Alpha-1 antitrypsin deficiency-associated panniculitis.

BACKGROUND: Panniculitis represents a rare and potentially lethal manifestation of alpha-1 antitrypsin deficiency (AATD). Evidence regarding management is limited to case reports and small case series. We sought to clarify typical features and investigation of AATD-associated panniculitis and assess the evidence regarding therapeutic options. SEARCH METHODOLOGY: Articles and abstracts published between 1970 and 2020 were identified by searches of MEDLINE, PubMed, and secondary searches of references from relevant articles using the search terms "panniculitis," "alpha-1," "antitrypsin," "deficiency," and "Weber-Christian." FINDINGS: We identified 117 cases of AATD-associated panniculitis. In 1 series, AATD was present in 15% of all cases of biopsy-proven panniculitis. Failure to achieve clinical response was seen in all instances of systemic steroid use. Dapsone, although effective and accessible, is frequently associated with failure to achieve remission. In these instances, intravenous AAT augmentation therapy generally resulted in response. CONCLUSIONS: AATD may be more prevalent among patients presenting with panniculitis than previously thought. Patients presenting with panniculitis and systemic illness show high mortality risk. Although most cases are associated with the severe ZZ-genotype, moderate genotypes may also predispose to panniculitis. Dapsone remains the most cost-effective therapeutic option, whereas intravenous AAT augmentation remains the most efficacious. Finally, glucocorticoids appear ineffective in this setting.

Differential Expression Profiles of Oxidative Stress Levels, 8-oxo-dG and 4-HNE, in Barrett's Esophagus Compared to Esophageal Adenocarcinoma.

Barrett's esophagus (BE), a chronic inflammatory condition, is the leading risk factor for esophageal adenocarcinoma (EAC). In inflammation to cancer pathways, oxidative stress profiles have been linked to cancer progression. However, the relevance of oxidative stress profiles along the BE-disease sequence remains to be elucidated. In this study, markers of oxidative stress; DNA adducts (8-oxo-dG) and lipoperoxidation (4-HNE), and markers of proliferation (Ki67) were measured in patient biopsies representing the BE-disease sequence. Differences in expression of these markers in Barrett's patients with cancer-progression and non-progression were examined. Proliferation was reduced in Barrett's specialized intestinal metaplasia (SIM) compared with EAC (p < 0.035). Correcting for cell proliferation levels, a confounding factor, linked to oxidative stress profiles, SIM demonstrated increased levels of 8-oxo-dG and 4-HNE (p < 0.05) compared with EAC. Longitudinal analysis of Barrett's patients demonstrated decreased levels of 8-oxo-dG in SIM cancer progression (p < 0.05). BE is an environment of increased oxidative stress and inflammation. Patients with progressive disease demonstrated reduced oxidative stress levels in 8-oxo-dG. Perhaps these alterations facilitate Barrett's progression, whereas in non-progressive disease, cells follow the rules of increased oxidative stress ultimately triggers cell apoptosis, thereby preventing propagation and survival.

HLA-DR expression in tumor epithelium is an independent prognostic indicator in esophageal adenocarcinoma patients.

Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis, and incidence is increasing rapidly in the Western world. Measurement of immune markers has been shown to have prognostic significance in a growing number of cancers, but whether this is true for EAC has yet to be evaluated. This study aimed to characterize HLA-DR expression in the esophagus across the inflammation to cancer progression sequence and to assess the prognostic significance of HLA-DR expression in EAC. Tissue microarrays (TMA) were constructed from esophageal tissue taken from patients at different stages in the cancer progression sequence; normal, esophagitis, Barrett's esophagus (BE), low- and high-grade dysplasia (LGD, HGD) and EAC. HLA-DR expression in tissue epithelium and stroma was assessed by immunohistochemistry. HLA-DR expression increased early in the inflammation to cancer progression sequence; with higher expression detected in esophagitis and BE compared to normal tissue. Patients with low (<50%) HLA-DR expression in the EAC tumor epithelium had significantly worse survival outcomes, compared to those with high expression, in both the tumor core (hazard ratio, HR = 2.178, p = 0.024, n = 70) and leading edge (HR = 2.86, p = 0.013, n = 41). Multivariate analysis demonstrated that low HLA-DR expression in leading edge tumor epithelium was an independent predictor of poor survival, associated with a 2.8-fold increase in disease-associated death (p = 0.023). This study shows that HLA-DR is an independent prognostic marker in EAC tumor epithelium. This may have implications for patient stratification strategies as well as EAC tumor immunology.

