrent/residual dysplasia.

The transcription factor CUX1 negatively regulates invasion in castrate resistant prostate cancer.

Metastatic prostate cancer is treated with androgen ablation therapy but progress to castrate resistant prostate cancer (CRPC). This study aimed to investigate the role of CUX1 in CRPC using clinical samples and in vitro models. CUX1 expression was increased in androgen-independent cells compared to androgen-sensitive cells. The multi-isoform nature of CUX1 makes it difficult to assay in tissue microarrays as there is no epitope able to distinguish the many isoforms for immunohistochemistry. Using surrogate markers, we found no differential expression between castrate resistant and local hormone naïve tissue. However, differences have been demonstrated at the transcript level. In androgen-sensitive cells, migration, but not invasion, increased following CUX1 knockdown. Conversely, in androgen-independent cells, invasion was increased. This observed difference in invasion capacity is not E-cadherin mediated, as CUX1 knockdown increases the expression of E-cadherin in both cell lines with no inter-cell line difference. Cells expressed different ratios of p110/p200 isoforms depending on androgen status and cathepsin L was only detectable in androgen-sensitive cells. MMP3 is upregulated in the androgen-independent cells. Rather than a simple presence or absence of CUX1, the relative balance of CUX1 isoforms and their interplay may be a significant factor in the functional role of CUX1 in CRPC.

MARCKS promotes invasion and is associated with biochemical recurrence in prostate cancer.

BACKGROUND: Overtreatment of low-grade prostate cancer is a recognised problem for clinicians and patients. However, under-treatment runs the risk of missing the opportunity for cure in those who could benefit. Identification of new biomarkers of disease progression, including metastases, is required to better stratify and appropriately treat these patients. The ability to predict if prostate cancer will recur is an important clinical question that would impact treatment options for patients. Studies in other cancers have associated MARCKS with metastasis. METHODS: Tissue microarrays of local prostatectomy samples from a cohort of biochemical recurrent and non-biochemical recurrent tumours were assayed for MARCKS protein expression. Prostate cancer cell lines were transfected with siRNA targeting MARCKS or a control and functional endpoints of migration, invasion, proliferation, viability and apoptosis were measured. Actin was visualised by fluorescent microscopy and evidence of a cadherin switch and activation of the AKT pathway were assayed. RESULTS: MARCKS was upregulated in biochemical recurrent patients compared to non-biochemical recurrent. Knockdown of MARCKS reduced migration and invasion of prostate cancer cells, reduced MMP9 mRNA expression, as well as decreasing cell spreading and increased cell:cell adhesion in prostate cancer cell colonies. Knockdown of MARCKS had no effect on proliferation, viability or apoptosis of the prostate cancer cells. CONCLUSIONS: In conclusion, MARCKS promotes migration and invasion and is associated with biochemical recurrence in localised prostate cancer tumours. The mechanisms by which this occurs have yet to be fully elucidated but lack of a cadherin switch indicates it is not via epithelial-to-mesenchymal transition. Actin rearrangement indicates that MARCKS promotes invasion through regulating the architecture of the cell.

Dystocia increases with advancing maternal age.

OBJECTIVE: The purpose of this study was to assess the influence of maternal age on obstetric indices of uterine efficiency in spontaneous nulliparous labor managed according to a standardized protocol in order to determine whether increasing maternal age is more commonly associated with dystocia. STUDY DESIGN: Information was collected prospectively and retrieved retrospectively from an obstetric database for a 5-year period on a consecutive series of nulliparas in spontaneous term (> or = 37 weeks' gestation) labor with singleton cephalic presentations. All women were managed according to an established Active Management protocol. Indices for dystocia, including need for oxytocin augmentation, prolonged labor (> 12 hr), instrumental delivery, and cesarean section were compared between 5 maternal age categories (< 20 years, 20-24, 25-29, 30-34, and > or = 35 years). RESULTS: The obstetric outcomes of 10,737 consecutive nulliparas in spontaneous term labor were analyzed for the 5 years 1998 to 2002. The incidences of oxytocin augmentation, prolonged labor, instrumental delivery, and intrapartum cesarean section including cesareans for dystocia all increased significantly and progressively with increasing maternal age. Mean gestational age and birth weight were similar in each age category. CONCLUSION: In a context of uniform labor management, all 4 indices of dystocia examined were increased progressively with maternal age, although oxytocin augmentation proved a generally effective intervention in all age categories. These findings have implications for the analysis of intervention rates by health care providers, particularly in developed countries where the proportion of older nulliparas is increasing.

