Risk of Subsequent Primary Cancers in Thyroid Cancer Survivors according to the Dose of Levothyroxine: A Nationwide Cohort Study.

BACKGRUOUND: Current research has not investigated the effect of thyroid-stimulating hormone suppression therapy with levothyroxine on the risk for developing subsequent primary cancers (SPCs). This study aimed to investigate the association between levothyroxine dosage and the risk for SPCs in thyroid cancer patients. METHODS: We conducted a nationwide population-based retrospective cohort study form Korean National Health Insurance database. This cohort included 342,920 thyroid cancer patients between 2004 and 2018. Patients were divided into the non-levothyroxine and the levothyroxine groups, the latter consisting of four dosage subgroups according to quartiles. Cox proportional hazard models were performed to evaluate the risk for SPCs by adjusting for variables including cumulative doses of radioactive iodine (RAI) therapy. RESULTS: A total of 17,410 SPC cases were observed over a median 7.3 years of follow-up. The high-dose levothyroxine subgroups (Q3 and Q4) had a higher risk for SPC (adjusted hazard ratio [HR], 1.14 and 1.27; 95% confidence interval [CI], 1.05-1.24 and 1.17- 1.37; respectively) compared to the non-levothyroxine group. In particular, the adjusted HR of stomach (1.31), colorectal (1.60), liver and biliary tract (1.95), and pancreatic (2.48) cancers were increased in the Q4 subgroup. We consistently observed a positive association between high levothyroxine dosage per body weight and risk of SPCs, even after adjusting for various confounding variables. Moreover, similar results were identified in the stratified analyses according to thyroidectomy type and RAI therapy, as well as in a subgroup analysis of patients with good adherence. CONCLUSION: High-dose levothyroxine use was associated with increased risk of SPCs among thyroid cancer patients regardless of RAI therapy.

Improved guideline compliance and textbook oncologic outcomes among patients undergoing multimodal treatment and minimally invasive surgery for locally advanced gastric cancer.

BACKGROUND: Although receipt of neoadjuvant chemotherapy has been identified to improve unfavorable survival outcomes among patients with locally advanced gastric cancer (LAGC), several randomized controlled trials have not demonstrated a difference in oncological outcomes/overall survival (OS) among patients undergoing minimally invasive surgery (MIS) versus open gastrectomy. This study aimed to investigate National Comprehensive Cancer Network (NCCN) guideline adherence and textbook oncological outcome (TOO) among patients undergoing MIS versus open surgery for LAGC. METHODS: In this cross-sectional study, patients with stage II/III LAGC (cT2-T4N0-3M0) who underwent curative-intent treatment between 2013 and 2019 were evaluated using the National Cancer Database. Multivariable analysis was performed to assess the association between surgical approach, NCCN guideline adherence, TOO, and OS. The study was registered on the International Standard Randomised Controlled Trial Number registry (registration number: ISRCTN53410429) and conducted according to the Strengthening The Reporting Of Cohort Studies in Surgery and Strengthening the Reporting of Observational Studies in Epidemiology guidelines. RESULTS: Among 13,885 patients, median age at diagnosis was 68 years (IQR, 59-76); most patients were male (n = 9887, 71.2%) and identified as White (n = 10,295, 74.1%). Patients who underwent MIS (n = 4692, 33.8%) had improved NCCN guideline adherence and TOO compared with patients who underwent open surgery (51.3% vs 43.5% and 36.7% vs 27.3%, respectively; both P < .001). Adherence to NCCN guidelines and likelihood to achieve TOO increased from 2013 to 2019 (35.6% vs 50.9% and 31.4% vs 46.4%, respectively; both P < .001). Moreover, improved median OS was observed among patients with NCCN guideline adherence and TOO undergoing MIS versus open surgery (57.3 vs 49.8 months [P = .041] and 68.4 vs 60.6 months [P = .025], respectively). CONCLUSIONS: An overall increase in guideline-adherent treatment and achievement of TOO among patients with LAGC undergoing multimodal and curative-intent treatment in the United States was observed. Adoption of minimally invasive gastrectomy may result in improved short- and long-term outcomes.

Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma.

Importance: Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma. Objective: To assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma. Design, Setting, and Participants: This is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least 1 tumor marker measured at MD Anderson between March 2016 and May 2023. Data were analyzed from January to December 2023. Main Outcomes and Measures: Association of serum tumor markers with survival in patients with appendiceal adenocarcinoma. Cox proportional hazards regression analyses were also performed to assess associations between clinical factors (serum tumor marker levels, demographics, and patient and disease characteristics) and patient outcomes (overall survival). Results: A total of 1338 patients with appendiceal adenocarcinoma were included, with a median (range) age at diagnosis of 56.5 (22.3-89.6) years. The majority of the patients had metastatic disease (1080 patients [80.7%]). CEA was elevated in 742 of the patients tested (56%), while CA19-9 and CA125 were elevated in 381 patients (34%) and 312 patients (27%), respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; elevated vs normal was 81% vs 95% for CEA (hazard ratio [HR], 4.0; 95% CI, 2.9-5.6), 84% vs 92% for CA19-9 (HR, 2.2; 95% CI, 1.4-3.4), and 69% vs 93% for CA125 (HR, 4.6; 95% CI, 2.7-7.8) (P < .001 for all). Quantitative evaluation of tumor markers was associated with outcomes. Patients with highly elevated (top 10th percentile) CEA, CA19-9, or CA125 had markedly worse survival, with 5-year survival rates of 59% for CEA (HR, 9.8; 95% CI, 5.3-18.0), 64% for CA19-9 (HR, 6.0; 95% CI, 3.0-11.7), and 57% for CA125 (HR, 7.6; 95% CI, 3.5-16.5) (P < .001 for all). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease, elevated CEA, CA19-9, or CA125 were all still associated worse survival (HR for CEA, 3.4; 95% CI, 2.5-4.8; P < .001; HR for CA19-9, 1.8; 95% CI, 1.2-2.7; P = .002; and HR for CA125, 3.9; 95% CI, 2.4-6.4; P < .001). Interestingly, tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high-grade tumors relative to low-grade tumors (mean value, 18.3 vs 15.0; difference, 3.3; 95% CI, 0.9-3.7; P < .001). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with an 11-fold increased risk of death in patients with all 3 tumor markers elevated relative to those with none elevated. Somatic mutations in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9. Conclusions and Relevance: In this retrospective study of serum tumor markers in patients with appendiceal adenocarcinoma, CEA, CA19-9, and CA125 were associated with overall survival in appendiceal adenocarcinoma. Given their value, all 3 biomarkers should be included in the initial workup of patients with a diagnosis of appendiceal adenocarcinoma.

Early morning immune checkpoint blockade and overall survival of patients with metastatic cancer: An In-depth chronotherapeutic study.

INTRODUCTION: Recent retrospective studies suggest potential large patient's benefit through proper timing of immune checkpoint blockers (ICB). The association between ICB treatment timing and patient survival, neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex. METHODS: A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied. RESULTS: 361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICB were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p = 0.0024; HR 1.56 [1.17-2.1], p = 0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p = 0.011; PS2-3 patients, HR=0.50 [0.25-0.97], p = 0.042). Morning PS0-1 patients displayed increased OS (median 36.7 vs 21.3 months, p = 0.023), partial/complete response rate (58% vs 41%, p = 0.027), and grade1-3 toxicities (49% vs 34%, p = 0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48-14:23], and in early morning was equal to 4.8 ([2.3-10.1], p = 0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p < 0.001 vs 0.4). CONCLUSIONS: Early morning ICB infusion was associated with increased OS, response, and toxicities in patients with PS0-1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.

Risk model-based management for second primary lung cancer among lung cancer survivors through a validated risk prediction model.

