Hepatocellular carcinoma presenting as an extrahepatic mass: A case report and review of literature.

BACKGROUND: Hepatocellular carcinoma (HCC) is a primary liver tumor generally diagnosed based on radiographic findings. Metastatic disease is typically associated with increased tumor diameter, multifocality, and vascular invasion. We report a case of a patient who presented with extrahepatic HCC metastasis to a portocaval lymph node with occult hepatic primary on computed tomography (CT). We review the literature for cases of extrahepatic HCC presentation without known hepatic lesions and discuss strategies to differentiate between metastatic and ectopic HCC. CASE SUMMARY: A 67-year-old male with remotely treated hepatis C was referred for evaluation of an enlarging portocaval, mixed cystic-solid mass. Serial CT evaluations demonstrated steatosis, but no cirrhosis or liver lesions. Endoscopic ultrasound demonstrated a normal-appearing pancreas, biliary tree, and liver. Fine needle aspiration yielded atypical cells. The differential diagnosis included duodenal or pancreatic cyst, lymphoproliferative cyst, stromal or mesenchymal lesions, nodal involvement from gastrointestinal or hematologic malignancy, or duodenal gastro-intestinal stromal tumor. After review by a multidisciplinary tumor board, the patient underwent open surgical resection of a 5.2 cm × 5.5 cm retroperitoneal mass with pathology consistent with moderately-differentiated HCC. Magnetic resonance imaging (MRI) subsequently demonstrated a 1.2 cm segment VIII hepatic lesion with late arterial enhancement, fatty sparing, and intrinsic T1 hyperintensity. Alpha fetoprotein was 23.3 ng/mL. The patient was diagnosed with HCC with portocaval nodal involvement. Review: We surveyed the literature for HCC presenting as extrahepatic masses without history of concurrent or prior intrahepatic HCC. We identified 18 cases of extrahepatic HCC ultimately found to represent metastatic lesions, and 30 cases of extrahepatic HCC found to be primary, ectopic HCC. CONCLUSION: Hepatocellular carcinoma can seldomly present with extrahepatic metastasis in the setting of occult primary. In patients with risk factors for HCC and lesions suspicious for metastatic disease, MRI may be integral to identifying small hepatic lesions and differentiating from ectopic HCC. Tumor markers may also have utility in establishing the diagnosis.

Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma.

OPINION STATEMENT: Biliary tract cancers are molecularly and anatomically diverse cancers which include intrahepatic cholangiocarcinoma, extrahepatic (perihilar and distal) cholangiocarcinoma, and gallbladder cancer. While recognized as distinct entities, the rarer incidence of these cancers combined with diagnostic challenges in classifying anatomic origin has resulted in clinical trials and guideline recommended strategies being generalized patients with all types of biliary tract cancer. In this review, we delve into the unique aspects, subtype-specific clinical trial outcomes, and multidisciplinary management of patients with extrahepatic cholangiocarcinoma. When resectable, definitive surgery followed by adjuvant chemotherapy (sometimes with selective radiation/chemoradiation) is current standard of care. Due to high recurrence rates, there is growing interest in the use of upfront/neoadjuvant therapy to improve surgical outcomes and to downstage patients who may not initially be resectable. Select patients with perihilar cholangiocarcinoma are being successfully treated with novel approaches such as liver transplant. In the advanced disease setting, combination gemcitabine and cisplatin remains the standard base for systemic therapy and was recently improved upon with the addition of immune checkpoint blockade to the chemotherapy doublet in the recently reported TOPAZ-1 and KEYNOTE-966 trials. Second-line all-comer treatments for these patients remain limited in both options and efficacy, so clinical trial participation should be strongly considered. With increased use of molecular testing, detection of actionable mutations and opportunities to receive indicated targeted therapies are on the rise and are the most significant driver of improved survival for patients with advanced stage disease. Though these targeted therapies are currently reserved for the second or later line, future trials are looking at moving these to earlier treatment settings and use in combination with chemotherapy and immunotherapy. In addition to cross-disciplinary management with surgical, medical, and radiation oncology, patient-centered care should also include collaboration with advanced endoscopists, palliative care specialists, and nutritionists to improve global patient outcomes.

Accuracy and Reliability of Chatbot Responses to Physician Questions.

