Charting the metabolic biogeography of the colorectum in cancer: challenging the right sided versus left sided classification.

OBJECTIVE: Colorectal cancer (CRC) is conventionally classified as right sided, left sided, and rectal cancer. Clinicopathological, molecular features and risk factors do not change abruptly along the colorectum, and variations exist even within the refined subsites, which may contribute to inconsistencies in the identification of clinically relevant CRC biomarkers. We generated a CRC metabolome map to describe the association between metabolites, diagnostic and survival heterogeneity in cancers of different subsites of the colorectum. DESIGN: Utilizing 372 patient-matched tumor and normal mucosa tissues, liquid chromatography-mass spectrometry was applied to examine metabolomic profiles along seven subsites of the colorectum: cecum (n = 63), ascending colon (n = 44), transverse colon (n = 32), descending colon (n = 28), sigmoid colon (n = 75), rectosigmoid colon (n = 38), and rectum (n = 92). RESULTS: 39 and 70 significantly altered metabolites (including bile acids, lysophosphatidylcholines and lysophosphatidylethanolamines) among tumors and normal mucosa, respectively, showed inter-subsite metabolic heterogeneity between CRC subsites. Gradual changes in metabolite abundances with significantly linear trends from cecum to rectum were observed: 23 tumor-specific metabolites, 30 normal mucosa-specific metabolites, and 15 metabolites in both tumor and normal mucosa, had concentration gradients across the colorectum, and is disease status dependent. The metabolites that showed a linear trend included bile acids, amino acids, lysophosphatidylcholines, and lysophosphatidylethanolamines. Comparison of tumors to patient-matched normal mucosa revealed metabolite changes exclusive to each subsite, thereby further highlighting differences in cancer metabolism across the 7 subsites of the colorectum. Furthermore, metabolites associated with survival were different and unique to each subsite. Finally, an interactive and publicly accessible CRC metabolome database was designed to enable access and utilization of this rich data resource ( https://colorectal-cancer-metabolome.com/yale-university ). CONCLUSIONS: Gradual changes exist in metabolite abundances from the cecum to the rectum. The association between patient survival and distinct metabolites with anatomic subsite of the colorectum, reveals differences between cancers across the colorectum. These inter-subsite metabolic heterogeneities enrich the current understanding and substantiate previous studies that have challenged the conventional classification of right-sided, left-sided, and rectal cancers, by identifying specific metabolites that offer new biological insights into CRC subsite heterogeneity. The database designed in this study will enable researchers to delve into granular information on the CRC metabolome, which until now has not been available.

Surgical treatment of stage IV gastroenteropancreatic neuroendocrine carcinoma: Experience and outcomes in the United States.

BACKGROUND AND OBJECTIVES: Surgery for metastatic gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) has not been well-studied. This retrospective cohort study describes patients in the United States with stage IV GEP-NEC and their survival outcomes segregated by surgery. METHODS: Patients diagnosed with stage IV GEP-NEC from 2004 to 2017 in the National Cancer Database were categorized into three groups: no surgery, primary site or metastatic site ("single-site") surgery, and primary site and metastatic site ("multisite") surgery. Factors associated with surgical treatment were identified, and risk-adjusted overall survival of each group was compared. RESULTS: Of 4171 patients included, 958 (23.0%) underwent single-site surgery and 374 (9.0%) underwent multisite surgery. The strongest predictor of surgery was primary tumor type. Compared with no surgery, the risk-adjusted mortality reduction associated with single-site surgery ranged from 63% for small bowel (HR = 0.37, 0.23-0.58, p < 0.001) NEC to 30% for colon and appendix NEC (HR = 0.70, 0.61-0.80, p < 0.001), while the mortality reduction associated with multisite surgery ranged from 77% for pancreas NEC (HR = 0.23, 0.17-0.33, p < 0.001) to 48% for colon and appendix NEC (HR = 0.52, 0.44-0.63, p < 0.001). CONCLUSIONS: We observed an association between extent of surgical intervention and overall survival for patients with stage IV GEP-NEC. Surgical resection should be further investigated as a treatment option for highly-selected patients with this aggressive disease.