BACKGROUND: Recent therapeutic advances and screening technologies have improved survival among patients with lung cancer, who are now at high risk of developing second primary lung cancer (SPLC). Recently, an SPLC risk-prediction model (called SPLC-RAT) was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. The predictive performance of SPLC-RAT was evaluated in a hospital-based cohort of lung cancer survivors. METHODS: The authors analyzed data from 8448 ever-smoking patients diagnosed with initial primary lung cancer (IPLC) in 1997-2006 at Mayo Clinic, with each patient followed for SPLC through 2018. The predictive performance of SPLC-RAT and further explored the potential of improving SPLC detection through risk model-based surveillance using SPLC-RAT versus existing clinical surveillance guidelines. RESULTS: Of 8448 IPLC patients, 483 (5.7%) developed SPLC over 26,470 person-years. The application of SPLC-RAT showed high discrimination area under the receiver operating characteristics curve: 0.81). When the cohort was stratified by a 10-year risk threshold of ≥5.6% (i.e., 80th percentile from the SPLC-RAT development cohort), the observed SPLC incidence was significantly elevated in the high-risk versus low-risk subgroup (13.1% vs. 1.1%, p < 1 × 10-6 ). The risk-based surveillance through SPLC-RAT (≥5.6% threshold) outperformed the National Comprehensive Cancer Network guidelines with higher sensitivity (86.4% vs. 79.4%) and specificity (38.9% vs. 30.4%) and required 20% fewer computed tomography follow-ups needed to detect one SPLC (162 vs. 202). CONCLUSION: In a large, hospital-based cohort, the authors validated the predictive performance of SPLC-RAT in identifying high-risk survivors of SPLC and showed its potential to improve SPLC detection through risk-based surveillance. PLAIN LANGUAGE SUMMARY: Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC). However, no evidence-based guidelines for SPLC surveillance are available for lung cancer survivors. Recently, an SPLC risk-prediction model was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. Using a large, real-world cohort of lung cancer survivors, we showed the high predictive accuracy and risk-stratification ability of the SPLC risk-prediction model. Furthermore, we demonstrated the potential to enhance efficiency in detecting SPLC using risk model-based surveillance strategies compared to the existing consensus-based clinical guidelines, including the National Comprehensive Cancer Network.

Ganoderma lucidum spore oil synergistically enhances the function of cyclophosphamide in the prevention of breast cancer metastasis.

BACKGROUND: Ganoderma lucidum ( G . lucidum ) is a traditional Chinese herbal medicine that has shown potential as an alternative adjuvant therapy for cancer patients. However, the mechanisms and adjuvant therapeutic effects of G . lucidum in cancer treatment remain unclear. METHODS: In this work, G . lucidum spore oil (GanoOil), a newly developed oily G . lucidum spore extract was used to investigate the mechanisms and adjuvant therapeutic effects of GanoOil in conjunction with the chemotherapeutic drug cyclophosphamide (CTX) for preventing breast cancer metastasis. RESULTS: In the model of lung metastasis, orally administered GanoOil increased the population of CD8 + T cells and interleukin (IL)-6 cytokine levels in mouse blood, whereas also enhancing the activity of natural killer cells in the spleen. Furthermore, the combination of GanoOil and CTX effectively suppressed the lung metastasis of circulating breast cancer cells, alleviated CTX-induced weight loss, and reduced the ratio of lung and spleen weight to body weight in mice. Moreover, high concentrations of GanoOil exhibited no significant toxicity or side effects in both in vitro and in vivo experiments. CONCLUSION: In conclusion, GanoOil is a safe drug that can enhance immune activity in mice to achieve therapeutic effects on cancer, and can also synergistically inhibit tumor metastasis with CTX.

Re-imagining metastatic breast cancer care delivery: a patient-partnered qualitative study.