Metabolic tumor volume provides complementary prognostic information to EUS staging in esophageal and junctional cancer.

To determine the correlation between 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) derived esophageal tumor parameters [maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV)] and endoscopic ultrasound (EUS) derived tumor parameters (T stage, N stage) and their prognostic implications. 150 consecutive patients with cancer of the esophagus or esophagogastric junction underwent staging PET-CT and staging EUS. PET-CT derived SUVmax and MTV of the primary tumor was recorded. EUS evaluated T and N stage. Relationships between parameters were investigated using the Mann-Whitney U tests, survival analysis performed using Kaplan-Meier and independent prognostic factors determined using Cox regression multivariate analysis. A significant difference in MTV was noted between EUS T1/T2 tumors (median 6.7 cm3) and EUS T3/T4 tumors (median 35.7 cm3; P < 0.0001). An MTV of <23.4 cm3 (P = 0.0001), SUVmax < 4.1 (P = 0014), EUS T stage (P < 0.0001), EUS N stage (P < 0.0001), and clinical stage (P < 0.0001) were all significantly associated with survival, with MTV <23.4 cm3 (P = 0.004), EUS T stage (P = 0.01), and EUS N stage (P = 0.01) significant in multivariate analysis. MTV, a volumetric parameter of PET-CT, has more prognostic importance than SUVmax and provides valuable prognostic information in esophageal and junctional cancer, along with EUS T and N stage. MTV provides complementary information to EUS and should be included in the staging of esophageal and junctional cancer.

Excess visceral adiposity induces alterations in mitochondrial function and energy metabolism in esophageal adenocarcinoma.

BACKGROUND: Visceral obesity has a strong association with both the incidence and mortality of esophageal adenocarcinoma (EAC). Alterations in mitochondrial function and energy metabolism is an emerging hallmark of cancer, however, the potential role that obesity plays in driving these alterations in EAC is currently unknown. METHODS: Adipose conditioned media (ACM) was prepared from visceral adipose tissue taken from computed tomography-determined viscerally-obese and non-obese EAC patients. Mitochondrial function in EAC cell lines was assessed using fluorescent probes, mitochondrial gene expression was assessed using qPCR-based gene arrays and intracellular ATP levels were determined using a luminescence-based kit. Glycolysis and oxidative phosphophorylation was measured using Seahorse XF technology and metabolomic analysis was performed using 1H NMR. Expression of metabolic markers was assessed in EAC tumor biopsies by qPCR. RESULTS: ACM from obese EAC patients significantly increased mitochondrial mass and mitochondrial membrane potential in EAC cells, which was significantly associated with visceral fat area, and was coupled with a significant decrease in reactive oxygen species. This mitochondrial dysfunction was accompanied by altered expression of 19 mitochondrial-associated genes and significantly reduced intracellular ATP levels. ACM from obese EAC patients induced a metabolic shift to glycolysis in EAC cells, which was coupled with significantly increased sensitivity to the glycolytic inhibitor 2-deoxyglucose. Metabolomic profiling demonstrated an altered glycolysis and amino acid-related signature in ACM from obese patients. In EAC tumors, expression of the glycolytic marker PKM2 was significantly positively associated with obesity. CONCLUSION: This study demonstrates for the first time that ACM from viscerally-obese EAC patients elicits an altered metabolic profile and can drive mitochondrial dysfunction and altered energy metabolism in EAC cells in vitro. In vivo, in EAC patient tumors, expression of the glycolytic enzyme PKM2 is positively associated with obesity.

Classification of pathologic response to neoadjuvant therapy in esophageal and junctional cancer: assessment of existing measures and proposal of a novel 3-point standard.

