ENDOSCOPIC ULTRASOUND-GUIDED RADIOFREQUENCY ABLATION FOR PANCREATIC ADENOCARCINOMA.

BACKGROUND AND AIMS: Emerging data suggest neoadjuvant chemotherapy (NAC) for resectable pancreatic ductal adenocarcinoma (PDAC) is associated with improved survival. However, less than 40% demonstrate a meaningful radiographic response to NAC. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has emerged as a new modality to treat PDAC. We hypothesize that NAC plus EUS-RFA can be used in the management of resectable PDAC. METHODS: Prospective review of PDAC patients meeting criteria of resectable tumor anatomy that underwent NAC chemotherapy plus EUS-RFA followed by pancreatic resection. Radiographic imaging, perioperative and short-term outcomes were recorded. Surgical pathology specimens were analyzed for treatment response. RESULTS: Three eligible patients with resectable PDAC received 4 months of NAC plus EUS-RFA. One month after NAC and EUS-RFA completion, all 3 patients underwent standard pancreaticoduodenectomy without complications. After a 6-week recovery, all patients completed 2 months of post-op adjuvant chemotherapy. CONCLUSIONS: In our institutional experience, this treatment protocol appears safe as patients tolerated the combination of chemotherapy and ablation. Patients underwent pancreatic resection with uneventful recovery. This novel neoadjuvant approach may provide a more effective alternative to chemotherapy alone.

A preoperative serum signature of CEA+/CA125+/CA19-9 ≥ 1000 U/mL indicates poor outcome to pancreatectomy for pancreatic cancer.

Pancreatectomy is associated with significant morbidity and unpredictable outcome, with few diagnostic tools to determine, which patients gain the most benefit from this treatment, especially before the operation. This study aimed to define a preoperative signature panel of serum markers to indicate response to pancreatectomy for pancreatic cancer. Over 1000 patients with pancreatic cancer treated at two independent high-volume institutions were included in this study and were divided into three groups, including resected, locally advanced and metastatic. Eight serum tumor markers most commonly used in gastrointestinal cancers were analyzed for patient outcome. Preoperative CA19-9 independently indicated surgical response in pancreatic cancer. Patients with CA19-9 ≥1000 U/mL generally had a poor surgical benefit. However, a subset of these patients still achieved a survival advantage when CA19-9 levels decreased postoperatively. CEA and CA125 in the presence of CA19-9 ≥1000 U/mL could independently predict the non-decrease of CA19-9 postoperatively. The combination of the three markers was useful for predicting a worse surgical outcome with a median survival of 5.1 months vs. 23.0 months (p < 0.001) for the training cohort and 7.0 months vs. 18.2 months (p < 0.001) for the validation cohort and also suggested a higher prevalence of early distant metastasis after surgery. Resected patients with this proposed signature showed no survival advantage over patients in the locally advanced group who did not receive pancreatectomy. Therefore, a preoperative serum signature of CEA(+)/CA125(+)/CA19-9 ≥1000 U/mL is associated with poor surgical outcome and can be used to select appropriate patients with pancreatic cancer for pancreatectomy.

Eradication of gastric cancer is now both possible and practical.

In 1994, Helicobacter pylori was declared a human carcinogen. Evidence has now accumulated to show that at least 95% of gastric cancers are etiologically related to H. pylori. An extensive literature regarding atrophic gastritis and its effects on acid secretion, gastric microflora, and its tight association with gastric cancer has been rediscovered, confirmed, and expanded. Methods to stratify cancer risk based on endoscopic and histologic findings or serologic testing of pepsinogen levels and H. pylori testing have been developed producing practical primary and secondary gastric cancer prevention strategies. H. pylori eradication halts progressive mucosal damage. Cure of the infection in those with non-atrophic gastritis will essentially prevent subsequent development of gastric cancer. For all, the age-related progression in cancer risk is halted and likely reduced as eradication reduces or eliminates mucosal inflammation and reverses or reduces H. pylori-associated molecular events such aberrant activation-induced cytidine deaminase expression, double strand DNA breaks, impaired DNA mismatch repair and aberrant DNA methylation. Those who have developed atrophic gastritis/gastric atrophy however retain some residual risk for gastric cancer which is proportional to the extent and severity of atrophic gastritis. Primary and secondary cancer prevention starts with H. pylori eradication and cancer risk stratification to identify those at higher risk who should also be considered for secondary cancer prevention programs. Japan has embarked on population-wide H. pylori eradication coupled with surveillance targeted to those with significant remaining risk. We anticipate that countries with high gastric cancer burdens will follow their lead. We provide specific recommendations on instituting practical primary and secondary gastric cancer prevention programs as well identifying research needed to make elimination of gastric cancer both efficient and cost effective.