PURPOSE: While significant progress in metastatic breast cancer (MBC) treatment has prolonged survival and improved prognosis, there remain substantial gaps in providing patient-centered supportive care. The specific care delivery needs for metastatic cancer differ from that of early-stage cancer due to the incurable nature and lifelong duration of the condition. The objective of this study was to assess how patients living with MBC would re-imagine cancer care delivery. METHODS: This qualitative study was conducted in partnership with patient-led organizations Guiding Researchers and Advocates to Scientific Partnerships (GRASP) and Project Life, a nonprofit, online wellness community founded by patients with MBC for patients living with MBC. Virtual semi-structured interviews (n = 36) were conducted with Project Life members purposively sampled from the groups' overall membership. The interview guide contained items surrounding patients' lived experiences of MBC, greatest unmet needs related to care, and perspectives on virtual wellness community involvement. Interviews were coded using two-stage deductive and inductive analysis. RESULTS: Three major themes for re-imagining cancer care delivery were identified, including holistic care, information needs, and conceptual shifts. Within these several subthemes emerged with patients re-imagining referrals to non-oncological services, caregiver support, acceptance of integrative medicine, streamlined clinical trial enrollment, curated quality patient resources, MBC-specific terminology and approaches, long-term life and goal-of-care planning, and patient-centered voice throughout. CONCLUSION: People living with metastatic cancers have specific supportive care needs. These findings highlight patient-driven areas for re-imagination that are most salient for individuals with MBC.

Mode of Detection of Second Breast Cancers in Patients Undergoing Surveillance After Treatment of Ductal Carcinoma in Situ.

BACKGROUND: For patients undergoing posttreatment surveillance after ductal carcinoma in situ (DCIS), the NCCN Guidelines for Breast Cancer recommend annual breast imaging and physical examination every 6 to 12 months for 5 years, and then annually. The aim of our study was to evaluate the modes of detection (imaging, patient reported, or physical examination) of second cancers in a cohort of patients undergoing surveillance after primary DCIS treatment to better inform surveillance recommendations. METHODS: We performed a retrospective cohort study of patients with DCIS treated between January 1, 2008, and December 31, 2011, within a large integrated health care system. Information on patient demographics, index DCIS treatment, tumor characteristics, and mode of detection of second breast cancer was obtained from the electronic health record or chart review. RESULTS: Our study cohort consisted of 1,550 women, with a median age of 59 years at diagnosis. Surgical treatment of DCIS included lumpectomy (75.0%; n=1,162), unilateral mastectomy (21.1%; n=327), or bilateral mastectomy (3.9%; n=61), with or without sentinel lymph node biopsy. Additionally, 44.4% (n=688) and 28.3% (n=438) received radiation and endocrine therapies, respectively. Median follow-up was 10 years, during which 179 (11.5%) women were diagnosed with a second breast cancer. Of the second cancers, 43.0% (n=77) were ipsilateral and 54.8% (n=98) contralateral, and 2.2% (n=4) presented with distant metastases; 61.5% (n=110) were invasive, 36.3% (n=65) were DCIS, and 2.2% (n=4) were Paget's disease. Second breast cancers were imaging-detected in 74.3% (n=133) of cases, patient-detected in 20.1% (n=36), physician-detected in 2.2% (n=4), and detected incidentally on imaging or pathology from procedures unrelated to oncologic care in 3.4% (n=6). CONCLUSIONS: In our cohort of patients undergoing surveillance following diagnosis and treatment of DCIS, 2% of second breast cancers were detected by a clinical breast examination. This suggests that survivorship care should prioritize mammography and patient education regarding breast self-examination and symptoms that warrant evaluation to detect second breast cancers.

Association of metabolic syndrome conditions with risk of second primary uterine cancer in breast cancer survivors.