Importance: Natural language processing tools, such as ChatGPT (generative pretrained transformer, hereafter referred to as chatbot), have the potential to radically enhance the accessibility of medical information for health professionals and patients. Assessing the safety and efficacy of these tools in answering physician-generated questions is critical to determining their suitability in clinical settings, facilitating complex decision-making, and optimizing health care efficiency. Objective: To assess the accuracy and comprehensiveness of chatbot-generated responses to physician-developed medical queries, highlighting the reliability and limitations of artificial intelligence-generated medical information. Design, Setting, and Participants: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes or no) or descriptive answers. The physicians then graded the chatbot-generated answers to these questions for accuracy (6-point Likert scale with 1 being completely incorrect and 6 being completely correct) and completeness (3-point Likert scale, with 1 being incomplete and 3 being complete plus additional context). Scores were summarized with descriptive statistics and compared using the Mann-Whitney U test or the Kruskal-Wallis test. The study (including data analysis) was conducted from January to May 2023. Main Outcomes and Measures: Accuracy, completeness, and consistency over time and between 2 different versions (GPT-3.5 and GPT-4) of chatbot-generated medical responses. Results: Across all questions (n = 284) generated by 33 physicians (31 faculty members and 2 recent graduates from residency or fellowship programs) across 17 specialties, the median accuracy score was 5.5 (IQR, 4.0-6.0) (between almost completely and complete correct) with a mean (SD) score of 4.8 (1.6) (between mostly and almost completely correct). The median completeness score was 3.0 (IQR, 2.0-3.0) (complete and comprehensive) with a mean (SD) score of 2.5 (0.7). For questions rated easy, medium, and hard, the median accuracy scores were 6.0 (IQR, 5.0-6.0), 5.5 (IQR, 5.0-6.0), and 5.0 (IQR, 4.0-6.0), respectively (mean [SD] scores were 5.0 [1.5], 4.7 [1.7], and 4.6 [1.6], respectively; P = .05). Accuracy scores for binary and descriptive questions were similar (median score, 6.0 [IQR, 4.0-6.0] vs 5.0 [IQR, 3.4-6.0]; mean [SD] score, 4.9 [1.6] vs 4.7 [1.6]; P = .07). Of 36 questions with scores of 1.0 to 2.0, 34 were requeried or regraded 8 to 17 days later with substantial improvement (median score 2.0 [IQR, 1.0-3.0] vs 4.0 [IQR, 2.0-5.3]; P < .01). A subset of questions, regardless of initial scores (version 3.5), were regenerated and rescored using version 4 with improvement (mean accuracy [SD] score, 5.2 [1.5] vs 5.7 [0.8]; median score, 6.0 [IQR, 5.0-6.0] for original and 6.0 [IQR, 6.0-6.0] for rescored; P = .002). Conclusions and Relevance: In this cross-sectional study, chatbot generated largely accurate information to diverse medical queries as judged by academic physician specialists with improvement over time, although it had important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Five-year outcomes of off and on-pump CABG: Insights from PROMOTE Patency Trial.

BACKGROUND: There are limited studies reporting follow-up outcome data comparing of off-pump coronary artery bypass (OPCAB) with on-pump (ONCAB) technique. The aim of the study was to report the 5-year clinical outcomes of OPCAB and ONCAB in a post hoc analysis of the PROMOTE patency trial. METHODS: From March 2016 through March 2017, a total of 321 patients undergoing coronary artery bypass grafting (CABG) were randomised to either the off-pump or the on-pump technique. Data on all-cause mortality, myocardial infarction (MI), cerebrovascular accident (CVA), repeat revascularisation and need for renal replacement therapy (RRT) were recorded. The composite and each of these individual outcomes are reported at 5-year interval. RESULTS: The mean follow-up period was 65.9 months (±3.39). A total of 275 (85.93%) patients followed up at the 5-year interval who underwent CABG by the off-pump (n = 158) and the on-pump (n = 162) technique. The all-cause mortality was 8.9% and 5.7% in ONCAB and OPCAB, respectively (hazard ratio [HR] = 0.62; 95% confidence interval [CI] 0.25-1.57, p = 0.31). The composite of all-cause mortality, non-fatal MI, non-fatal CVA, RRT and need for repeat revascularisation was comparable in both groups (7.1% vs. 11.9%, HR = 0.57; 95% CI 0.25-1.31, p = 0.18 in OPCAB and ONCAB, respectively). The rates of 5-year non-fatal MI (p = 0.2), non-fatal CVA (p = 0.36) and need for repeat revascularisation (p = 1) were similar in both groups. A sub-group analysis did not show any significant interaction or effect modification with either of the techniques. CONCLUSIONS: The 5-year clinical outcomes of OPCAB are comparable to ONCAB in low-risk patients undergoing CABG. Off-pump coronary artery bypass had no additional benefit in any subgroup.