Pseudotumour formation in atheromatous coronary arteries.

Three cases with mass like lesions (pseudotumours) surrounding atheromatous coronary arteries were referred to the Royal Brompton Hospital for expert pathology review. All were males with mean age 74 years (range 55-91). In all cases, coronial autopsies were carried out for sudden deaths in the community. Past medical histories of note were hypertension (N = 2) and ischaemic heart disease (N = 1), with one patient having a past history of aortic aneurysm repair. At autopsy, firm, white and whorled masses surrounded both right and left coronary arteries ranging in size from 9 to 25 mm in diameter. Each coronary artery had intimal atheroma with associated stenosis ranging from moderate to severe. A thrombus was identified in one case. Histological sections showed a mixed inflammatory infiltrate extending from the media into the adventitia of each coronary artery, composed predominantly of plasma cells and lymphocytes with rare neutrophils and eosinophils. There was accompanying dense fibrosis accounting for approximately 50% of the mass size on microscopic examination of slides. The presence of intimal circumferential atheroma was confirmed in all cases. Immunohistochemical studies showed staining with IgG4 in two of three cases. Atheroma may be associated with mild chronic inflammation present in the intima or associated with plaques and adventitia. The differential diagnosis for coronary artery inflammatory masses would include vasculitis, syphilis, inflammatory pseudotumor and IgG4 associated disease. This is the first report of isolated coronary artery IgG4 related disease in association with atheroma.

HER2 Genetic Heterogeneity in Gastric Cancer: Evaluation According to the College of American Pathologists Breast Cancer Criteria.

Gastric and gastroesophageal junction (GEJ) adenocarcinomas have been shown to display significant HER2 genetic heterogeneity (GH). This is typically seen as a cluster of HER2-positive cells but can also take the form of intermingled cells, referred to a "mosaic" pattern. GH is not well defined in gastric/GEJ tumors and the "mosaic" pattern has never been studied. We sought to evaluate the frequency and distribution of the "mosaic" pattern of GH in gastric/GEJ tumors using the College of American Pathologists-endorsed breast criteria of 5% to <50% amplified nuclei. We also postulated that the lower limit of this GH definition might be seen by chance in normal gastric epithelium. A total of 360 consecutive gastric/GEJ tumors were tested for HER2 by immunohistochemistry and in situ hybridization. Individual tumor cell HER2:CEP17 ratios were calculated for each case and the percentage of tumor cells with a ratio ≥2.0 determined. In addition, 300 normal gastric epithelial cells were scored for HER2 and CEP17 signals. Overall, 265 cases (73.4%) showed GH. The percentage of amplified cells in GH cases linearly correlated with the overall HER2:CEP17 ratio. In normal gastric epithelium, a cell with an "amplified" 2:1 ratio was seen in 9.7% (29/300) of cells, thus reaching GH. The chance of "GH" in scoring 20 normal epithelial cells was 87%. We conclude that GH is very common in gastric/GEJ tumors when College of American Pathologists breast criteria are applied and the lower threshold is likely of little clinical significance due to the finding "amplified" 2:1 nuclei in normal cells.

Expression patterns of bone morphogenetic protein antagonists in colorectal cancer desmoplastic invasion fronts.