PURPOSE: Uterine cancer risk is high in breast cancer survivors. Although breast cancer and uterine cancer share some common epidemiological risk factors, association of metabolic syndrome with incident uterine cancer in breast cancer survivors is under-studied. We evaluated the association of metabolic syndrome conditions with second primary uterine cancer in breast cancer survivors. METHODS: In this retrospective cohort study, 37,303 breast cancer patients diagnosed between 2008 and 2020 at Kaiser Permanente Southern California, an integrated healthcare system, were included. Data on cancer-related variables, sociodemographic, and clinical variables were extracted from KPSC's Surveillance, Epidemiology, and End Results (SEER)-affiliated cancer registry and electronic health records, as appropriate. Patients were followed from breast cancer diagnosis until 12/31/2021 for incident uterine cancer. Proportional hazards regression was used to report association [HR (95% CI)] between metabolic conditions and uterine cancer. RESULTS: More than half (53.1%) of the breast cancer survivors had 1-2 metabolic conditions; 19.4% had 3 + , while 27. 5% had no metabolic conditions. Median time to follow-up was 5.33 years and 185 (0.5%) patients developed second primary uterine cancer. Obesity was associated with an elevated uterine cancer risk in the adjusted model [HR (95% CI) 1.64 (1.20-2.25)]. Having 1-2 metabolic conditions (versus none) was not associated with increased uterine cancer risk [adjusted HR (95% CI) 1.24 (0.85-1.82)]; however, there was an increased uterine cancer risk with 3 + metabolic conditions [adjusted HR (95% CI) 1.82 (1.16-2.87)]. CONCLUSION: Although not statistically significant, we found a trend demonstrating greater uterine cancer risk by increasing numbers of metabolic syndrome conditions in breast cancer survivors.

Advances in radiation therapy for testicular seminoma.

PURPOSE: Novel techniques and advances in radiation therapy (RT) have been explored to treat testicular seminoma, a highly radiosensitive and curable histology. We evaluated the historical and current indications for radiation therapy (RT) in testicular seminoma. METHODS: A narrative literature review was performed. Studies of RT for testicular seminoma were included. Additionally, recent trials testing the use of combination or surgical therapies for clinical stage (CS) II were included. Search parameters included radiation therapy, testicular seminoma, surgery, and chemoradiation. Parameters and outcomes assessed were progression-free survival (PFS), overall survival (OS), acute toxicities, long-term sequelae, and rates of secondary malignancies. RESULTS: Practice defining and changing studies in the use or omission of radiation therapy for testicular seminoma were identified along with resultant changes in National Comprehensive Cancer Network (NCCN) and European guidelines. Recent trials in combined chemoradiation and upfront surgical approaches to CS II disease were reviewed. CONCLUSION: RT has historically been used as adjuvant treatment for CS I disease and is highly effective at treating CS II (A/B) testicular seminoma. The drive to maintain therapeutic efficacy and reduce acute and long-term side effects, namely secondary malignancies, is being tested using new radiation technologies, combined modality therapy in the form of chemoradiation and with upfront surgical approaches. Also, as guidelines now "strongly prefer" surveillance instead of adjuvant RT for CS I disease, the current CS II population comprises patients presenting with CS II disease ("de novo") and those who present with CSII after relapsing post orchiectomy for CS I ("relapsed"). Emerging evidence suggests that these two groups have different outcomes with respect to RT and chemoradiation. Consequently, future trials may need to sub-stratify according to these groups.

Euphorbia factor L1 suppresses breast cancer liver metastasis via DDR1-mediated immune infiltration.

