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Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of death in the United States and is expected to be ranked second in the next 10 years due to poor prognosis and a rising incidence. Distant metastatic PDAC is associated with the worst prognosis among the different phases of PDAC. The diagnostic options for PDAC are convenient and available for staging, tumor response evaluation, and management of resectable or borderline resectable PDAC. However, imaging is crucial in PDAC diagnosis, monitoring, resectability appraisal, and response evaluation. The advancement of medical technologies is evolving, hence the use of imaging in PDAC treatment options has grown as well as the utilization of ctDNA as a tumor marker. Treatment options for metastatic PDAC are minimal with the primary goal of therapy limited to symptom relief or palliation, especially in patients with low functional capacity at the point of diagnosis. Molecular profiling has shown promising potential solutions that would push the treatment boundaries for patients with PDAC. In this review, we will discuss the latest updates from evidence-based guidelines regarding diagnosis, therapy response evaluation, prognosis, and surveillance, as well as illustrating novel therapies that have been recently investigated for PDAC, in addition to discussing the molecular profiling advances in PDAC. [ABSTRACT FROM AUTHOR]

Aim: In contrast to significant advances in organ preservation in locally advanced rectal cancer, the contemporary management of early-stage rectal cancer, including the frequency of abdominoperineal resections, remains largely unexplored in the United States. Therefore, we assessed the utilization of neoadjuvant therapy and oncological resections in early-stage rectal cancer patients., Study Design: This is a retrospective cohort study of patients with cT1-T3N0 rectal cancer who underwent proctectomies between 2016 and 2022 in the National Surgical Quality Improvement Project proctectomy files. Multivariable logistic regression was used to identify factors associated with abdominoperineal resections and Kendall's tau statistics to evaluate clinical-pathological staging agreement., Results: In all, 3078 patients (29.6% cT1-2N0, 70.4% cT3N0) were included with 55.3% of tumours <5 cm from the anal verge. Overall, 58.2% received neoadjuvant therapy within 3 months of surgery (30.6% for cT1-T2N0 vs. 69.8% for cT3N0, P < 0.001), and 58.6% underwent abdominoperineal resection (55.5% for cT1-T2N0 vs. 59.9% for cT3N0, P = 0.058). The adjusted odds of undergoing abdominoperineal resection were associated with increasing age (OR 1.4 per every 10-year increase; 95% CI 1.2-1.5), cT3N0 tumours (OR 1.7; 95% CI 1.1-2.7) and tumour location <5 cm from the anal verge (OR 10.6; 95% CI 7.7-14.7). There was a weak clinical-pathological T staging correlation (Kendal tau coefficient 0.25; 95% CI 0.20-0.29)., Conclusion: In this large cohort of patients with early-stage rectal cancer with high rates of neoadjuvant therapy, over half of patients underwent abdominoperineal resection and one in five had a pathological complete response. These findings underscore opportunities for organ preservation in early-stage rectal cancer, suggesting that treatments typically reserved for locally advanced disease may extend to early stages with the completion of ongoing clinical trials., (© 2025 Association of Coloproctology of Great Britain and Ireland.)

Ki-67 (MIB-1) immunostaining to quantify the proliferative index of neuroendocrine tumors (NETs) has been recommended (especially for small biopsies). However, this has a number of challenges with nonrepresentative Ki-67 index due to interference by Ki-67 immunoreactive proliferating lymphocytes infiltrating the tumor and also some proliferating stromal cells including endothelial cells in the background. Our pilot project showed that dual-color immunostaining with inclusion of leukocyte common antigen (LCA) (Ki-67: nuclear brown; LCA: cytoplasmic red) can facilitate the weeding out of lymphocyte interference. We analyzed the results with 23 surgical cases of pancreatic NETs. This was followed by poststudy examination of 11 cases of endoscopic ultrasound-guided fine-needle aspiration of the pancreatic NETs (PanNETs) to evaluate the findings of the study. Dual-color immunostaining for Ki-67 with LCA increased the precision of quantifying Ki-67 index, due to ability to exclude LCA immunoreactive lymphocytes. Other nontumor Ki-67 immunoreactive cells such as endothelial and stromal cells could be distinguished morphologically. Digital methods were also attempted, but this approach could not distinguish infiltrating lymphocytes and other cells in sections resulting in erroneous results. This study demonstrated that grading of PanNET can be performed with increased precision with dual-color Ki-67 immunostaining protocol standardized in this study. As evaluated on a few cytopathology cases, this protocol is especially useful for the evaluation of small biopsies and cell block sections of fine-needle aspiration biopsy material where 50 high-power fields cannot be evaluated but have >500 tumor cell nuclei. [ABSTRACT FROM AUTHOR]

