Outcomes of patients with gallbladder cancer presenting with acute cholecystitis.

The main purpose of this study is to explore the outcomes of patients found to have gallbladder cancer during investigation and diagnosis of acute cholecystitis. The incidence of primary gallbladder cancer co-existing in acute cholecystitis is not well defined in the literature, with anecdotal reports suggesting that they experience worse outcomes than patients with gallbladder cancer found incidentally. METHODS: A retrospective review of all patients with gallbladder cancer managed at the Canberra Health Service between 1998 and May 2022 were identified and reviewed. RESULTS: A total of 65 patients were diagnosed with primary gallbladder cancer during the study period with a mean age of 70.4 years (SD 11.4, range 59-81.8 years) and a female preponderance (74% versus 26%) with a ratio of 2.8. Twenty (31%) patients presented with acute calculus cholecystitis and were found to have a primary gallbladder cancer. This group of patients were older and predominantly female, but the difference was not statistically significant. The overall 5-year survival in the cohort was 20% (stage 1 63%, stage 2 23%, stage 3 16%, and stage 4 0%). There was no statistically significant difference in survival between those who presented with acute cholecystitis vs other presentations. CONCLUSIONS: A third of the patients with gallbladder cancer presented with acute cholecystitis. There was no statistically significant difference in survival in those with bile spillage during cholecystectomy as well those presenting with acute cholecystitis.

Histologic Remission (NANCY Index) is Superior to Endoscopic Mucosal Healing in Predicting Relapse Free Survival in Patients With Ulcerative Colitis in Clinical and Endoscopic Remission.

BACKGROUND: Histologic activity is recognized as an important predictor of relapse in ulcerative colitis (UC) patients. Current treatment targets aim at mucosal healing; however, many patients continue to have histologic activity. GOALS: The aim was to assess histologic activity using the validated Nancy histologic index (NHI) score as a predictor of future relapse amongst UC patients in endoscopic and clinical remission. STUDY: In this retrospective cohort study, UC patients in clinical and endoscopic remission at a single tertiary center between 2015 and 2018, who underwent a surveillance colonoscopy were included. Clinical remission was defined by partial Mayo score (MSp) <2, and endoscopic remission was defined by Mayo endoscopic subscore (MES) ≤1. Histologic remission was defined by NHI <2. Predictive factors associated with the primary endpoint of clinical relapse were analyzed. RESULTS: A total of 74 of 184 UC patients were included in the study. Amongst this cohort, 33 patients (45%) demonstrated histologic activity (NHI >1) at enrollment. The median follow-up time was 42 months (interquartile range: 26 to 63 mo) with median relapse free period of 30 months (interquartile range: 18 to 48 mo). Kaplan-Meier analysis demonstrated patients with MES 0 ( P =0.02) and histologic remission ( P <0.0001) had significantly longer relapse free survival. On multivariate analysis only histologic activity remained an independent risk factor of future clinical relapse (hazard ratio: 4.36, confidence interval: 1.68-11.27, P =0.002). CONCLUSION: Histologic remission using the NHI independently predicts significantly longer relapse free survival and may be a superior therapeutic target than endoscopic remission.

CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma.

BACKGROUND: Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. We aimed to identify therapies to prevent and/or treat ALK inhibitor resistance. METHODS: Malignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts. RESULTS: Xenografts were validated by confirmation of RANBP2-ALK rearrangement, perinuclear ALK localisation and CD30 expression. Although brentuximab-vedotin (BV) demonstrated single-agent activity, tumours regrew during BV therapy. BV resistance was associated with reduced CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse xenograft. CONCLUSIONS: CD30 is a therapeutic target in eIMS. BV efficacy is limited by the rapid emergence of resistance. Prolonged survival with combination ALK and CD30-targeted-therapy in the diagnosis model provides the rationale to trial this combination in eIMS patients at diagnosis. This combination could also be considered for other CD30-positive, ALK-rearranged malignancies.

Altered decidual DC-SIGN+ antigen-presenting cells and impaired regulatory T-cell induction in preeclampsia.