Assessing the Accuracy and Reliability of AI-Generated Medical Responses: An Evaluation of the Chat-GPT Model.

Background: Natural language processing models such as ChatGPT can generate text-based content and are poised to become a major information source in medicine and beyond. The accuracy and completeness of ChatGPT for medical queries is not known. Methods: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes/no) or descriptive answers. The physicians then graded ChatGPT-generated answers to these questions for accuracy (6-point Likert scale; range 1 - completely incorrect to 6 - completely correct) and completeness (3-point Likert scale; range 1 - incomplete to 3 - complete plus additional context). Scores were summarized with descriptive statistics and compared using Mann-Whitney U or Kruskal-Wallis testing. Results: Across all questions (n=284), median accuracy score was 5.5 (between almost completely and completely correct) with mean score of 4.8 (between mostly and almost completely correct). Median completeness score was 3 (complete and comprehensive) with mean score of 2.5. For questions rated easy, medium, and hard, median accuracy scores were 6, 5.5, and 5 (mean 5.0, 4.7, and 4.6; p=0.05). Accuracy scores for binary and descriptive questions were similar (median 6 vs. 5; mean 4.9 vs. 4.7; p=0.07). Of 36 questions with scores of 1-2, 34 were re-queried/re-graded 8-17 days later with substantial improvement (median 2 vs. 4; p<0.01). Conclusions: ChatGPT generated largely accurate information to diverse medical queries as judged by academic physician specialists although with important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Surgical Management of Colorectal Cancer Liver Metastases.

Approximately 50% of colorectal cancer patients develop liver metastases. Hepatic metastases represent the most common cause of colorectal cancer-related mortality. Metastasectomy, if possible, represents the most effective treatment strategy; 20% of patients will be cured and more than 50% survive at least 5 years. Nuances to treatment planning hinge on whether patients present with resectable disease upfront, whether the future liver remnant is adequate, and whether the primary tumor, if present, is colon versus rectal in origin. This article discusses considerations impacting our approach to patients with colorectal liver metastases and the role for various multimodal treatment options.

Differential Cell Susceptibilities to KrasG12D in the Setting of Obstructive Chronic Pancreatitis.

BACKGROUND & AIMS: Activating mutation of the KRAS gene is common in some cancers, such as pancreatic cancer, but rare in other cancers. Chronic pancreatitis is a predisposing condition for pancreatic ductal adenocarcinoma (PDAC), but how it synergizes with KRAS mutation is not known. METHODS: We used a mouse model to express an activating mutation of Kras in conjunction with obstruction of the main pancreatic duct to recapitulate a common etiology of human chronic pancreatitis. Because the cell of origin of PDAC is not clear, Kras mutation was introduced into either duct cells or acinar cells. RESULTS: Although KrasG12D expression in both cell types was protective against damage-associated cell death, chronic pancreatitis induced p53, p21, and growth arrest only in acinar-derived cells. Mutant duct cells did not elevate p53 or p21 expression and exhibited increased proliferation driving the appearance of PDAC over time. CONCLUSIONS: One mechanism by which tissues may be susceptible or resistant to KRASG12D-initiated tumorigenesis is whether they undergo a p53-mediated damage response. In summary, we have uncovered a mechanism by which inflammation and intrinsic cellular programming synergize for the development of PDAC.

Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer.

Background & Aims: Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor ß (TGFß) family signaling through SMAD4 in colonic epithelial cells. Methods: The Smad4 gene was deleted specifically in adult murine intestinal epithelium. Colitis was induced by 3 rounds of dextran sodium sulfate in drinking water, after which mice were observed for up to 3 months. Nontransformed mouse colonocyte cell lines and colonoid cultures and human colorectal cancer cell lines were analyzed for responses to TGFß1 and bone morphogenetic protein 2. Results: Dextran sodium sulfate treatment was sufficient to drive carcinogenesis in mice lacking colonic Smad4 expression, with resulting tumors bearing striking resemblance to human colitis-associated carcinoma. Loss of SMAD4 protein was observed in 48% of human colitis-associated carcinoma samples as compared with 19% of sporadic colorectal carcinomas. Loss of Smad4 increased the expression of inflammatory mediators within nontransformed mouse colon epithelial cells in vivo. In vitro analysis of mouse and human colonic epithelial cell lines and organoids indicated that much of this regulation was cell autonomous. Furthermore, TGFß signaling inhibited the epithelial inflammatory response to proinflammatory cytokines. Conclusions: TGFß suppresses the expression of proinflammatory genes in the colon epithelium, and loss of its downstream mediator, SMAD4, is sufficient to initiate inflammation-driven colon cancer. Transcript profiling: GSE100082.

