American Radium Society Appropriate Use Criteria for the use of liver-directed therapies for nonsurgical management of liver metastases: Systematic review and guidelines.

The liver is a common site of cancer metastases. Systemic therapy is widely accepted as the standard treatment for liver metastases (LM), although select patients with liver oligometastases may be candidates for potentially curative liver resection. Recent data support the role of nonsurgical local therapies such as ablation, external beam radiotherapy, embolization, and hepatic artery infusion therapy for management of LM. Additionally, for patients with advanced, symptomatic LM, local therapies may provide palliative benefit. The American Radium Society gastrointestinal expert panel, including members representing radiation oncology, interventional radiology, surgical oncology, and medical oncology, performed a systemic review and developed Appropriate Use Criteria for the use of nonsurgical local therapies for LM. Preferred Reporting Items for Systematic reviews and Meta-Analyses methodology was used. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in seven representative clinical scenarios through a well-established consensus methodology (modified Delphi). A summary of recommendations is outlined to guide practitioners on the use of nonsurgical local therapies for patients with LM.

Perioperative chemotherapy versus postoperative chemoradiotherapy in patients with resectable gastric/gastroesophageal junction adenocarcinomas: A survival analysis of 5058 patients.

BACKGROUND: Both perioperative chemotherapy (PECT) and postoperative chemoradiotherapy (POCRT) have a significant survival advantage over surgery alone for the treatment of patients with gastric cancer. However, to the best of our knowledge, these regimens have not been compared in a randomized clinical trial. The purpose of the current observational study was to compare overall survival among patients receiving PECT versus POCRT for the treatment of gastric/gastroesophageal junction (GEJ) adenocarcinomas. METHODS: Patients with resected clinical American Joint Committee on Cancer TNM stage II or III adenocarcinomas of the stomach or GEJ from 2004 through 2013 were identified utilizing the National Cancer Data Base. Hazard ratios (HRs), 95% confidence intervals, and P values were computed using a Cox proportional hazards procedure. Multivariable models were adjusted for treatment regimen, age, race, ethnicity, tumor size, TNM stage, Charlson comorbidity index, and tumor grade. RESULTS: Patients receiving PECT had a 72% survival advantage compared with those treated with POCRT (5058 patients; HR, 0.58 [adjusted P<.0001]). The 5-year actuarial survival rate for PECT was 44% compared with 38% for POCRT. A statistically significant survival advantage for PECT also was observed when the analysis was stratified by clinical stage of disease (stage II [3192 patients]: adjusted HR, 0.79 [P = .041]; and stage III [1866 patients]: adjusted HR, 0.49 [P<.0001]). This benefit was greatest among patients with lymph node-positive disease who converted to lymph node-negative status with PECT. CONCLUSIONS: In this large series of patients with stage II/III resected gastric/GEJ adenocarcinomas from >1500 American College of Surgeons Commission on Cancer-accredited facilities, patients receiving PECT were shown to survive longer than those receiving POCRT. Cancer 2017;123:2909-17. © 2017 American Cancer Society.

Current topics in the multimodality treatment of locally advanced rectal cancer.

The multimodality approach to the treatment of locally advanced rectal cancer has evolved to include neoadjuvant radiotherapy with or without concurrent chemotherapy, total mesorectal excision and adjuvant fluoropyrimidine-based chemotherapy. Though this broad strategy has yielded improvements in local control compared with historical data, overall survival remains largely unchanged. Current investigations focus on improving patient selection through new imaging modalities, improving surgical techniques, incorporating more aggressive systemic treatment regimens and the selective use of radiation. Here, we review emerging data regarding newer staging techniques, neoadjuvant chemotherapy, optimal timing of surgery, selective use of radiation and nonoperative approaches to the management of locally advanced rectal cancers.

The role of neoadjuvant therapy in pancreatic cancer: a review.

Controversy remains regarding neoadjuvant approaches in the treatment of pancreatic cancer. Neoadjuvant therapy has several potential advantages over adjuvant therapy including earlier delivery of systemic treatment, in vivo assessment of response, increased resectability rate in borderline resectable patients and increased margin-negative resection rate. At present, there are no randomized data favoring neoadjuvant over adjuvant therapy and multiple neoadjuvant approaches are under investigation. Combination chemotherapy regimens including 5-fluorouracil, irinotecan and oxaliplatin, gemcitabine with or without abraxane, or docetaxel and capecitabine have been used in the neoadjuvant setting. Radiation and chemoradiation have also been incorporated into neoadjuvant strategies, and delivery of alternative fractionation regimens is being explored. This review provides an overview of neoadjuvant therapies for pancreatic cancer.