Background: Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens.Methods: Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Fisher exact and Kruskal-Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan-Meier methods evaluated differences in overall survival from the time of surgery between mutations.Results: A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54-81 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32-73 years]) and the United States (49 patients; median age, 66 years [range, 46-87 years]) (P = .002) and had more well-differentiated tumors (46% vs 0% for Chile/United States; P < .001) and fewer gallstone-associated cancers (36% vs 67% for Chile and 69% for the United States; P = .13). Japanese patients had a median mutation burden of 6 (range, 1-23) compared with Chile (median mutation burden, 7 [range, 3-20]) and the United States (median mutation burden, 4 [range, 0-27]) (P = .006). Tumors from Japanese patients lacked AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, whereas Chilean tumors lacked Erb-B2 receptor tyrosine kinase 3 (ERBB3) and AT-rich interaction domain 2 (ARID2) mutations. SMAD family member 4 (SMAD4) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States; P = .68) and was univariately associated with worse overall survival (median, 10 months vs 25 months; P = .039). At least one potentially actionable gene was found to be altered in 80% of tumors.Conclusions: Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers, SMAD4 mutations were detected in approximately one-third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a major public health problem, both in the USA and globally. Over the past 20 years, significant advances have been made in the treatment of patients with metastatic CRC (mCRC). Recent efforts in the field of biomarkers have focused on the development of molecular diagnostics to define the subset of patients with mCRC that is likely to derive most benefit from anti-EGFR therapy. Herein, we review the recent advancements in molecular stratification of CRC and the role of current as well as emerging biomarkers in this disease. It is now clear that the presence of activating mutations in the KRAS and NRAS genes serves as reliable predictive markers for resistance to anti-EGFR therapy in mCRC. It is also clear that further improvements in the survival of mCRC patients will probably be made possible only with identification of new predictive molecular biomarkers and their evaluation using rational and innovative clinical trials. The recent advances in DNA sequencing technology and "omics"-based approaches have provided promising new strategies for the development of novel molecular biomarkers in this disease. [ABSTRACT FROM AUTHOR]

Background. In colorectal cancer (CRC), evidence shows that expanding RAS testing to analyze more mutations may better predict benefit from anti-EGFR therapy. The economic implications of expanding RAS testing for metastatic CRC were analyzed. Materials and Methods. Estimates of standard KRAS exon 2 testing were based on the Centers for Medicare and Medicaid Services (CMS) 2014 Diagnostic Laboratory Fee Schedule, and expanded RAS testingwas estimated using a sensitivity analysis donewithvarious potential cost scenarios (1, 2,10, and30times the cost of the standard KRAS test). The cost estimates for cetuximab and panitumumab were based on the CMSpayment allowance limits for Medicare Part B. Results. A total of 28,692 patients with metastatic CRC were estimated to be eligible annually for RAS testing. For cetuximab, the societal cost of standard KRAS testing plus the drug versus expanded testing plus the drug would be $1.16 billion versus $816 million if the cost of the tests were the same. If the cost of the expanded RAS test were 30 times the cost of the standard test, then the societal cost of standard KRAS testing plus the drug versus expanded testing plus the drug would be $1.16 billion versus $980 million, a continued savings of more than $184 million annually. Similar savings were seen with panitumumab. Conclusion. The increased societal cost of expanded RAS testing versus standard approved KRAS exon 2 testing was inconsequential when compared with the amount of money saved by not treating the additional 18% of patients who harbor additional RAS mutations (beyond exon 2) with anti- EGFR therapy. [ABSTRACT FROM AUTHOR]