Role of colectomy in the management of appendiceal tumors: a retrospective cohort study.

BACKGROUND: Appendiceal tumors represent a range of histologies that vary in behavior. Recommendations for treatment with appendectomy versus right hemicolectomy (RHC) for different tumor types are evolving and sometimes conflicting. This study sought to characterize variation in the United States around surgical treatment of major appendiceal tumor types over time and describe differences in outcomes based on procedure. METHODS: Patients diagnosed with appendiceal goblet cell adenocarcinoma (GCA), mucinous adenocarcinoma, neuroendocrine neoplasm (NEN), or non-mucinous adenocarcinoma from 2004-2017 were identified in the National Cancer Database. Trends in RHC over time and predictors of RHC were identified. Surgical outcomes for each histologic type and stage were compared. RESULTS: Of 18,216 patients, 11% had GCAs, 34% mucinous adenocarcinoma, 31% NENs, and 24% non-mucinous adenocarcinoma. Rate of RHC for NEN decreased from 68% in 2004 to 40% in 2017 (p = 0.008) but remained constant around 60-75% for other tumor types. Higher stage was associated with increased odds of RHC for all tumor types. RHC was associated with higher rate of unplanned readmission (5% vs. 3%, p < 0.001) and longer postoperative hospital stay (median 5 days vs. 3 days, p < 0.001). On risk-adjusted analysis, RHC was significantly associated with increased survival versus appendectomy for stage 2 disease of all tumor types (HRs 0.43 to 0.63) and for stage 1 non-mucinous adenocarcinoma (HR = 0.56). CONCLUSIONS: Most patients with appendiceal tumors undergo RHC, which is associated with increased readmission, longer length of stay, and improved survival for stage 2 disease of all types. RHC should be offered selectively for appendiceal tumors.

CD56+ immune cell infiltration and MICA are decreased in breast lobules with fibrocystic changes.

PURPOSE: While the role of natural killer (NK) cells in breast cancer therapy has been investigated, little information is known about NK cell function and presence in nonmalignant and premalignant breast tissue. Here, we investigate and quantify NK cell marker CD56 and activating ligand MICA in breast tissue with benign breast disease. METHODS: Serial tissue sections from 88 subjects, 44 with benign breast disease (BBD) who remained cancer-free, and 44 with BBD who later developed cancer, were stained with H&E, anti-MICA, and anti-CD56. Up to ten representative lobules were identified on each section. Using digital image analysis, MICA and CD56 densities were determined for each lobule, reported as percent of pixels in the lobule that registered as stained by each antibody. Analyses were performed on a per-subject and per-lobule basis. RESULTS: Per-subject multivariate analyses showed associations of CD56 and MICA with age: CD56 was increased in older subjects (p = 0.03), while MICA was increased in younger subjects (p = 0.005). Per-lobule analyses showed that CD56 and MICA levels were both decreased in lobules with fibrocystic change, with median levels of CD56 and MICA staining, respectively, at 0.31 and 7.0% in fibrocystic lobules compared to 0.76 and 12.2% in lobules without fibrocystic change (p < 0.001 for each). Among fibrocystic lobules, proliferative/atypical lobules showed significantly lower expression compared to nonproliferative lobules for MICA (p = 0.02) but not for CD56 (p = 0.80). CONCLUSION: Levels of CD56+ NK cells and activating ligand MICA were decreased in breast lobules with fibrocystic change, and MICA levels showed a significant stepwise decrease with increasing histopathologic abnormality. MICA levels were also significantly decreased in older subjects, who generally have higher risk of developing cancer. These findings advance a model in which MICA promotes cytotoxic activity in CD56+ NK cells to protect against tumorigenesis in breast lobules, and suggest further research is warranted.

Precision Oncology in Gastrointestinal and Colorectal Cancer Surgery.