OBJECTIVE: To assess existing measures of pathologic response to neoadjuvant therapy in esophageal and junctional cancer, and to recommend an optimum classification. BACKGROUND: Multimodal therapy is increasingly the standard of care for locally advanced esophageal cancer. Numerous measures of pathologic response have been studied; however, no international standardization exists and no measure is incorporated into the current American Joint Committee on Cancer staging system. METHODS: A total of 393 consecutive patients completing multimodal therapy were studied, all with prospectively recorded Mandard tumor regression grades (TRG). Seven other published methods of response were compared, and a novel 3-point TRG [TRG 1 (complete); TRG 2/3 (partial); TRG 4/5 (none/minimal)] was tested. Clinical and pathologic evidence of nodal regression was assessed in a consecutive subset of 200 comprehensively staged patients. RESULTS: All models had similar discriminatory and stratification power, and they predicted survival (P < 0.0001) on univariate analysis. Conversely, only the 3-point TRG (P = 0.042) along with ypN (P < 0.001) and ypT stage (P < 0.001) independently predicted survival. The median survival for TRG 1 was 71 months compared with 30 and 17 months for TRG 2/3 and TRG 4/5, respectively (P < 0.0001). Apparent complete nodal response (cN1 to ypN0) was seen in 64% of the TRG 1 group, 30% of the TRG 2/3 group, and 5% of the TRG 4/5 group (P < 0.0001). CONCLUSIONS: No existing response measure independently predicts outcome. A complete response (TRG 1) defines a unique cohort after neoadjuvant therapy, associated closely with nodal response, and overall survival. This classification merits consideration for standardization of treatment response, and for inclusion in staging nomenclature.

Appraisal of staging endoscopic ultrasonography in a modern high-volume esophageal program.

BACKGROUND: Accurate pretreatment staging is essential to decision making for patients with esophageal and junctional cancers, particularly when choosing endoscopic therapy or a multimodal approach. As the efficacy of endoscopic ultrasonography (EUS) has been reported as variable, we assessed it prospectively in a large cohort from a high-volume center. METHODS: The EUS data from 2007 to 2011 were reviewed and analyzed. We conducted a comparative analysis with computed tomography-positron emission tomography (CT-PET) staging and pathology. Survival was analyzed by Kaplan-Meier testing on EUS-predicted T- and N-stage cohorts. RESULTS: Altogether, 222 patients underwent EUS. Among patients undergoing primary surgical resection, preoperative EUS diagnosed the T stage correctly in 71 % (55/77) of cases. Sensitivity and specificity for T1, T2, and T3 tumors were 94 and 89 %, 55 and 80 %, and 66 and 93 %, respectively. Mean maximum standard uptake volume on CT-PET correlated moderately with the EUS T stage (r = 0.42, p < 0.0001). EUS accuracy for nodal disease was 65 %. Survival was statistically better for the EUS T1 group than for those with T3 tumors (p = 0.01). Nodal metastases diagnosed on EUS predicted a significantly worse prognosis than EUS-negative nodes on both univariate and multivariate analyses (p < 0.0001 and p = 0.005 respectively). CONCLUSIONS: There was a significant relation between EUS T and N stages and overall survival. EUS demonstrated 71 % accuracy for the overall T stage. Staging accuracy of EUS for large lesions was less effective than for T1 tumors, underlining the need for a multimodal investigative approach to stage esophageal tumors accurately.

Evidence-based selective application of transhiatal esophagectomy in a high-volume esophageal center.