Euphorbia factor L1 (EFL1), a lathyrane-type diterpenoid from the medicinal herb Euphorbia lathyris L., has been documented to possess various pharmacologic actives. However, the function of EFL1 on breast cancer is not clear. In this study, we explored the effect and mechanism of EFL1 on breast cancer liver metastasis. Female BALB/c mice were subjected to breast cancer-surgical hepatic implantation (SHI) to establish breast cancer liver metastasis model in vivo. At 10 days post-surgery, mice were administrated with EFL1 once daily for a total of 2 weeks. Serum AST and ALT activities, abdominal circumference, peritoneal fluid, tumor weight and volume were determined to assess liver and mesenteric re-metastasis of breast cancer. H&E staining was used to observe morphology changes in tumor, liver and small intestine tissues. ELISA was applied to observe inflammatory levels. Tumor DDR1 expression and immune infiltration were determined using western blotting, immunohistochemistry and flow cytometer methods. Our results showed that EFL1 administration improved liver function (AST and ALT activities), ascites, liver metastasis and mesenteric re-metastasis in SHI mice. Also, SHI-induced inflammatory cell infiltration and IL-1ß, IL-6, TNF-α generation in ascites were decreased by EFL1 treatment. Mechanism study revealed that EFL1 intervention enhanced the ratios of CD4+ and CD8+ and CD49b+(NK) T lymphocytes and decreased Treg cells through downregulating DDR1 in the tumor of SHI mice. Furthermore, overexpression of DDR1 abolished the anti-liver metastasis effect and pro-immune infiltration action of EFL1 in SHI mice. Together, our findings suggested that EFL1 protects against breast cancer liver metastasis in vivo by targeting DDR1-mediated immune infiltration.

Total neoadjuvant treatment to increase the clinical complete response rate for distal locally advanced rectal cancer (TESS): A study protocol of a prospective, open-label, multicenter, single-arm, phase 2 trial.

BACKGROUND: Standard treatment of locally advanced rectal cancer (LARC) was neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Patients treated with neoadjuvant chemotherapy were more likely to show higher tumor regression. The objective of this trial was to increase complete clinical rate (cCR) for LARC patients by optimizing tumor response, using TNT regimen as compared to conventional chemoradiotherapy. TESS, a prospective, open-label, multicenter, single-arm, phase 2 study, is underway. METHODS: Main inclusion criteria include cT3-4aNany or cT1-4aN+ rectal adenocarcinoma aged 18-70y; Eastern Cooperative Oncology Group (ECOG) performance 0-1; location ≤5 cm from anal verge. Ninety-eight patients will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplatin) before, during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease-free survival; locoregional recurrence-free survival; acute toxicity; surgical complications; long-term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment. DISCUSSION: The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.

Functional Magnetic Resonance Imaging in Cervical Cancer Diagnosis and Treatment.

Cervical Cancer is the fourth most common cancer in women worldwide. Treatment with chemoradiotherapy followed by brachytherapy achieves high local control, but recurrence with metastatic disease impacts survival. This highlights the need for predictive and prognostic biomarkers identifying populations at risk of poorer treatment response and survival. Magnetic resonance imaging (MRI) is routinely used in cervical cancer and is a potential source for biomarkers. Functional MRI (fMRI) can characterise tumour beyond anatomical MRI, which is limited to the assessment of morphology. This review summarises fMRI techniques used in cervical cancer and examines the role of fMRI parameters as predictive or prognostic biomarkers. Different techniques characterise different tumour factors, which helps to explain the variation in patient outcomes. These can impact simultaneously on outcomes, making biomarker identification challenging. Most studies are small, focussing on single MRI techniques, which raises the need to investigate combined fMRI approaches for a more holistic characterisation of tumour.

A 6-Week Program to Strengthen Resiliency Among Women With Metastatic Cancer: A Randomized Clinical Trial.

PURPOSE: The objective of this study was to evaluate the effect of an intervention (Growing Resilience And CouragE; GRACE) on spiritual well-being, quality of life, and general well-being in women with metastatic cancers reporting existential or spiritual distress. PATIENTS AND METHODS: Prospective, randomized, wait-list control clinical trial. Women with metastatic cancer experiencing existential or spiritual concerns were randomized to GRACE or waitlist control. Survey data were collected at baseline, end of program, and 1-month follow-up. Participants included English-speaking women, 18 or older, with metastatic cancer, existential or spiritual concerns, and reasonable medical stability. Eighty-one women were assessed for eligibility; 10 were excluded (not meeting exclusion criteria, refusal to participate, and death). The primary outcome was spiritual well-being measured pre- and post-program. Secondary measures assessed quality of life, anxiety, depression, hopelessness, and loneliness. RESULTS: Seventy-one women (aged 47-72) were enrolled (GRACE n = 37, waitlist control n = 34). GRACE participants demonstrated significant improvements in spiritual well-being compared to control at end of program (parameter estimate (PE), 16.67, 95% CI, 13.17, 20.16) and 1-month follow-up (PE, 10.31, 95% CI, 6.73, 13.89). Additionally, significant improvements were demonstrated in quality of life at the end of program (PE, 8.51, 95% CI, 4.26, 12.76) and 1-month follow-up (PE, 6.17, 95% CI, 1.75, 10.58). GRACE participants also demonstrated improved depression and hopelessness at follow-up, as well as improved anxiety. CONCLUSIONS: Findings suggest the value of evidence-based psychoeducational and experiential interventions for improving the well-being and quality of life of women with advanced cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02707510.