Executive Summary of the American Radium Society Appropriate Use Criteria for Neoadjuvant Therapy for Nonmetastatic Pancreatic Adenocarcinoma: Systematic Review and Guidelines.

For patients with locoregionally confined pancreatic ductal adenocarcinoma (PDAC), margin-negative surgical resection is the only known curative treatment; however, the majority of patients are not operable candidates at initial diagnosis. Among patients with resectable disease who undergo surgery alone, the 5-year survival remains poor. Adjuvant therapies, including systemic therapy or chemoradiation, are utilized as they improve locoregional control and overall survival. There has been increasing interest in the use of neoadjuvant therapy to obtain early control of occult metastatic disease, allow local tumor response to facilitate margin-negative resection, and provide a test of time and biology to assist with the selection of candidates most likely to benefit from radical surgical resection. However, limited guidance exists regarding the relative effectiveness of treatment options. In this systematic review, the American Radium Society multidisciplinary gastrointestinal expert panel convened to develop Appropriate Use Criteria evaluating the evidence regarding neoadjuvant treatment for patients with PDAC, including surgery, systemic therapy, and radiotherapy, in terms of oncologic outcomes and quality of life. The evidence was assessed using the Population, Intervention, Comparator, Outcome, and Study (PICOS) design framework and "Preferred Reporting Items for Systematic Reviews and Meta-analyses" 2020 methodology. Eligible studies included phases 2 to 3 trials, meta-analyses, and retrospective analyses published between January 1, 2012 and December 30, 2022 in the Ovid Medline database. A summary of recommendations based on the available literature is outlined to guide practitioners in the management of patients with PDAC.

Executive Summary of the American Radium Society® (ARS) Appropriate Use Criteria (AUC) for Non-Operative Management (NOM) for Rectal Adenocarcinoma: Systematic Review and Guidelines.

PURPOSE: For rectal cancer patients, the standard approach of chemotherapy, radiation therapy (RT), and surgery (Trimodality Therapy, TMT) is associated with significant long-term toxicity and/or colostomy for most patients. Patient options focused on quality-of-life (QOL) have dramatically improved, but there remains limited guidance regarding comparative effectiveness. This systematic review and associated guidelines evaluate how various treatment strategies compare to each other in terms of oncologic outcomes and QOL. MATERIALS AND METHODS: Cochrane and PRISMA methodology were used to search for prospective and retrospective trials and meta-analyses of adequate quality within the Ovid Medline database between 1/1/2012-6/15/2023. These studies informed the expert panel, which rated the appropriateness of various treatments in 6 clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS: The search process yielded 197 articles that advised voting. Increasing data show non-operative management (NOM) and primary surgery result in QOL benefits noted over TMT without detriment to oncologic outcomes. For rectal cancer patients for whom TME would result in permanent colostomy or inadequate bowel continence, NOM was strongly recommended as usually appropriate. Restaging with tumor response assessment 8-12 weeks following completion of RT/CRT was deemed a necessary component of NOM. The panel recommended active surveillance in the setting of a near complete or complete response. In the setting of NOM, 54-56 Gy in 27-33 fractions concurrent with chemotherapy and followed by consolidation chemotherapy was recommended. The panel strongly recommends primary surgery as usually appropriate for a T3N0 high rectal tumor for whom LAR and adequate bowel function is possible, with adjuvant chemotherapy considered if N+. CONCLUSIONS: Recent data supports NOM and primary surgery as important options that should be offered to eligible patients. Considering the complexity of multi-disciplinary management, patients should be discussed in a multi-disciplinary setting and therapy should be tailored to individual patient goals/values.

Establishment and Culture of Patient-Derived Breast Organoids.