Complete Pathologic Response With Pembrolizumab and Enfortumab Vedotin in Urothelial Carcinoma of the Upper Urinary Tract.

Urothelial carcinoma of the upper urinary tract (UTUC) presents a significant clinical challenge, often requiring aggressive surgical intervention for optimal management. We present a case of an 84-year-old woman with recurrent high-grade papillary UTUC of the left renal pelvis, refractory to prior endourologic interventions, who underwent neoadjuvant treatment with pembrolizumab and enfortumab vedotin (Pembro/EV) due to contraindications to cisplatin therapy. Following a favorable response to neoadjuvant therapy, the patient underwent laparoscopic left radical nephroureterectomy, achieving a pathologic complete response. We discuss the utility of Pembro/EV in the perioperative management of patients with UTUC, particularly in those ineligible for cisplatin-based therapy. In addition, we highlight the potential role of somatic mutation testing and the integration of novel therapeutic agents such as olaparib in personalized treatment strategies for UTUC. This case underscores the importance of exploring innovative treatment approaches and optimizing patient selection for kidney preservation strategies in the management of UTUC. Further research and clinical trials are warranted to elucidate the full therapeutic potential of Pembro/EV and other emerging therapies in this setting.

Belzutifan, HIF-2α Inhibitor, and Clear Cell Renal Cell Carcinoma With Somatic Von-Hippel-Lindau Loss-of-Function Mutation.

The Von-Hippel-Lindau (VHL) gene, acting as a tumor suppressor, plays a crucial role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Approximately 90% of individuals with advanced ccRCC exhibit somatic mutations in the VHL gene. Belzutifan, orally administered small-molecule inhibitor of hypoxia-induced factor-2α, has demonstrated promising efficacy in solid tumors associated with germline loss-of-function mutations in VHL, including ccRCC. However, its impact on cases with somatic or sporadic VHL mutations remains unclear. Here, we present 2 cases where belzutifan monotherapy was employed in patients with advanced ccRCC and somatic loss-of-function mutations in VHL. Both patients exhibited a swift and sustained response, underscoring the potential role of belzutifan as a viable option in second or subsequent lines of therapy for individuals with somatic VHL mutations. Despite both patients experiencing a pulmonary crisis with respiratory compromise, their rapid response to belzutifan further emphasizes its potential utility in cases involving pulmonary or visceral crises. This report contributes valuable insights into the treatment landscape for advanced ccRCC with somatic VHL mutations.

Promising Response of Olaparib in Patient With Germline ATM-Mutated Metastatic Gastric Cancer.

Gastric cancer ranks as the fifth leading cause of global cancer incidences, exhibiting varied prevalence influenced by geographical, ethnic, and lifestyle factors, as well as Helicobacter pylori infection. The ATM gene on chromosome 11q22 is vital for genomic stability as an initiator of the DNA damage response, and mutations in this gene have been associated with various cancers. Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, have shown efficacy in cancers with homologous recombination repair deficiencies, notably in those with ATM mutations. Here, we present a case of a 66-year-old patient with germline ATM-mutated metastatic gastric cancer with very high CA 19-9 (48 000 units/mL) who demonstrated an exceptional response to the addition of olaparib to chemo-immunotherapy and subsequent olaparib maintenance monotherapy for 12 months. CA 19-9 was maintained at low level for 18 months. Despite the failure of a phase II clinical trial on olaparib in gastric cancer (NCT01063517) to meet its primary endpoint, intriguing findings emerged in the subset of ATM-mutated patients, who exhibited notable improvements in overall survival. Our case underscores the potential clinical utility of olaparib in germline ATM-mutated gastric cancer and emphasizes the need for further exploration through larger clinical trials. Ongoing research and clinical trials are essential for optimizing the use of PARP inhibitors, identifying biomarkers, and advancing personalized treatment strategies for gastric cancer.