Precision medicine is used to treat gastrointestinal malignancies including esophageal, gastric, small bowel, colorectal, and pancreatic cancers. Cutting-edge assays to detect and treat these cancers are active areas of research and will soon become standard of care. Colorectal cancer is a prime example of precision oncology as disease site is no longer the final determinate of treatment. Here, the authors describe how leveraging an understanding of tumor biology translates to individualized patient care using evidence-based practices.

Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US.

Importance: While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown. Objective: To describe patient characteristics, practice patterns, and risk factors concerning EOL-initiated (EOL-I) immunotherapy over time. Design, Setting, and Participants: Retrospective cohort study using a US national clinical database of patients with metastatic melanoma, non-small cell lung cancer (NSCLC), or kidney cell carcinoma (KCC) diagnosed after US Food and Drug Administration approval of immune checkpoint inhibitors for the treatment of each disease through December 2019. Mean follow-up was 13.7 months. Data analysis was performed from December 2022 to May 2023. Exposures: Age, sex, race and ethnicity, insurance, location, facility type, hospital volume, Charlson-Deyo Comorbidity Index, and location of metastases. Main Outcomes and Measures: Main outcomes were EOL-I immunotherapy, defined as immunotherapy initiated within 1 month of death, and characteristics of the cohort receiving EOL-I immunotherapy and factors associated with its use. Results: Overall, data for 242 371 patients were analyzed. The study included 20 415 patients with stage IV melanoma, 197 331 patients with stage IV NSCLC, and 24 625 patients with stage IV KCC. Mean (SD) age was 67.9 (11.4) years, 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. The percentage of patients who received EOL-I immunotherapy increased over time for all cancers. More than 1 in 14 immunotherapy treatments in 2019 were initiated within 1 month of death. Risk-adjusted patients with 3 or more organs involved in metastatic disease were 3.8-fold more likely (95% CI, 3.1-4.7; P < .001) to die within 1 month of immunotherapy initiation than those with lymph node involvement only. Treatment at an academic or high-volume center rather than a nonacademic or very low-volume center was associated with a 31% (odds ratio, 0.69; 95% CI, 0.65-0.74; P < .001) and 30% (odds ratio, 0.70; 95% CI, 0.65-0.76; P < .001) decrease in odds of death within a month of initiating immunotherapy, respectively. Conclusions and Relevance: Findings of this cohort study show that the initiation of immunotherapy at the EOL is increasing over time. Patients with higher metastatic burden and who were treated at nonacademic or low-volume facilities had higher odds of receiving EOL-I immunotherapy. Tracking EOL-I immunotherapy can offer insights into national prescribing patterns and serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.

Immunotherapy utilization in stage IIIA melanoma: less may be more.

Background: Immunotherapy agents are approved for adjuvant treatment of stage III melanoma; however, evidence for survival benefit in early stage III disease is lacking. Current guidelines for adjuvant immunotherapy utilization in stage IIIA rely on clinician judgment, creating an opportunity for significant variation in prescribing patterns. This study aimed to characterize current immunotherapy practice variations and to compare patient outcomes for different prescribing practices in stage IIIA melanoma. Study design: Patients with melanoma diagnosed from 2015-2019 that met American Joint Committee on Cancer 8th edition criteria for stage IIIA and underwent resection were identified in the National Cancer Database. Multiple imputation by chained equations replaced missing values. Factors associated with receipt of adjuvant immunotherapy were identified. Multivariable Cox proportional hazards regression compared overall survival across groups. Results: Of 4,432 patients included in the study, 34% received adjuvant immunotherapy. Patients had lower risk-adjusted odds of receiving immunotherapy if they were treated at an academic center (OR=0.48, 95%CI=0.33-0.72, p<0.001 vs. community facility) or at a high-volume center (OR=0.69, 0.56-0.84, p<0.001 vs. low-volume). Immunotherapy receipt was not associated with risk-adjusted survival (p=0.095). Moreover, patients treated at high-volume centers experienced longer overall risk-adjusted survival than those treated at low-volume centers (HR=0.52, 0.29-0.93, p=0.030). Risk-adjusted survival trended toward being longer at academic centers than at community centers, but the difference was not statistically significant. Conclusion: Academic and high-volume centers utilize significantly less adjuvant immunotherapy in stage IIIA melanoma than community and low-volume centers without compromise in overall survival. These findings suggest that this population may benefit from more judicious immunotherapy utilization.