Breast cancer is a complex disease that has been classified into several different histological and molecular subtypes. Patient-derived breast tumor organoids developed in our laboratory consist of a mix of multiple tumor-derived cell populations, and thus represent a better approximation of tumor cell diversity and milieu than the established 2D cancer cell lines. Organoids serve as an ideal in vitro model, allowing for cell-extracellular matrix interactions, known to play an important role in cell-cell interactions and cancer progression. Patient-derived organoids also have advantages over mouse models as they are of human origin. Furthermore, they have been shown to recapitulate the genomic, transcriptomic as well as metabolic heterogeneity of patient tumors; thus, they are capable of representing tumor complexity as well as patient diversity. As a result, they are poised to provide more accurate insights into target discovery and validation and drug sensitivity assays. In this protocol, we provide a detailed demonstration of how patient-derived breast organoids are established from resected breast tumors (cancer organoids) or reductive mammoplasty-derived breast tissue (normal organoids). This is followed by a comprehensive account of 3D organoid culture, expansion, passaging, freezing, as well as thawing of patient-derived breast organoid cultures.

American Radium Society (ARS) Appropriate Use Criteria (AUC) for Extrahepatic Cholangiocarcinoma.

Although uncommon, extrahepatic cholangiocarcinoma (EHCC) is a deadly malignancy, and the treatment approaches remain controversial. While surgery remains the only cure, few patients are candidates for resection up front, and there are high rates of both local and distant failure following resection. Herein, we systematically review the available evidence regarding treatment approaches for patients with EHCC, including surgery, radiation, and chemotherapy. The evidence regarding treatment outcomes was assessed using the Population, Intervention, Comparator, Outcome, and Study design (PICOS) framework. A summary of recommendations based on the available literature is outlined for specific clinical scenarios encountered by providers in the clinic to guide the management of these patients.

Adjuvant strategies for resectable pancreatic cancer: have we made progress?

Substantial controversy remains regarding the optimal adjuvant treatment for patients with resectable pancreatic adenocarcinoma. Despite improvements in radiation techniques, systemic therapies, and incorporation of targeted agents, the 5-year survival rates for early stage patients remains less than 25% and the optimal adjuvant treatment approach remains unclear. Here we summarize the data presented at the 2012 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium regarding controversial issues surrounding the role, timing, and selection of patients for adjuvant chemoradiation strategies following curative resection for pancreatic adenocarcinoma. (Abstracts #301, #333, and #206).

Resectable pancreatic cancer: is surgery the best first step?

Controversy exist regarding the potential benefit of the neoadjuvant approach to pancreatic cancer as limited retrospective data exists comparing pre- with post-operative chemoradiation. The optimal treatment approach remains unclear as we await prospective randomized clinical trials evaluating the hypothesized benefit of the neoadjuvant therapy for resectable pancreatic cancer and as there has been no proven survival benefit to date. Here we summarize the data presented at the 2012 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium providing additional insight into the potential of neoadjuvant therapy in the treatment of pancreatic cancer. (Abstracts #156, #162, #168 and #177).

Is there a role of radiotherapy in the management of pancreatic neuroendocrine tumors (PNET)?

Pancreatic neuroendocrine tumors (PNET) represent a heterogeneous group of tumors with varying tumor biology and prognosis. Advanced PNETs remain a difficult therapeutic challenge because of their high malignant potential and their resistance to conventional chemotherapy although there have been recent developments with promising results with the use of novel agents for the treatment of this disease. Combined modality chemoradiation is not widely used in the management of locally advanced pancreatic endocrine tumors. We discuss Abstract #335 from 2012 ASCO GI Cancers Symposium and share our experience to discuss efficacy and toxicity of concurrent capecitabine or infusional 5-fluorouracil and radiotherapy in patients with resected, locally advanced and metastatic PNET. Prospective studies to investigate the role of radiation and chemoradiation are warranted.

Patient-Derived Triple-Negative Breast Cancer Organoids Provide Robust Model Systems That Recapitulate Tumor Intrinsic Characteristics.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, highlighting the unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDO) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBC). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven, basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, this study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and tailored treatment options. SIGNIFICANCE: A comprehensive analysis of patient-derived organoids of TNBC provides insights into cellular heterogeneity and mechanisms of tumorigenesis at the single-cell level.

American Radium Society (ARS) Appropriate Use Criteria (AUC) for Locoregional Gastric Adenocarcinoma: Systematic Review and Guidelines.