Circulating tumor cells in the diagnosis and management of pancreatic cancer.

Pancreatic cancers are typically resistant to chemo and radiation therapy and are predisposed to distant metastases. Circulating tumor cells (CTCs) are tumor cells disseminated from primary and metastatic sites and can be isolated from peripheral blood. CTC may overcome the limitation of the current available tumor markers, CA19-9. As a surrogate for 'real-time biopsy', CTCs allow recurrent assessment of a tumor's biological activity. We review the current methodologies for CTC extraction and characterization including antibody-based immunological assays, PCR-based assays, and novel technologies based on the physical or biological characteristics of CTCs. CTCs also provide an accessible link to the existence of epithelial to mesenchymal transition, tumor stem cell markers, and ongoing clonal mutations and epigenetic changes in the tumor. We also explore the potential of using CTC profiling in diagnosis, selection of neoadjuvant and adjuvant therapy, detection of recurrent disease, examination of pharmacodynamic biomarkers, as well as in gene therapy and immunotherapy for pancreatic cancer. Ongoing CTC characterization not only has the potential to represent all cells shed from primary pancreatic tumor and each metastatic site, but also allows dynamic sampling at multiple time points during the clinical course to identify the subpopulations of CTCs and the specific molecules driving metastasis and chemo resistance. We predict that CTC genotyping and phenotyping will play an increasing role in personalized therapy and in identification of novel therapeutic targets as well as monitoring the course and status of the disease.

Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) presents a 5-year overall survival rate of 11%, despite efforts to improve clinical outcomes in the past two decades. Therapeutic resistance is a hallmark of this disease, due to its dense and suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a promising local ablative and potential immunomodulatory therapy for PDAC. In this study, we performed RFA in a preclinical tumor-bearing KrasG12D; Trp53R172H/+; Pdx1:Cre (KPC) syngeneic model, analyzed local and abscopal affects after RFA and compared our findings with resected PDAC specimens. We found that RFA reduced PDAC tumor progression in vivo and promoted strong TME remodeling. In addition, we discovered tumor-infiltrating neutrophils determined abscopal effects. Using imaging mass cytometry, we showed that RFA elevated dendritic cell numbers in RFA-treated tumors and promoted a significant CD4+ and CD8+ T-cell abscopal response. In addition, RFA elevated levels of programmed death-ligand 1 (PD-L1) and checkpoint blockade inhibition targeting PD-L1 sustained tumor growth reduction in the context of RFA. This study indicates RFA treatment, which has been shown to increase tumor antigen shedding, promotes antitumor immunity. This is critical in PDAC where recent clinical immunotherapy trials have not resulted in substantial changes in overall survival.

Pancreatic cancer tumour initiating cells: the molecular regulation and therapeutic values.

Pancreatic cancer is an aggressive solid tumour characterized by its local invasion, early metastasis and resistance to standard chemotherapy or radiation therapy. Tumour initiating cells (TICs) are not only capable of self-renewal and differentiation, but also play an important role in multi-drug resistance, and thus become a popular topic in cancer research especially in pancreatic cancer. In this review, we summarize the current progress of TICs in tumourigenesis, various newly identified surface markers of pancreatic TICs, and the signalling pathways such as epithelial-mesenchymal transition, sonic hedgehog and Notch that regulate TICs. We also discuss the role which microRNA plays in TICs as well as its application in TIC-targeted therapy along with other approaches.

Changes in age, stage distribution, and survival of patients with esophageal adenocarcinoma over three decades in the United States.