Pro-Apoptotic and Anti-Cancer Activity of the Vernonanthura Nudiflora Hydroethanolic Extract.

The mitochondrial voltage-dependent anion channel 1 (VDAC1) protein is involved in several essential cancer hallmarks, including energy and metabolism reprogramming and apoptotic cell death evasion. In this study, we demonstrated the ability of hydroethanolic extracts from three different plants, Vernonanthura nudiflora (Vern), Baccharis trimera (Bac), and Plantago major (Pla), to induce cell death. We focused on the most active Vern extract. We demonstrated that it activates multiple pathways that lead to impaired cell energy and metabolism homeostasis, elevated ROS production, increased intracellular Ca2+, and mitochondria-mediated apoptosis. The massive cell death generated by this plant extract's active compounds involves the induction of VDAC1 overexpression and oligomerization and, thereby, apoptosis. Gas chromatography of the hydroethanolic plant extract identified dozens of compounds, including phytol and ethyl linoleate, with the former producing similar effects as the Vern hydroethanolic extract but at 10-fold higher concentrations than those found in the extract. In a xenograft glioblastoma mouse model, both the Vern extract and phytol strongly inhibited tumor growth and cell proliferation and induced massive tumor cell death, including of cancer stem cells, inhibiting angiogenesis and modulating the tumor microenvironment. Taken together, the multiple effects of Vern extract make it a promising potential cancer therapeutic.

Hepatopancreatobiliary malignancies: time to treatment matters.

Background: Initiation of oncologic care is often delayed, yet little is known about delays in hepatopancreatobiliary (HPB) cancers or their impact. This retrospective cohort study describes trends in time to treatment initiation (TTI), assesses the association between TTI and survival, and identifies predictors of TTI in HPB cancers. Methods: The National Cancer Database was queried for patients with cancers of the pancreas, liver, and bile ducts between 2004 and 2017. Kaplan-Meier survival analysis and Cox regression were used to investigate the association between TTI and overall survival for each cancer type and stage. Multivariable regression identified factors associated with longer TTI. Results: Of 318,931 patients with HPB cancers, median TTI was 31 days. Longer TTI was associated with increased mortality in patients with stages I-III extrahepatic bile duct (EHBD) cancer and stages I-II pancreatic adenocarcinoma. Patients treated within 3-30, 31-60, and 61-90 days had median survivals of 51.5, 34.9, and 25.4 months (log-rank P<0.001), respectively, for stage I EHBD cancer, and 18.8, 16.6, and 15.2 months for stage I pancreatic cancer, respectively (P<0.001). Factors associated with increased TTI included stage I disease (+13.7 days vs. stage IV, P<0.001), treatment with radiation only (ß=+13.9 days, P<0.001), Black race (+4.6 days, P<0.001) and Hispanic ethnicity (+4.3 days, P<0.001). Conclusions: Some HPB cancer patients with longer time to definitive care experienced higher mortality than patients treated expeditiously, particularly in non-metastatic EHBD cancer. Black and Hispanic patients are at risk for delayed treatment. Further research into these associations is needed.

Impact of COVID-19 on the gastrointestinal surgical oncology patient population.