Regulatory T (Treg) cell expansion is required for tolerance of the semi-allogeneic fetus in healthy pregnancy and impaired in preeclampsia in humans. However, the reasons remain unknown. Herein, we show that expansion of CD4(+)Helios(-)Foxp3(+) adaptive Treg (iTreg) cells, rather than CD4(+)Helios(+)Foxp3(+) natural Treg cells, accounts for this expansion in healthy pregnancy. This expansion is even more pronounced in the decidua, where there is an overrepresentation of iTreg cells. In preeclampsia, however, there is impaired systemic iTreg cell expansion, associated with a lack of iTreg cell overrepresentation in the decidua. Because decidual antigen-presenting cells (APCs) may be important for iTreg cell induction, we studied decidual CD14(+) APCs using immunohistochemistry and flow cytometry. We show that decidual CD14(+)DC-SIGN(+) APCs are closely associated with Foxp3(+) Treg cells. Furthermore, CD14(+)DC-SIGN(+) cells display a distinct phenotype compared with their CD14(+)DC-SIGN(-) counterparts. In particular, they have increased expression of tolerogenic molecules, HLA-G, and immunoglobulin-like transcript 4. In vitro, CD14(+)DC-SIGN(+) APCs from healthy pregnant women induced iTreg cells significantly more efficiently than CD14(+)DC-SIGN(-) APCs. Conversely, in preeclampsia, both CD14(+)DC-SIGN(+) and CD14(+)DC-SIGN(-) APCs induced iTreg cells poorly. These results suggest that decidual CD14(+)DC-SIGN(+) APCs may play important roles in iTreg cell induction, a process that is defective in preeclampsia and likely contributes to its pathogenesis.

Adult pilomyxoid astrocytoma presenting in the temporal lobe.

Pilomyxoid astrocytoma (PMA) is a rare variant of astrocytoma that is usually present in the hypothalamic and chiasmatic areas in the paediatric population. PMA shares many similar histopathological features to Pilocytic astrocytoma (PA), with some notable differences in its radiological and histopathological findings. On the contrary, PMA has been reported to behave more aggressively in its clinical progression than PA. Here, we describe a rare case of PMA in a 25-year-old female involving the temporal lobe, presenting with recurrent partial seizures. To our knowledge, this is the first reported case of PMA presenting in the temporal lobe in an adult female with an atypical location of the tumour, uncommon age group, and unusual radiological features being unique in this case report.

IgG4-related sclerosing cholangitis mimicking cholangiocarcinoma.

A man in his 70s presented to the emergency department with painless obstructive jaundice. Initial blood test results show a predominantly cholestatic picture with elevated tumour markers, and imaging findings are concerning for a pancreatic head neoplasm or cholangiocarcinoma with involvement of the entire common bile duct. The patient underwent staging laparoscopy and biopsies including peritoneal washing, but did not identify any features of malignancy. Immunoglobulin G and immunoglobulin G4 testing were subsequently tested and shown to be elevated. The provisional diagnosis of immunoglobulin G4-related sclerosing cholangitis was made, and steroid treatment was empirically started. Treatment with steroids was successful, with complete resolution of symptoms and abnormal imaging findings and near complete resolution of liver function test results after 1 month.

Hyperprogressive Disease (HPD) in Solid Tumours Receiving Immune Checkpoint Inhibitors in a Real-World Setting.

Introduction: Hyperprogressive disease (HPD) is a state of accelerated tumor growth from cancer immunotherapy, associated with poor outcome. The reported incidence is 6% to 29% among studies using varying definitions of HPD, with no predictive biomarkers. Tumor infiltrating lymphocytes (TILs) are prognostic and predictive for immunotherapy benefit in various tumor types, but have only been tested for correlation with HPD in one study. Objectives: The objective of the study was to determine the prevalence of HPD in solid tumor patients treated with immune checkpoint inhibitor therapy in a real-world setting, and to assess clinicopathological features as potential biomarkers for HPD. Methods: We conducted a retrospective analysis of solid tumor patients treated with immune checkpoint inhibitors at a single institution. Imaging pre-immunotherapy and postimmunotherapy were assessed for HPD, and correlated against clinicopathological factors, including TILs and programmed death-ligand 1 (PD-L1) status through archival tumor assessment. HPD was defined per Matos et al as response evaluation criteria in solid tumors (RECIST) progressive disease, minimum increase in measurable lesions of 10 mm, plus increase of ≥40% in sum of target lesions compared with baseline and/or increase of ≥20% in sum of target lesions compared with baseline plus new lesions in at least 2 different organs. Results: HPD occurred in 11 of 87 patients (13%), and associated with inferior overall survival (median 5.5 months vs 18.3 months, P = .002). However, on multivariate analysis, only liver metastases (hazard ratio [HR] 4.66, 95% confidence interval [CI] 2.27-9.56, P < .001) and PD-L1 status (HR 0.53, 95% CI 0.30-0.95, P = .03) were significantly associated with survival. Presence of liver metastases correlated with occurence of HPD (P = .01). Age, sex, and monotherapy versus combination immunotherapy were not predictive for HPD. PD-L1 status and TILs were not associated with HPD. Conclusions: We found 13% HPD among solid tumor patients treated with immunotherapy, consistent with the range reported in prior series. Assessment for HPD is feasible outside of a clinical trials setting, using modified criteria that require comparison of 2 imaging studies. Liver metastases were associated with risk of HPD, while TILs and PD-L1 status were not predictive for HPD.