BACKGROUND: Our aim was to evaluate the changes in age, stage distribution, and overall survival (OS) of patients with esophageal adenocarcinoma (EAC) over time. METHODS: Patients from the Surveillance, Epidemiology, and End Results (SEER) database aged ≥ 20 with invasive EAC, diagnosed from 1973-2003 were reviewed. Survival follow-up ended in 2006. RESULTS: There were 11,620 patients; 6580 (57%) aged ≥ 65. The stage distribution was 22%, 35%, and 43% for localized, regional, and distant metastasis for patients aged <65, and 33%, 33%, and 34% for patients aged ≥ 65. The number of patients ≥ 65 years with localized stage increased over time. Three-year OS for localized, regional, and distant disease increased from 19%, 10%, and 1% in 1973-1976, to 34%, 13%, and 2% in 1987-1991, and to 45%, 25%, and 4% in 2002-2003 (P < 0.001). A sub-analysis of 5475 patients from 1988-2002 showed better survival for patients with esophagectomy for all stages. Three-year OS for 2074 patients with esophagectomy improved every 5 years from 1988-2002 (39%, 43% to 54%, P < 0.001). Stratified by stage, year and esophagectomy status, patients aged <65 had better survival compared to patients aged ≥ 65 (P < 0.001). CONCLUSIONS: There has been a substantial improvement in overall survival among patients with invasive EAC over the last 3 decades. Patients receiving esophagectomy had longer survival. Survival with esophagectomy improved in each time period. Although younger EAC patients were diagnosed at more advanced stages over time, they had better survival.

Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) for advanced pancreatic and periampullary adenocarcinoma.

Long term prognosis and 5-year survival for pancreatic adenocarcinoma (PDAC) remains suboptimal. Endoscopic ultrasound (EUS) guided RFA (EUS-RFA) is an emerging technology and limited data exist regarding safety and long-term outcomes. The aim of this study is to report safety-profile, feasibility and outcomes of EUS-RFA for advanced PDAC. Prospective review of patients with diagnosis of locally-advanced or metastatic PDAC undergoing EUS-RFA between October 2016 to March 2018 with long-term follow up (> 30 months). Study patients underwent a total of 1-4 RFA sessions. All patients were enrolled in longitudinal cohort study and received standard of care chemotherapy. 10 patients underwent EUS-RFA. Location of the lesions was in the head(4), neck(2), body(2), and tail(2). 22 RFA sessions were performed with a range of 1-4 sessions per patient. There were no major adverse events (bleeding, perforation, infection, pancreatitis) in immediate (up to 72 h) and short-term follow up (4 weeks). Mild worsening of existing abdominal pain was noted during post-procedure observation in 12/22 (55%) of RFA treatments. Follow-up imaging demonstrated tumor progression in 2 patients, whereas tumor regression was noted in 6 patients (> 50% reduction in size in 3 patients). Median survival for the cohort was 20.5 months (95% CI, 9.93-42.2 months). Currently, 2 patients remain alive at 61 and 81 months follow-up since initial diagnosis. One patient had 3 cm PDAC with encasement of the portal confluence, abutment of the celiac axis, common hepatic and superior mesenteric artery. This patient had significant reduction in tumor size and underwent standard pancreaticoduodenectomy. In our experience, EUS-RFA was safe, well-tolerated and could be concurrently performed with standard chemotherapy. In this select cohort, median survival was improved when compared to published survival based upon SEER database and clinical trials. Future prospective trials are needed to understand the role of EUS-RFA in overall management of PDAC.

Palliative Endoscopic Salvage of a Functionally Obstructed Gastrojejunostomy - Report of Technique.

Background: Gastric outlet obstruction secondary to foregut gastrointestinal malignancies can be managed with a variety of medical, endoscopic, and surgical options. Laparoscopic gastrojejunostomy is an option for those patients who are able to tolerate an operation as a long-term palliative option. This operation may be associated with some significant postoperative technical and nontechnical complications, including delayed gastric emptying. This paper describes an incision-less, endoscopic option that we propose can be used to salvage a functionally obstructed gastrojejunostomy. Case Description: A 57-year old male patient had a history of pancreatic adenocarcinoma causing gastric outlet obstruction and underwent a previously created surgical gastrojejunostomy at an outside hospital. His procedure was complicated by anastomotic leak and essentially persistent obstructive symptoms secondary to delayed gastric emptying. Though his anastomosis was demonstrably patent, these symptoms were thought to be secondary to a functional obstruction at the gastrojejunostomy. After repeated workups and many failed attempts to treat these symptoms, he ultimately underwent endoscopic placement of an uncovered colonic stent into the efferent limb of his gastrojejunostomy. This allowed for preferential drainage of gastric contents down the efferent limb, and improvement of his delayed gastric emptying. Conclusions: In a select group of patients with advanced foregut malignancy, and with high re-operative risks, salvage endoscopic stenting may be useful in the palliation of symptoms from a functionally obstructed gastrojejunostomy.