OBJECTIVE: The objective of this study was to systematically evaluate the data regarding the use of neoadjuvant, perioperative, surgical, and adjuvant treatment options in localized gastric cancer patients and to develop Appropriate Use Criteria recommended by a panel of experts convened by the American Radium Society. METHODS: Preferred reporting items for systematic reviews and meta-analyses methodology was used to develop an extensive analysis of peer-reviewed phase 2/2R/3 trials, as well as meta-analyses found within the Ovid Medline database between 2010 and 2020. The expert panel then rated the appropriateness of various treatments in 5 representative clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS: For patients with medically operable locally advanced gastric cancer, the strongest recommendation was for perioperative chemotherapy based on high-quality data. Acceptable alternatives included surgery followed by either chemotherapy or concurrent chemoradiotherapy (CRT). For patients with upfront resection of stages I to III gastric cancer (no neoadjuvant therapy), the group strongly recommended adjuvant therapy with either chemotherapy alone or CRT, based on high-quality data. For patients with locally advanced disease who received preoperative chemotherapy without tumor regression, the group strongly recommended postoperative chemotherapy or postoperative CRT. Finally, for medically inoperable gastric cancer patients, there was moderate consensus recommending definitive concurrent CRT. CONCLUSIONS: The addition of chemotherapy and/or radiation, either in the neoadjuvant, adjuvant, or perioperative setting, results in improved survival rates for patients compared with surgery alone. For inoperable patients, definitive CRT is a reasonable treatment option, though largely palliative.

Identification of prognostic and predictive markers in pancreatic adenocarcinoma. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011.

Pancreatic cancer remains a significant cause of morbidity and mortality. While increasing treatment options have improved outcomes for many patients, they have also complicated decision-making for treatment. Unfortunately, most patients with pancreatic cancer die from their disease. Prognostic and predictive markers could play a role to improve treatment by identifying patients who may or may not require a given therapy, and determining those most likely to benefit from a therapy. At the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium held in San Francisco, January 2011, several interesting abstracts were presented that focused on prognostic and predictive markers associated with pancreatic adenocarcinomas. These abstracts discuss progress made in identifying molecular subtypes of pancreatic cancers that may provide insight into selection of patients likely to benefit from certain therapies.

Executive Summary of the American Radium Society Appropriate Use Criteria for Operable Esophageal and Gastroesophageal Junction Adenocarcinoma: Systematic Review and Guidelines.

PURPOSE: Limited guidance exists regarding the relative effectiveness of treatment options for nonmetastatic, operable patients with adenocarcinoma of the esophagus or gastroesophageal junction (GEJ). In this systematic review, the American Radium Society (ARS) gastrointestinal expert panel convened to develop Appropriate Use Criteria (AUC) evaluating how neoadjuvant and/or adjuvant treatment regimens compared with each other, surgery alone, or definitive chemoradiation in terms of response to therapy, quality of life, and oncologic outcomes. METHODS AND MATERIALS: Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology was used to develop an extensive analysis of peer-reviewed phase 2R and phase 3 randomized controlled trials as well as meta-analyses found within the Ovid Medline, Cochrane Central, and Embase databases between 2009 to 2019. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in 4 broadly representative clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS: For a medically operable nonmetastatic patient with a cT3 and/or cN+ adenocarcinoma of the esophagus or GEJ (Siewert I-II), the panel most strongly recommends neoadjuvant chemoradiation. For a cT2N0M0 patient with high-risk features, the panel recommends neoadjuvant chemoradiation as usually appropriate. For patients found to have pathologically involved nodes (pN+) who did not receive any neoadjuvant therapy, the panel recommends adjuvant chemoradiation as usually appropriate. These guidelines assess the appropriateness of various dose-fractionating schemes and target volumes. CONCLUSIONS: Chemotherapy and/or radiation regimens for esophageal cancer are still evolving with many areas of active investigation. These guidelines are intended for the use of practitioners and patients who desire information about the management of operable esophageal adenocarcinoma.

Emerging MEK inhibitors.

IMPORTANCE OF THE FIELD: The Ras/Raf/MEK/ERK pathway is often activated by genetic alterations in upstream signaling molecules. Integral components of this pathway such as Ras and B-Raf are also activated by mutation. The Ras/Raf/MEK/ERK pathway has profound effects on proliferative, apoptotic and differentiation pathways. This pathway can often be effectively silenced by MEK inhibitors. AREAS COVERED BY THIS REVIEW: This review will discuss targeting of MEK which could lead to novel methods to control abnormal proliferation which arises in cancer and other proliferative diseases. This review will cover the scientific literature from 1980 to present and is a follow on from a review which focused on Emerging Raf Inhibitors published in this same review series. WHAT THE READER WILL GAIN: By reading this review the reader will understand the important roles that genetics play in the response of patients to MEK inhibitors, the potential of combining MEK inhibitors with other types of therapy, the prevention of cellular aging and the development of cancer stem cells. TAKE HOME MESSAGE: Targeting MEK has been shown to be effective in suppressing many important pathways involved in cell growth and the prevention of apoptosis. MEK inhibitors have many potential therapeutic uses in the suppression of cancer, proliferative diseases and aging.