Metastatic colorectal cancer is a significant cause of morbidity and mortality in the US and around the world. While several novel cytotoxic and biologic therapies have been developed and proven efficacious in the past two decades, their optimal use in terms of patient selection, drug combinations, and regimen sequences has yet to be defined. Recent investigations regarding anti-epidermal growth factor receptor therapies include the comparison of single-agent panitumumab and cetuximab, the benefit of adding cetuximab to chemotherapy in the conversion therapy setting, the comparison of cetuximab and bevacizumab when added to first-line chemotherapy, and predictive biomarkers beyond KRAS exon 2 (codons 12 and 13) mutations. With respect to anti-vascular endothelial growth factor therapies, new data on continuing bevacizumab beyond disease progression on a bevacizumab-containing chemotherapy regimen, the addition of bevacizumab to triplet chemotherapy in the first-line setting, maintenance therapy with bevacizumab plus either capecitabine or erlotinib, the addition of aflibercept to chemotherapy, and regorafenib as monotherapy have emerged. Recent scientific and technologic advances in the field of metastatic colorectal cancer promise to elucidate the biological underpinnings of this disease and its therapies for the goal of improving personalized treatments for patients with metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

The ability to tailor biologic therapy based on the status of tumor biomarkers and monoclonal antibodies has become very important in the last years. The role of tumor biomarkers in treating colorectal cancer, specifically the K-RAS gene, was identified. KRAS had a higher interest after Lievre and colleagues reported at the 2008 American Society of Clinical Oncology (ASCO) meeting, their analysis of K-RAS mutations in tumors from patients who did not appear to benefit from cetuximab therapy, providing additional data involving K-RAS mutant tumors and their lack of response to cetuximab, as part of first-line therapy for metastatic colorectal cancer. Furthermore, other trials evaluated the K-RAS status and the first-line treatment of metastatic colorectal cancer, the treatment of refractory metastatic cancer and dual-antibody therapy in the first-line treatment of colorectal cancer. Patients with mutant K-RAS colorectal tumors have no benefit from cetuximab, no matter the type of chemotherapy regimen. [ABSTRACT FROM AUTHOR]

Aim A systematic review of treatment guidelines for metastatic colorectal cancer (mCRC) was performed to assess recommendations for monoclonal antibody therapy in these guidelines. Method Relevant papers were identified through electronic searches of MEDLINE, MEDLINE In Process, EMBASE and the Cochrane Library; through manual searches of reference lists; and by searching the Internet. Results A total of 57 relevant guidelines were identified, 32 through electronic database searches and 25 through the website searches. The majority of guidelines were published between 2004 and 2010. The country publishing the most guidelines was the USA (12), followed by the UK (10), Canada (eight), France (eight), Germany (three), Australia (two), Spain (two) and Italy (one). In addition, eight European and three international guidelines were identified. As monoclonal antibody therapy for mCRC was not introduced until 2004, no firm recommendations for monoclonal antibody therapy were made in guidelines published between 2004 and 2006. Recommendations for monoclonal antibody therapy first appeared in 2007 and evolved as more data became available. The most recent international, European and US guidelines recommend combination chemotherapy with the addition of a monoclonal antibody for the first-line treatment of mCRC. Second-line treatment depends on the first-line regimen used. For chemoresistant mCRC, cetuximab or panitumumab are recommended as monotherapy in patients with wild-type KRAS tumours. Conclusion The study indicates that recent treatment guidelines have recognized the role of monoclonal antibodies in the management of mCRC, and that treatment guidelines should be updated in a timely manner to reflect the most recently available data. [ABSTRACT FROM AUTHOR]

The approval of a new drug for cancer treatment by the regulatory authorities, such as the United States Food and Drug Administration or European Medicines Agency, is usually based on the positive results of one or more randomized phase III clinical trials comparing the investigational treatment with the standard treatment. A clinical trial is presented as positive if the new drug tested on an experimental group shows a statistically significant difference with the control group (P < .05) in the primary endpoint, which is usually a time-to-event endpoint (overall survival or progression-free survival). Such apparently positive clinical trials disregard whether the final value of the difference in the primary endpoints between the experimental and control groups (δ) meets the criterion that was predefined in the protocol. Currently, the trend is to design large trials that may detect statistically significant, but often trivial, differences in survival endpoints. However, recent appeals have been made in the oncology literature for the design of smaller clinical trials to detect or exclude only larger, clinically important, values of δ. Here, we have evaluated 18 randomized phase III clinical trials that were used for the approval of molecular-targeted anticancer drugs by the United States Food and Drug Administration. Results showed that in some of the articles the magnitude of the reported values of δ were lower than the values predefined in the protocol. We suggest that trials should not be declared positive based only on a statistically significant P value, but should also require detection of a difference in survival outcome that equals or exceeds a clinically important value that is specified in the protocol. [ABSTRACT FROM PUBLISHER]