Background: The onset of the COVID-19 pandemic led to substantial alterations in healthcare delivery and access. In this study, we aimed to evaluate the impact of COVID-19 on the presentation and surgical care of patients with gastrointestinal (GI) cancers. Methods: All patients who underwent GI cancer surgery at a large, tertiary referral center between March 15, 2019 and March 15, 2021 were included. March 15, 2020 was considered the start of the COVID-19 pandemic. Changes in patient, tumor, and treatment characteristics before the pandemic compared to during the pandemic were evaluated. Results: Of 522 patients that met study criteria, 252 (48.3%) were treated before the COVID-19 pandemic. During the first COVID-19 wave, weekly volume of GI cancer cases was one-third lower than baseline (p = 0.041); during the second wave, case volume remained at baseline levels (p = 0.519). There were no demographic or tumor characteristic differences between patients receiving GI cancer surgery before versus during COVID-19 (p > 0.05 for all), and no difference in rate of emergency surgery (p > 0.9). Patients were more likely to receive preoperative chemotherapy during the first six months of the pandemic compared to the subsequent six months (35.6% vs. 15.5%, p < 0.001). Telemedicine was rapidly adopted at the start of the pandemic, rising from 0% to 47% of GI surgical oncology visits within two months. Conclusions: The COVID-19 pandemic caused an initial disruption to the surgical care of GI cancers, but did not compromise stage at presentation. Preoperative chemotherapy and telemedicine were utilized to mitigate the impact of a high COVID-19 burden on cancer care.

Evaluation of Racial Disparities in Quality of Care for Patients With Gastrointestinal Tract Cancer Treated With Surgery.

Importance: Racial disparities have been demonstrated in many facets of health care, but a comprehensive understanding of who is most at risk for substandard surgical care of gastrointestinal tract cancers is lacking. Objective: To examine racial disparities in quality of care of patients with gastrointestinal tract cancers. Design, Setting, and Participants: This retrospective cohort study of patients with gastrointestinal tract cancer included the US population as captured in the National Cancer Database with a diagnosis from January 1, 2004, to December 31, 2017. Participants included 565 124 adults who underwent surgical resection of gastrointestinal tract cancers. Data were analyzed from June 21 to December 23, 2021. Exposures: Race and site of cancer. Main Outcomes and Measures: Oncologic standard of care, as defined by negative resection margin, adequate lymphadenectomy, and receipt of indicated adjuvant chemotherapy and/or radiotherapy. Results: Among 565 124 adult patients who underwent surgical resection of a gastrointestinal tract cancer, 10.9% were Black patients, 83.5% were White patients, 54.7% were men, and 50.7% had Medicare coverage. The most common age range at diagnosis was 60 to 69 years (28.5%). Longer median survival was associated with negative resection margins (87.3 [IQR, 28.5-161.9] months vs 22.9 [IQR, 8.8-69.2] months; P < .001) and adequate lymphadenectomies (80.7 [IQR, 25.6 to not reached] months vs 57.6 [IQR, 17.7-153.8] months; P < .001). After adjustment for covariates, Black patients were less likely than White patients to have negative surgical margins overall (odds ratio [OR], 0.96 [95% CI, 0.93-0.98]) and after esophagectomy (OR, 0.71 [95% CI, 0.58-0.87]), proctectomy (OR, 0.71 [95% CI, 0.66-0.76]), and biliary resection (OR, 0.75 [95% CI, 0.61-0.91]). Black patients were also less likely to have adequate lymphadenectomy overall (OR, 0.89 [95% CI, 0.87-0.91]) and after colectomy (OR, 0.89 [95% CI, 0.87-0.92]), esophagectomy (OR, 0.72 [95% CI, 0.63-0.83]), pancreatectomy (OR, 0.90 [95% CI, 0.85-0.96]), proctectomy (OR, 0.93 [95% CI, 0.88-0.98]), proctocolectomy (OR, 0.90 [95% CI, 0.81-1.00]), and enterectomy (OR, 0.71 [95% CI, 0.65-0.79]). Black patients were more likely than White patients not to be recommended for chemotherapy (OR, 1.15 [95% CI, 1.10-1.21]) and radiotherapy (OR, 1.49 [95% CI, 1.35-1.64]) because of comorbidities and more likely not to receive recommended chemotherapy (OR, 1.68 [95% CI, 1.55-1.82]) and radiotherapy (OR, 2.18 [95% CI, 1.97-2.41]) for unknown reasons. Conclusions and Relevance: These findings suggest that there are significant racial disparities in surgical care of gastrointestinal tract cancers. Black patients are less likely than White patients to receive standard of care with respect to negative surgical margins, adequate lymphadenectomies, and use of adjuvant therapies. Both system- and physician-level reforms are needed to eradicate these disparities in health care.