The Clinical Significance of Hemorrhagic Cholecystitis.

Background: Hemorrhagic cholecystitis (HC) is a rare complication of acute cholecystitis. HC is difficult to diagnose pre-operatively and previous case reports suggest a strong association with anticoagulation and an increased morbidity. The purpose of the study is to determine the clinical presentation and outcomes of patients with HC in a large cohort of patients. Method: A retrospective review of HC patients diagnosed following review of the clinical and pathological database between January 1, 2000 - June 30, 2021 at two hospitals. A search of the histopathology database, patient medical records, laboratory results, and imaging was conducted. Results: Thirty-five patients were diagnosed on the histopathology report from approximately 6458 patients who had cholecystectomies. Thirty-one had emergency presentation and four patients (11.4%) had elective surgery. Twenty-one patients (60%) were female and 15 patients (40%) were male. The median age was 51 years. All patients had laparoscopic cholecystectomy, four patients were converted to open and five patients required postoperative endoscopic retrograde cholangiopancreatography. Two patients (5.7%) were on anticoagulation therapy. Twenty-three (65.7%) had ultrasound, 12 patients (34.2%) had computed tomography, three patients (8.5%) had magnetic resonance cholangiopancreatography, and one patient with a pre-operative diagnosis of HC. Conclusion: HC is a rare form of acute cholecystitis. Anticoagulation only accounts for a small fraction of these patients. Pre-operative diagnosis of HC is not often made. Patients were treated with cholecystectomies and made a full recovery with no complications. Our study seems to show HC is a histological diagnosis with no clinical consequences for the patients.

Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease.

We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.1,2 We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1+/- mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.

Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo.

The glycolytic phenotype is a widespread phenomenon in solid cancer forms, including breast cancer. Dichloroacetate (DCA) has recently been proposed as a novel and relatively non-toxic anti-cancer agent that can reverse the glycolytic phenotype in cancer cells through the inhibition of pyruvate dehydrogenase kinase. We have examined the effect of DCA against breast cancer cells, including in a highly metastatic in vivo model. The growth of several breast cancer cell lines was found to be inhibited by DCA in vitro. Further examination of 13762 MAT rat mammary adenocarcinoma cells found that reversal of the glycolytic phenotype by DCA correlated with the inhibition of proliferation without any increase in cell death. This was despite a small but significant increase in caspase 3/7 activity, which may sensitize cancer cells to other apoptotic triggers. In vivo, DCA caused a 58% reduction in the number of lung metastases observed macroscopically after injection of 13762 MAT cells into the tail vein of rats (P = 0.0001, n > or = 9 per group). These results demonstrate that DCA has anti-proliferative properties in addition to pro-apoptotic properties, and can be effective against highly metastatic disease in vivo, highlighting its potential for clinical use.

PD-L1 expression in papillary thyroid cancer with and without lymphocytic thyroiditis: a cross sectional study.

The impact of concurrent autoimmune thyroid disease on the tumour microenvironment and disease progression in papillary thyroid cancer (PTC) is not well understood. Studies evaluating the programmed cell death ligand 1 (PD-L1) tumour expression in PTC have shown variable results, and the effect of lymphocytic thyroiditis (LT) on tumour PD-L1 expression has not been adequately assessed. The main aim of this study was to determine expression of PD-L1 in PTC with and without LT. We examined 81 PTC cases; 28.5% of all reviewed PTC had presence of LT. In PTC specimens without LT, tumour PD-L1 expression was significantly lower compared to PD-L1 expression in PTC with LT, 6.9% vs 39.1%, respectively. Expression of PD-L1 did not differ with PTC stage, even when sub-categorised according to the presence and absence of LT. Utility of PD- L1 expression as a prognostic marker in thyroid cancer needs to be interpreted with caution.