Colorectal cancer remains a major cause of morbidity and mortality in the United States. The advent of molecular therapies targeted against specific, stereotyped cellular mutations that occur in this disease has ushered in new hope for treatment options. However, key questions regarding optimal dosing schedules, dosing duration, and patient selection remain unanswered. In this review, we describe how recent advances in molecular imaging, specifically optical molecular imaging with fluorescent probes, offer potential solutions to these questions. We begin with an overview of optical molecular imaging, including discussions on the various methods of design for fluorescent probes and the clinically relevant imaging systems that have been built to image them. We then locus on the relevance of optical molecular imaging to colorectal cancer. We review the most recent data on how this imaging modality has been applied to the measurement of treatment efficacy for currently available as well as developmental molecularly targeted therapies. We then conclude with a discussion on how this imaging approach has already begun to be translated clinically for human use. [ABSTRACT FROM AUTHOR]

The article discusses a study on the benefit of preoperative radiotherapy combined with infusional 5-fluorouracil (FU) followed by total mesorectal excision (TME) in treating patients with T3 or lymph node-positive rectal cancer in the U.S. Some of the novel agents used for the preoperative chemoradiation include Capecitabine, Oxaliplatin and Irinotecan. The study suggests that adding newer cytotoxic agents to preoperative fluoro-pyrimidine-based chemoradiation in patients with locally advanced rectal may enhance pathologic response rates.

Systemic therapy for advanced non-small cell lung cancer (NSCLC) has evolved over the last two decades, with modest improvements in quality of life and overall survival. A plateau has been reached with traditional chemotherapy, and efforts are now being directed at developing molecularly targeted agents. To date, three such agents have been found to improve overall survival in advanced NSCLC. Erlotinib, a small-molecule inhibitor of the epidermal growth factor receptor, was approved by the US FDA in 2004 as second- or third-line treatment for advanced NSCLC. Bevacizumab, an antibody to vascular endothelial growth factor, a key mediator of angiogenesis, received approval in 2006, after a randomized trial reported a median survival of 1 year when bevacizumab was added to first-line chemotherapy. More recently, cetuximab, an antibody to the epidermal growth factor receptor, was found to improve outcome when added to chemotherapy, and FDA approval is anticipated. Several additional agents are currently being evaluated in randomized trials, with encouraging results from early studies. These and other studies are prospectively investigating predictive clinical and molecular characteristics, with the ultimate goal of individualizing therapy in advanced NSCLC. [ABSTRACT FROM AUTHOR]

Targeted biologic agents have an established role in treating metastatic colorectal cancer (mCRC). Bevacizumab, a recombinant monoclonal antibody against the vascular endothelial growth factor ligand is approved by the U.S. Food and Drug Administration (FDA) for bevacizumab-naïve patients. Cetuximab, a chimeric monoclonal antibody (mAb) against the epidermal growth factor receptor (EGFR) is FDA approved as a single agent, or in combination with irinotecan, in both irinotecan-naïve and refractory patients, and has additional efficacy in combination with oxaliplatin. Panitumumab, a fully human EGFR mAb, is FDA approved as a single agent in refractory patients but has additional efficacy in combination with chemotherapy. After reaching a temporary therapeutic plateau of FDA-approved agents for the treatment of mCRC, pivotal results have developed that critically affect the care for these patients. Correlative data from randomized trials of EGFR inhibitors across disease settings have demonstrated higher response rates, specifically for patients with wild-type K-RAS tumors. The interpretation of the B-RAF mutation and other molecular markers may further define the appropriateness of anti-EGFR therapy. Recent literature revealed that the first-line use of combined anti-EGFR therapy plus bevacizumab resulted in inferior outcomes and additional toxicities. Furthermore, the role of biologic agents for locally advanced colon cancer cannot be advocated at this time. With impending changes in the health care system, the economic impact of mAbs will continue to be scrutinized. Hence, as the significance of molecular markers continues to develop, their role as it pertains to the appropriate use of biologic agents in the treatment of mCRC will continue to evolve. The Oncologist 2010;15:73-84 [ABSTRACT FROM AUTHOR]