Bilateral internal carotid artery occlusions in a pediatric patient with refractory acute myeloid leukemia.

Thromboembolism is a well-known complication of cancer including acute myeloid leukemia (AML) especially in patients with high myeloblast counts. However, spontaneous vaso-occlusion in the main arteries is very rare especially in patients with low blast counts and no pre existing vasculopathy. We report the case of a 3-year-old male with refractory AML who developed spontaneous bilateral internal carotid artery occlusion with diffuse cerebral infarcts. Strokes are rarely secondary to spontaneous carotid artery thrombosis and few cases have been reported in the literature.

MaTAR25 lncRNA regulates the Tensin1 gene to impact breast cancer progression.

Misregulation of long non-coding RNA (lncRNA) genes has been linked to a wide variety of cancer types. Here we report on Mammary Tumor Associated RNA 25 (MaTAR25), a nuclear enriched and chromatin associated lncRNA that plays a role in mammary tumor cell proliferation, migration, and invasion, both in vitro and in vivo. MaTAR25 functions by interacting with purine rich element binding protein B (PURB), and associating with a major downstream target gene Tensin1 (Tns1) to regulate its expression in trans. The Tns1 protein product is a critical component of focal adhesions linking signaling between the extracellular matrix and the actin cytoskeleton. Knockout of MaTAR25 results in down-regulation of Tns1 leading to a reorganization of the actin cytoskeleton, and a reduction of focal adhesions and microvilli. We identify LINC01271 as the human ortholog of MaTAR25, and importantly, increased expression of LINC01271 is associated with poor patient prognosis and metastasis. Our findings demonstrate that LINC01271 represents a potential therapeutic target to alter breast cancer progression.

Emerging Raf inhibitors.

BACKGROUND: The Raf/MAPK kinase/extracellular-signal-regulated kinase pathway is often activated by genetic alterations in upstream signaling molecules. An integral component of this pathway, BRAF, is also activated by mutation, especially in melanoma and thyroid cancers. The Raf/MAPK kinase/extracellular-signal-regulated kinase pathway has profound effects on proliferative, apoptotic and differentiation pathways as well as the sensitivity and resistance to chemotherapeutic drugs. OBJECTIVES/METHODS: This review discusses targeting of Raf which could control abnormal proliferation in cancer and other proliferative diseases. The important roles that genetics plays in the response of patients to Raf inhibitors is also evaluated. We also discuss the rationales for approaches combining Raf inhibitors and chemotherapeutic drugs. RESULTS/CONCLUSIONS: Various Raf inhibitors have been developed and are being clinically used to treat patients with melanoma, thyroid, hepatocellular and renal cell cancers. Some 'Raf-kinase inhibitors' affect other kinases which are also expressed on malignant cells; yet, these inhibitors have proven useful in the therapy of certain cancer patients. Other more recently developed Raf specific inhibitors have shown success in the treatment of tumors bearing Raf mutations. The development of Raf inhibitors has significantly advanced cancer therapy in the past decade.

A Review of Chronic Leukoencephalopathy among Survivors of Childhood Cancer.

Currently, there are an estimated 400,000 long-term survivors of childhood cancer in the United States. Chronic leukoencephalopathy is a potential devastating late effect that can manifest as a range of neurological and neurocognitive sequelae. Survivors of the acute lymphocytic leukemia, central nervous system tumors, and stem cell transplant have frequently been exposed to cranial radiation, systemic and intrathecal chemotherapy, which places them at risk of developing chronic leukoencephalopathy. Defining leukoencephalopathy and its neuroimaging characteristics, the population of survivors at risk, its long-term consequences, and identifying prevention and intervention strategies can potentially mitigate the morbidity of these survivors. Better understanding of those at risk of leukoencephalopathy and its symptoms can lead to an improved quality of life for these cancer survivors.