Post-colonoscopy colorectal cancers identified by probabilistic and deterministic linkage: results in an Australian prospective cohort.

OBJECTIVE: Post-colonoscopy colorectal cancers (PCCRCs) are recognised as a critical quality indicator. Benchmarking of PCCRC rate has been hampered by the strong influence of different definitions and methodologies. We adopted a rigorous methodology with high-detail individual data to determine PCCRC rates in a prospective cohort representing a single jurisdiction. SETTING: We performed a cohort study of individuals who underwent colonoscopy between 2001 and 2008 at a single centre serving Australian Capital Territory (ACT) and enclaving New South Wales (NSW) region. These individuals were linked to subsequent colorectal cancer (CRC) diagnosis, within 5 years of a negative colonoscopy, through regional cancer registries and hospital records using probabilistic and deterministic record linkage. All cases were verified by pathology review. Predictors of PCCRCs were extracted. PARTICIPANTS: 7818 individuals had a colonoscopy in the cohort. Linkage to cancer registries detected 384 and 98 CRCs for notification dates of 2001-2013 (ACT) and 2001-2010 (NSW). A further 55 CRCs were identified from a search of electronic medical records using International Classification of Diseases-10 diagnosis codes. After verification and exclusions, 385/537 CRCs (58% male) were included. PRIMARY OUTCOME MEASURE: PCCRC rates. RESULTS: There were 15 PCCRCs in our cohort. The PCCRC incidence rate was 0.384/1000 person-years and the 5-year PCCRC risk was estimated as 0.192% (95% CI 0.095 to 0.289). The index colonoscopy prior to PCCRC was more likely to show diverticulosis (p=0.017 for association, OR 3.56, p=0.014) and have poor bowel preparation (p=0.017 for association, OR 4.19, p=0.009). CONCLUSION: In this population-based cohort study, the PCCRC incidence rate was 0.384/1000 person-years and the 5-year PCCRC risk was 0.192%. These data show the 'real world' accuracy of colonoscopy for CRC exclusion.

Crizotinib and Surgery for Long-Term Disease Control in Children and Adolescents With ALK-Positive Inflammatory Myofibroblastic Tumors.

PURPOSE: Before anaplastic lymphoma kinase (ALK) inhibitors, treatment options for ALK-positive inflammatory myofibroblastic tumors (AP-IMTs) were unsatisfactory. We retrospectively analyzed the outcome of patients with AP-IMT treated with crizotinib to document response, toxicity, survival, and features associated with relapse. METHODS: The cohort comprised eight patients with AP-IMT treated with crizotinib and surgery. Outcome measures were progression-free and overall survival after commencing crizotinib, treatment-related toxicities, features associated with relapse, outcome after relapse, and outcome after ceasing crizotinib. RESULTS: The median follow-up after commencing crizotinib was 3 years (range, 0.9 to 5.5 years). The major toxicity was neutropenia. All patients responded to crizotinib. Five were able to discontinue therapy without recurrence (median treatment duration, 1 year; range, 0.2 to 3.0 years); one continues on crizotinib. Two critically ill patients with initial complete response experienced relapse while on therapy. Both harbored RANBP2-ALK fusions and responded to alternative ALK inhibitors; one ultimately died as a result of progressive disease, whereas the other remains alive on treatment. Progression-free and overall survival since commencement of crizotinib is 0.75 ± 0.15% and 0.83 ± 0.15%, respectively. CONCLUSION: We confirm acceptable toxicity and excellent disease control in patients with AP-IMT treated with crizotinib, which may be ceased without recurrence in most. Relapses occurred in two of three patients with RANBP2-ALK translocated IMT, which suggests that such patients require additional therapy.

PD-L1 expression associated with worse survival outcome in malignant pleural mesothelioma.