Hepatocellular carcinoma survival in uninsured and underinsured patients.

BACKGROUND: The incidence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) is increasing. The purpose of this study is to establish baseline survival in a medically-underserved population and to evaluate the effect of HCV seropositivity on our patient population. MATERIALS AND METHODS: We reviewed clinicopathologic parameters from a prospective tumor registry and medical records from the Harris County Hospital District (HCHD). Outcomes were compared using Kaplan-Meier survival analysis and log-rank tests. RESULTS: A total of 298 HCC patients were identified. The median survival for the entire cohort was 3.4 mo. There was no difference in survival between the HCV seropositive and the HCV seronegative groups (3.6 mo versus 2.6 mo, P = 0.7). Patients with a survival <1 mo had a significant increase in αfetoprotein (AFP), international normalized ratio (INR), model for end-stage liver disease (MELD) score, and total bilirubin and decrease in albumin compared with patients with a survival ≥ 1 mo. CONCLUSIONS: Survival for HCC patients in the HCHD is extremely poor compared with an anticipated median survival of 7 mo reported in other studies. HCV seropositive patients have no survival advantage over HCV seronegative patients. Poorer liver function at diagnosis appears to be related to shorter survival. Further analysis into variables contributing to decreased survival is needed.

Durable response for ampullary and duodenal adenocarcinoma with a nab-paclitaxel plus gemcitabine ± cisplatin combination.

BACKGROUND/AIM: There is no standard salvage chemotherapy for metastatic periampullary adenocarcinoma and duodenal adenocarcinoma and the prognosis of those who fail oxaliplatin, irinotecan, and 5FU is dismal. We examined nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for these two malignancies. METHODS: Patients who failed oxaliplatin, irinotecan, and 5FU and whose archival tumors stained immunohistochemical (IHC) tumor positive for CK7 or MUC1 received nab-paclitaxel and gemcitabine therapy with or without cisplatin. RESULTS: Three patients, 2 with metastatic ampullary adenocarcinoma and 1 with duodenal adenocarcinoma with positive IHC staining for CK7 or MUC1 who failed 2 lines of chemotherapy with oxaliplatin, irinotecan, and 5FU received nab-paclitaxel and gemcitabine with or without cisplatin. All achieved excellent tumor response on CT scans with marked falls in tumor markers CA19-9 and CEA as well as ≥1 year of progression-free survival. All 3 have continued to survive 2-3 years since diagnosed with stage 4 metastatic adenocarcinoma. CONCLUSIONS: Nab-paclitaxel plus gemcitabine with or without cisplatin should be investigated as a standard-of-care chemotherapy regimen for patients with ampullary adenocarcinoma and duodenal adenocarcinoma.

A Phase II, Multicenter, Single-Arm Study of Mipsagargin (G-202) as a Second-Line Therapy Following Sorafenib for Adult Patients with Progressive Advanced Hepatocellular Carcinoma.