BACKGROUND: Transthoracic esophagectomy (TTE) with lymphadenectomy represents the gold standard of operative approaches to esophageal cancer. The TTE procedure carries significant operative risk, particularly in patients with co-morbidities, and the possible oncologic benefit of a mediastinal lymph node dissection in certain subgroups of patients with esophageal cancer is controversial. Transhiatal esophagectomy (THE), which avoids a thoracotomy, may reduce morbidity and mortality below levels seen with TTE, and there is no proof from randomized studies of any oncologic inferiority to TTE in patients with early tumors. Accordingly, the selective use of THE has increased in our high-volume center in recent years, and this study audits that experience over the last decade METHODS: Between 2000 and 2009 inclusive, 584 patients were treated surgically with curative intent. The standard operative approach in our unit is en bloc TTE, and THE represents 5.5% overall, and 11.1% in the second 5-year period (2004-2009), compared with 2% previously. The present study details the selection of these cases (n = 32) treated with THE and their outcomes, as well as the outcomes in the TTE (n = 438) group RESULT: Transhiatal esophagectomy was used for early stage carcinoma (n = 18) and for patients of advanced age who also had co-morbidities (n = 14). Patients undergoing THE were significantly older (68.46 versus 63.07 years of age; p = 0.002), and were at higher operative risk based on ASA grade (grade 3: 53.1% versus 17.3%; p < 0.001), compared with TTE patients. The THE cohort also included more patients with early cancers compared with the TTE cohort (56.3% versus 17.6%; p < 0.001). There were no differences in R0 resection rates for patients with early tumors or advanced co-morbidity. Nodal yields were lower in THE patients (p = 0.005). The overall complication rate was lower in the THE group (31.6% versus 44.2%; p = 0.021), and there were no postoperative deaths in the transhiatal group, whereas the in-hospital mortality rate for the TTE group was 3% (p < 0.001). Disease-specific survival was equivalent with each approach. CONCLUSIONS: Transhiatal esophagectomy has a role in a pragmatic individualized approach to esophageal cancer. As an alternative to a standardized en bloc transthoracic esophagectomy, the transhiatal approach may be suitable for patients with predicted node-negative cancers or those with resectable disease who are not candidates for TTE because of co-morbidity.

Human Epidermal Growth Factor Receptor-3 Expression Is Regulated at Transcriptional Level in Breast Cancer Settings by Junctional Adhesion Molecule-A via a Pathway Involving Beta-Catenin and FOXA1.

The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between putative pathway components connecting JAM-A and HER3. This study reveals for the first time that HER3 and its effectors are regulated at gene/protein expression level by JAM-A in breast cancer cell lines; with functional consequences in in vitro and semi-in vivo models. In bioinformatic, cellular and patient tissue models, this was associated with regulation of the HER3 transcription factor FOXA1 by JAM-A via a pathway involving ß-catenin. Our data suggest a novel model whereby JAM-A expression regulates ß-catenin localization, in turn regulating FOXA1 expression, which could drive HER3 gene transcription. JAM-A merits investigation as a novel target to prevent upregulation of HER3 during the development of resistance to HER2-targeted therapies, or to reduce HER3-dependent tumorigenic signaling.

The role of obesity in gastrointestinal cancer: evidence and opinion.

There is increasing recognition of the impact of being overweight and obese on the development of cancers at diverse sites including the gastrointestinal tract. Large epidemiological studies indicate that up to 14% of tumours may be related to obesity. Pathophysiological mechanisms underpinning this association are not well understood and so are discussed in this review.

Cellular origins and molecular mechanisms of Barrett's esophagus and esophageal adenocarcinoma.

This paper presents commentaries on animal models used for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) research; acid- and bile-induced chromosomal instability and clonal selection during the progression of BE to EAC; how the components of gastric refluxate, especially acid and bile salts, promote carcinogenesis in metaplastic BE; genome-wide changes in DNA methylation and transcription involved in BE carcinogenesis; the potential role of miRNA in the development of BE and EAC; the effect of inflammatory cytokines linked to obesity on the activation of cell-death pathways and cell survival in BE and esophageal cancer; and the role of autophagy in esophageal cancer development.

Defining esophageal landmarks, gastroesophageal reflux disease, and Barrett's esophagus.

The following paper on gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE) includes commentaries on defining esophageal landmarks; new techniques for evaluating upper esophageal sphincter (UES) tone; differential diagnosis of GERD, BE, and hiatal hernia (HH); the use of high-resolution manometry for evaluation of reflux; the role of fundic relaxation in reflux; the use of 24-h esophageal pH-impedance testing in differentiating acid from nonacid reflux and its potential inclusion in future Rome criteria; classification of endoscopic findings in GERD; the search for the cell origin that generates BE; and the relationship between BE, Barrett's carcinoma, and obesity.