Frequent BRAF mutations suggest a novel oncogenic driver in colonic neuroendocrine carcinoma.

BACKGROUND AND OBJECTIVES: The World Health Organization (WHO) 2010 has classified GI neuroendocrine neoplasms into neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). The genetic underpinnings of NEC are poorly understood. The aim of the study was to perform genomic profiling of NEC to better characterize this aggressive disease. METHODS: We identified nine patients with colonic NEC between January 1, 2005 and June 30, 2013. Whole exome sequencing (WES) was performed on tumor DNA from two patients with ≥80% tumor cellularity and matched normal tissue available. Focused BRAF mutational analysis was performed on an additional seven patients via sanger sequencing of BRAF exons 11 and 15. RESULTS: We identified BRAF exon 15 mutations (c.A1781G: p.D594G and c.T1799A: p.V600E) by WES in two patients. Upon additional screening of seven colonic NECs for BRAF exon 11 and 15 mutations, we identified BRAF V600E mutations in two of seven specimens (29%). Overall, BRAF exon 15 mutations were present in four of nine colonic NECs. CONCLUSION: Colonic NEC is a rare but aggressive tumor with high frequency (44%) of BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients.

cFLIP critically modulates apoptotic resistance in epithelial-to-mesenchymal transition.

Epithelial cancers (carcinomas) comprise the top four causes of cancer-related deaths in the United States. While overall survival has been steadily improving, therapy-resistant disease continues to present a major therapeutic challenge. Carcinomas often exploit the normal developmental program, epithelial-to-mesenchymal transition (EMT), to gain a mesenchymal phenotype associated with increased invasiveness and resistance to apoptosis. We have previously shown that an isoxazole-based small molecule, ML327, partially reverses TGF-ß-induced EMT in an immortalized mouse mammary epithelial cell line. Herein, we demonstrate that ML327 reverses much of the EMT gene expression program in cultured carcinoma cell lines. The reversal of EMT sensitizes these cancer cells to the apoptosis-inducing ligand TRAIL. This sensitization is independent of E-cadherin expression and rather relies on the downregulation of a major anti-apoptotic protein, cFLIPS. Loss of cFLIPS is sufficient to overcome resistance to TRAIL and exogenous overexpression of cFLIPS restores resistance to TRAIL-induced apoptosis despite EMT reversal with ML327. In summary, we have utilized an isoxazole-based small molecule that partially reverses EMT in carcinoma cells to demonstrate that cFLIPS critically regulates the apoptosis resistance phenotype associated with EMT.

Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma.

Neuroblastomas are the most common extracranial solid tumors in children and arise from the embryonic neural crest. MYCN-amplification is a feature of ∼30% of neuroblastoma tumors and portends a poor prognosis. Neural crest precursors undergo epithelial-to-mesenchymal transition (EMT) to gain migratory potential and populate the sympathoadrenal axis. Neuroblastomas are posited to arise due to a blockade of neural crest differentiation. We have recently reported effects of a novel MET inducing compound ML327 (N-(3-(2-hydroxynicotinamido) propyl)-5-phenylisoxazole-3-carboxamide) in colon cancer cells. Herein, we hypothesized that forced epithelial differentiation using ML327 would promote neuroblastoma differentiation. In this study, we demonstrate that ML327 in neuroblastoma cells induces a gene signature consistent with both epithelial and neuronal differentiation features with adaptation of an elongated phenotype. These features accompany induction of cell death and G1 cell cycle arrest with blockage of anchorage-independent growth and neurosphere formation. Furthermore, pretreatment with ML327 results in persistent defects in proliferative potential and tumor-initiating capacity, validating the pro-differentiating effects of our compound. Intriguingly, we have identified destabilization of MYC signaling as an early and consistent feature of ML327 treatment that is observed in both MYCN-amplified and MYCN-single copy neuroblastoma cell lines. Moreover, ML327 blocked MYCN mRNA levels and tumor progression in established MYCN-amplified xenografts. As such, ML327 may have potential efficacy, alone or in conjunction with existing therapeutic strategies against neuroblastoma. Future identification of the specific intracellular target of ML327 may inform future drug discovery efforts and enhance our understanding of MYC regulation.