Background: Mipsagargin (G-202) is a thapsigargin-based prodrug with cytotoxic activity masked by a peptide that is cleaved by prostate-specific membrane antigen (PSMA), a protease expressed in prostate cancer cells and the endothelium of tumor vasculature. It was hypothesized that PSMA-mediated activation of mipsagargin would result in disruption of the tumor vasculature, leading to a decrease in blood flow, and in direct cytotoxic effects on tumor cells, resulting in anti-tumor activity. Method: In this open-label, Phase II study, mipsagargin was administered intravenously on Days 1, 2, and 3 of a 28-day cycle to patients with hepatocellular carcinoma (HCC) who progressed on or after treatment with sorafenib or intolerant of sorafenib. Assessments included time to disease progression (TTP), response rate, progression-free survival (PFS), overall survival (OS), and safety. Blood flow metrics in hepatic lesions were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Of 25 treated patients, 19 were evaluable for efficacy. None had an objective response, 12 (63.2%) had a best response of stable disease, and 12 (63.2%) showed radiologic progression; seven patients (36.8%) were censored. The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days. Of five patients with DCE-MRI data for 11 HCC lesions, all demonstrated a reduced Ktrans (mean, 52%). The most common treatment-emergent AEs were Grade 1-2 and consisted of increased blood creatinine (68.0%), fatigue (56.0%), and nausea (44.0%). Conclusions: Mipsagargin is relatively well tolerated and promotes prolonged disease stabilization in patients with advanced HCC that had progressed on prior treatment with sorafenib. A significant decrease in Ktrans upon treatment suggests mipsagargin reduces blood flow in hepatic lesions.

Emerging drugs in the treatment of advanced gastric cancer.

BACKGROUND: Gastroesopheal cancer is one of the most common cancers worldwide. If detected early, curative treatment is possible. Often, gastroesophageal cancer is detected at an advanced stage when therapy is palliative. OBJECTIVES: To provide a critical evaluation of historic and recently developed chemotherapy regimens for the treatment of advanced gastroesophageal cancer (AGC). METHODS: Published clinical trials in AGC as well as selected abstracts presented at international oncology meetings were selected. RESULTS/CONCLUSION: Chemotherapy has demonstrated a benefit over best supportive care alone by improving the quality and quantity of life for patients with advanced disease. Recent Phase III trials investigating cytotoxic chemotherapy and Phase II trials incorporating biotherapy for the treatment of AGC show promise for the future.

Increased cancer antigen 27.29 (CA27.29) level in patients with mycosis fungoides.

BACKGROUND: Mycosis fungoides, also called cutaneous T-cell lymphoma, comprise a group of extranodal, indolent non-Hodgkin's lymphomas of T-cell origin with primary involvement of the skin. There are few data available on tumor markers in these patients. Cancer antigen 27.29 (CA27.29), which is expressed on most carcinoma cells, is a soluble form of the glycoprotein MUC1. Measuring CA27.29 has been approved by the US Food and Drug Administration for monitoring disease activity in patients with breast cancer. OBJECTIVE: We sought to assess whether CA27.29 levels were increased in patients with cutaneous T-cell lymphoma and whether there was a correlation of this marker with tumor response. METHODS: We evaluated the CA27.29 blood levels from 6 patients with advanced mycosis fungoides (who had no evidence of breast cancer) and reviewed their charts for information about history and physical examinations, laboratory data, pathology findings, and radiologic examinations. RESULTS: We demonstrated that 3 of 6 patients with advanced mycosis fungoides had markedly elevated CA27.29 blood levels. In the two patients who had serial blood levels drawn, CA27.29 increased or decreased during treatment as the disease progressed or responded, respectively. LIMITATIONS: This study reflects pilot data on a limited number of patients. CONCLUSIONS: Our observations suggest that CA27.29 merits further investigation as a tumor marker in patients who have cutaneous T-cell lymphoma.

TroVax in colorectal cancer.

Currently, the backbone of therapy for metastatic disease is cytotoxic chemotherapy, along with the recent addition of targeted therapy based on molecular markers with KRAS testing. Despite the improvement in survival for metastatic colon cancer, newer agents are still needed. The clinical activity of TroVax in metastatic colon cancer has been studied in a small number of clinical trials. There is evidence that supports the vaccine's ability to induce humoral and cellular responses, as demonstrated by positive 5T4 and MVA-specific antibody titers and cellular proliferation assays. Future strategies should focus on investigating the immunomodulatory effects of chemotherapy in conjunction with TroVax, understanding the optimal dosing and schedule of the combination, and examining potential predictive biomarkers to determine which patients may benefit from immunotherapy from those who do not.