Local and Distant Recurrence in Resected Sacral Chordomas: A Systematic Review and Pooled Cohort Analysis.

STUDY DESIGN: Systematic review. OBJECTIVES: Sacral chordomas are rare, primary tumors of the spine, best treated with en bloc resection. The purpose of this study was to assess the literature for resected sacral chordoma and to quantify the prevalence of, risk factors for, and treatment outcomes of local and distant recurrence therein. METHODS: We searched 5 online databases from January 1980 to May 2016 to find articles that report survival, recurrence outcomes, and/or prognostic factors for the resected sacral chordoma patient population. Characteristics and clinical outcomes of the pooled cohort are reported. Fisher exact tests, unpaired t tests, and one-way analysis of variance were used to investigate patient- and treatment-associated prognostic factors for local and distant recurrence. Survival analyses were performed for time to local recurrence and death. The protocol's PROSPERO ID is CRD42015024384. RESULTS: Fifty-seven studies, with 1235 unique sacral chordoma patients, were included in this review. Local and distant recurrence occurred in 42.6% and 22.4% of patients with adequate follow-up, respectively. Kaplan-Meier overall median survival for patients with and without recurrence were 98 and 209 months after surgery, respectively. Wide surgical margin was associated with a lower rate of local recurrence; and wide surgical margin, female sex, and patient age ≥65 years were associated with lower rates of distant recurrence. CONCLUSIONS: While surgical margin remains the most significant prognostic factor for local and distant recurrence, combined surgical approach may be associated with local recurrence. Male sex and age <65 years may be associated with distant recurrence. Patients with risk factors for recurrence should undergo close monitoring to maximize survival.

Predicting survival for metastatic spine disease: a comparison of nine scoring systems.

BACKGROUND CONTEXT: Despite advances in spinal oncology, research in patient-based prognostic calculators for metastatic spine disease is lacking. Much of the literature in this area investigates the general predictive accuracy of scoring systems in heterogeneous populations, with few studies considering the accuracy of scoring systems based on patient specifics such as type of primary tumor. PURPOSE: The aim of the present study was to compare the ability of widespread scoring systems to estimate both overall survival at various time points and tumor-specific survival for patients undergoing surgical treatment for metastatic spine disease in order to provide surgeons with information to determine the most appropriate scoring system for a specific patient and timeline. STUDY DESIGN: This is a retrospective study. PATIENT SAMPLE: Patients who underwent surgical resection for metastatic spine disease at a single institution were included. OUTCOME MEASURES: Areas under the receiver operating characteristic curves were generated from comparison of actual survival of patients and survival as predicted by application of prevalent scoring systems. METHODS: A preoperative score for all 176 patients was retrospectively calculated utilizing the Skeletal Oncology Research Group (SORG) Classic Scoring Algorithm, SORG Nomogram, original Tokuhashi, revised Tokuhashi, Tomita, original Bauer, modified Bauer, Katagiri, and van der Linden scoring systems. Univariate and multivariate Cox proportional hazard models were constructed to assess the association of patient variables with survival. Receiver operating characteristic analysis modeling was utilized to quantify the accuracy of each test at different end points and for different primary tumor subgroups. No funds were received in support of this work. The authors have no conflicts of interest to disclose. RESULTS: Among all patients surgically treated for metastatic spine disease, the SORG Nomogram demonstrated the highest accuracy at predicting 30-day (area under the curve [AUC] 0.81) and 90-day (AUC 0.70) survival after surgery. The original Tokuhashi was the most accurate at predicting 365-day survival (AUC 0.78). Multivariate analysis demonstrated multiple preoperative factors strongly associated with survival after surgery for spinal metastasis. The accuracy of each scoring system in determining survival probability relative to primary tumor etiology and time elapsed since surgery was assessed. CONCLUSIONS: Among the nine scoring systems assessed, the present study determined the most accurate scoring system for short-term (30-day), intermediate (90-day), and long-term (365-day) survival, relative to primary tumor etiology. The findings of the present study may be utilized by surgeons in a personalized effort to select the most appropriate scoring system for a given patient.