Bone morphogenetic proteins (BMPs) are a group of growth factors with dual functions in cancer development and progression. Recently, certain tumor-promoting roles have been identified for selected antagonists/inhibitors (BMPIs) of this developmental pathway. A recent focus on the implication of BMP in colorectal cancer progression has emerged, mainly due to the presence of inactivating mutations in several members of the canonical signaling cascade. However, the detailed expression profiles of BMPIs remain largely unknown. Based on our previous work, whereby three specific BMPIs, gremlin-1 (GREM1), high-temperature requirement A3 (HTRA3) and follistatin (FST) were collectively overexpressed in desmoplastic cocultures of colorectal cancer (CRC), here, we undertook an immunohistochemical approach to describe the patterns of their expression in CRC patients. Two major characteristics described the BMPI expression signature: First, the synchronous and coordinated stromal and epithelial overexpression of individual BMPIs in desmoplastic lesions, which demonstrated that all three of them contribute to increasing levels of BMP antagonism in such areas. Second, the presence of microenvironmental polarity in the BMPI pattern of expression, which was indicated through the preferential expression of HTRA3 in the stromal, and the parallel FST/GREM1 expression in the epithelial component of the investigated sections. In addition, expression of HTRA3 in the epithelial compartment of the tumors demonstrated a significant predictive power to discriminate between tumor-budding-bearing and tumor-budding-free desmoplastic microenvironments. Together, these findings contribute to the understanding of signaling dynamics of BMP antagonism in the colorectal cancer desmoplastic invasion front.

Cardiomyopathy and diastolic dysfunction in the embryo and neonate of a type 1 diabetic mouse model.

OBJECTIVE: The purpose of this study was to examine the effect of maternal type 1 diabetes on the structure and function of the embryonic and neonatal mouse heart. METHODS: Type 1 diabetes was induced in female C57BL6/J mice using streptozotocin. Embryonic (n = 105) and neonatal hearts (n = 46) were examined using high-frequency ultrasound (US) and a cohort of E18.5 (n = 34) and 1-day-old pup hearts (n = 27) underwent histological examination. RESULTS: Global cardiac hypertrophy in late gestation (E18.5) was evident on US in the diabetic group compared to controls with increased interventricular septal (IVS) thickness (0.44 ± 0.08 mm vs 0.36 ± 0.08 mm, P < .05) and increased left ventricular wall thickness (0.38 ± 0.04 mm vs 0.29 mm ± 0.05, P < .01). Isovolumetric relaxation time was initially prolonged in the diabetic group but resolved by E18.5 to control values. Histological examination at E18.5 demonstrated increased transverse measurements (2.42 ± 0.72 mm/g vs 1.86 ± 0.55 mm/g, P < .05) and increased IVS thickness (0.64 ± 0.20 mm/g vs 0.43 ± 0.15 mm/g, P < .05) in diabetic embryos compared to control embryos. CONCLUSION: Maternal hyperglycemia has severe effects on offspring with evidence of cardiac impairment and cardiac hypertrophy in the embryo. These effects persisted in the 1-day old but attenuated in the 1-week old suggesting cardiac remodeling after the hyperglycemic milieu of pregnancy is removed.

Giant fibroepithelial polyp of the glans penis not associated with condom-catheter use: A case report and literature review.

Fibroepithelial polyps are rare benign tumours of the glans penis; there are only a few reported cases. The pathogenesis is unknown. However, they have been linked with chronic condom catheter use or prior penile surgery. We report a case of a 62-year-old man with a large fibroepithelial polyp of the glans penis of 11 years duration, which was not associated with condom catheter use or prior surgery. The mass was large, measuring 7 × 5 × 3 cm. Fibroepithelial polyps have been reported in a range of genito-urinary sites in males and females, adults and children, and in rare cases may be associated with malignant transformation. They should be considered in the differential diagnosis of both cutaneous and mucosal genitourinary lesions.