Elevated TIMP-1 expression is associated with a prometastatic phenotype, disease relapse, and poor survival in neuroblastoma.

Approximately two-thirds of patients with neuroblastoma are found to have metastatic disease at time of diagnosis with frequent skeletal, lymph node, central nervous system, and liver involvement. Using a serial in vivo splenic injection model, we have isolated an aggressive subclone (BE(2)-C/LM2) from MYCN-amplified neuroblastomas that demonstrate an enhanced propensity to develop metastatic liver lesions. BE(2)-C/LM2 subclone cells demonstrate increased adherent, soft agar colony and tumorsphere growth in vitro. Components of the tumor microenvironment regulate cancer progression, via networks of cytokines and growth factors. Cytokine array analysis identified increased TIMP-1 in the plasma of mice injected with BE(2)-C/LM2 subclone cells, leading us to hypothesize that TIMP-1 may play a role in our observed prometastatic phenotype. Immunoblotting and ELISA demonstrated enhanced endogenous TIMP-1 expression in our isolated neuroblastoma subclone. Silencing endogenous TIMP-1 successfully blocked in vitro proliferation, soft agar colony formation and tumorsphere formation by BE(2)-C/LM2 cells. Stable RNA interference of endogenous TIMP-1 failed to reverse the prometastatic phenotype of our BE(2)-C/LM2 subclone in our liver metastasis model, suggesting that endogenous TIMP-1 levels may not be an essential component of this in vivo behavior. Notably, tissue microarray analysis and Kaplan-Meier by gene expression demonstrates that elevated TIMP-1 expression is correlated with increased disease relapse and mortality in patients with neuroblastoma. Taken together, our study identifies TIMP-1 as a novel soluble factor that is associated with a prometastatic phenotype in our in vivo model and adverse outcomes in patients with neuroblastoma.

ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand.

Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG0 cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.

Evaluation of frozen tissue-derived prognostic gene expression signatures in FFPE colorectal cancer samples.

Defining molecular features that can predict the recurrence of colorectal cancer (CRC) for stage II-III patients remains challenging in cancer research. Most available clinical samples are Formalin-Fixed, Paraffin-Embedded (FFPE). NanoString nCounter® and Affymetrix GeneChip® Human Transcriptome Array 2.0 (HTA) are the two platforms marketed for high-throughput gene expression profiling for FFPE samples. In this study, to evaluate the gene expression of frozen tissue-derived prognostic signatures in FFPE CRC samples, we evaluated the expression of 516 genes from published frozen tissue-derived prognostic signatures in 42 FFPE CRC samples measured by both platforms. Based on HTA platform-derived data, we identified both gene (99 individual genes, FDR < 0.05) and gene set (four of the six reported multi-gene signatures with sufficient information for evaluation, P < 0.05) expression differences associated with survival outcomes. Using nCounter platform-derived data, one of the six multi-gene signatures (P < 0.05) but no individual gene was associated with survival outcomes. Our study indicated that sufficiently high quality RNA could be obtained from FFPE tumor tissues to detect frozen tissue-derived prognostic gene expression signatures for CRC patients.

Perioperative chemotherapy for resectable colorectal hepatic metastases-What does the EORTC 40983 trial update mean?

The liver is the most common site of colorectal cancer metastasis. Although successful resection leads to durable overall survival (OS), local and distant recurrence is common. As a result, multidisciplinary strategies have been developed to decrease recurrence rates as well as increase the number of candidates for resection. A recent update to the European Organisation for Research and Treatment of Cancer (EORTC) Intergroup trial 40983 has been published comparing perioperative chemotherapy to surgery alone. This randomized trial initially demonstrated a benefit in progression free survival (PFS) with the administration of perioperative FOLFOX chemotherapy, albeit with an increased rate of complications. Although this led many investigators and clinicians to adopt the perioperative approach, the recent update failed to report any advantage in OS and therefore results in further controversy as to the role of perioperative systemic chemotherapy in the treatment of resectable colorectal hepatic metastases.