AIM: There is currently a need to identify prognostic biomarkers to assist in a risk adopted approach in treatment of malignant pleural mesothelioma (MPM). Expression of programmed death ligand 1 (PD-L1) has been studied as a prognostic biomarker in a number of tumors given its central role in antitumoral immune response evasion. Four previously published analyses found PD-L1 positivity to be an adverse survival prognostic factor in MPM. This study aims to further investigate the relationship between PD-L1 expression in mesothelioma tissues and survival outcome. METHODS: Clinical data of MPM patients from a single institution between 2006 and 2016 were reviewed. Patient's archived tissues were stained with PD-L1 (Clone Ventana SP263). PD-L1 positivity was defined as > 1% membranous staining regardless of intensity. RESULTS: Data from fifty eight patients were analyzed. Median age was 73, majority was male (49, 84%) and had ECOG between 0 and 2 (46, 79%). Most common histopathological subtype was epithelioid (42, 72%), 9 (16%) biphasic subtype and 7 (12%) sarcomatoid. Thirty one patients (53%) received best supportive care and twenty seven patients (47%) received chemotherapy or combination treatment. Forty-two patients had positive PD-L1 expression (72.4%). The median survival time for PD-L1 negative group is 15.5 months and 6 months for the positive group. Positive PD-L1 expression is independently correlated with worse prognosis (HR = 2.02; 95% CI, 1.005-4.057; P-value = 0.0484). CONCLUSIONS: Our analysis found a higher percentage of MPM patients with positive PD-L1 (> 1%) compared to other studies. Highly positive PD-L1 expression was associated with statistically significantly lower median survival time.

Universal molecular screening does not effectively detect Lynch syndrome in clinical practice.

BACKGROUND: Lynch syndrome (LS) due to an inherited damaging mutation in mismatch repair (MMR) genes comprises 3% of all incident colorectal cancer (CRC). Molecular testing using immunohistochemistry (IHC) for MMR proteins is a recommended screening tool to identify LS in incident CRC. This study assessed outcomes of population-based routine molecular screening for diagnosis of LS in a regional center. METHODS: We conducted a prospective, consecutive case series study of universal IHC testing on cases of resected CRC from September 2004-December 2013. Referred cases with abnormal IHC results that attended a familial cancer clinic were assessed according to modified Bethesda criteria (until 2009) or molecular criteria (from 2009). RESULTS: 1612 individuals underwent resection for CRC in the study period and had MMR testing by IHC. Of these, 274 cases (16.9%) exhibited loss of expression of MMR genes. The mean age at CRC diagnosis was 68.1 years (± standard deviation 12.7) and the mean age of those with an IHC abnormality was 71.6 (± 11.8). A total of 82 (29.9%) patients with an abnormal result were seen in a subspecialty familial cancer clinic. Patients aged under 50 (p = 0.009) and those with loss of MSH6 staining (p = 0.027) were more likely to be referred and to attend. After germ-line sequencing, 0.6% (10 of 82) were identified as having a clinically significant abnormality. A further eight probands with pathogenic germ-line mutations were identified from other referrals to the service over the same time period. CONCLUSIONS: While technically accurate, the yield of 'universal' IHC in detecting new Lynch probands is limited by real-world factors that reduce referrals and genetic testing. We propose an alternative approach for universal, incident case detection of Lynch syndrome with 'one-stop' MMR testing and sequencing.

MMP2 and MMP9 associate with crescentic glomerulonephritis.

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiple organ involvement. Lupus nephritis (LN) is a common manifestation with a wide variety of histological appearances. Matrix metalloproteinases (MMP) 2 and 9 are gelatinases capable of degrading glomerular basement membrane type IV collagen, which have been associated with LN. We examine the expression of MMP2 and MMP9 in different classes of LN. Methods: MMP2 and MMP9 expression was detected by immunohistochemistry in sections from renal biopsy specimens with class III, class IV and class V LN (total n = 31), crescentic immunoglobulin A nephropathy (n = 6), pauci-immune glomerulonephritis (n = 7), minimal change disease (n = 2), mesangiocapillary glomerulonephritis (n = 7), diabetic nephropathy (n = 12) and histologically normal controls (n = 8). Results: MMP2 and MMP9 were not expressed in all classes of LN, but were observed in LN with cellular and fibrocellular crescents. MMP2/MMP9 was expressed in cellular and fibrocellular crescents regardless of glomerulonephritis but not observed in inactive fibrous crescents or with mesangial proliferation. This suggests that MMP2 and MMP9 are involved in the development of extracapillary proliferative lesions. Conclusions: MMP2/MMP9 is expressed with active extracapillary proliferation. Further study is necessary to define whether the expression of MMP2/MMP9 reflects a role in glomerular repair after injury, a role in organ-level immune responses or a role as a marker of epithelialization.

Spontaneous inversion of left atrial appendage.

Inversion of the left atrial appendage is a rare phenomenon and frequently occurs as a complication following cardiac operations. Spontaneous inversion is even rarer, and so far, only three cases have been reported. We report an additional case of spontaneous inversion in 4-month female with Down's syndrome, hypothyroidism, and complete atrioventricular canal defect.