Status of Using Complementary and Alternative Medicine among Patients with Cancer in Korea: an Online Survey of Online Cancer Support Groups (KCSG PC21-20).

PURPOSE: An increasing number of patients with cancers are interested in complementary and alternative medicine (CAM), which lacks scientific evidence. This study aimed to determine how CAM was used and how media affected patients in online cancer support groups (OCSG). Materials and Methods: Between August 18 and September 12, 2021, an online survey was conducted among the members of OCSG. The survey consisted of five parts: baseline characteristics, attitudes toward and experience with CAM, source of information and reliabilities, experience with anthelmintics, and online health information literacy and usage. RESULTS: Among the 644 responders, a total of 221 patients with cancer completed the survey, and 78.2% (173/221) used CAM. The users' median age was 52 years; 46.8% were males, and 43.9% had metastatic disease. Fifty-three CAM users (30.6%) discussed their physicians about CAM. In addition, 16.2% (28/173) of CAM users had the experience of anthelmintics. The use of anthelmintics in patients with cancers was associated with younger age (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.84 to 0.95), metastatic disease (OR, 10.88; 95% CI, 3.39 to 34.86), previous exposure to CAM information (OR, 5.57; 95% CI, 1.01 to 30.72), experience with more types of CAM (OR, 1.98; 95% CI, 1.29 to 3.05), and side effects (OR, 5.10; 95% CI 1.46 to 17.75). CONCLUSION: Use of anthelmintics, a CAM of which information is widespread online, is affected by several factors. This study will provide essential information for developing a CAM management strategy in this digital age.

Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma.

PURPOSE: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. PATIENTS AND METHODS: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). RESULTS: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. CONCLUSIONS: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.

Deep Learning-Based Model for Identifying Tumors in Endoscopic Images From Patients With Locally Advanced Rectal Cancer Treated With Total Neoadjuvant Therapy.

BACKGROUND: A barrier to the widespread adoption of watch-and-wait management for locally advanced rectal cancer is the inaccuracy and variability of identifying tumor response endoscopically in patients who have completed total neoadjuvant therapy (chemoradiotherapy and systemic chemotherapy). OBJECTIVE: This study aimed to develop a novel method of identifying the presence or absence of a tumor in endoscopic images using deep convolutional neural network-based automatic classification and to assess the accuracy of the method. DESIGN: In this prospective pilot study, endoscopic images obtained before, during, and after total neoadjuvant therapy were grouped on the basis of tumor presence. A convolutional neural network was modified for probabilistic classification of tumor versus no tumor and trained with an endoscopic image set. After training, a testing endoscopic imaging set was applied to the network. SETTINGS: The study was conducted at a comprehensive cancer center. PATIENTS: Images were analyzed from 109 patients who were diagnosed with locally advanced rectal cancer between December 2012 and July 2017 and who underwent total neoadjuvant therapy. MAIN OUTCOME MEASURES: The main outcomes were accuracy of identifying tumor presence or absence in endoscopic images measured as area under the receiver operating characteristic for the training and testing image sets. RESULTS: A total of 1392 images were included; 1099 images (468 of no tumor and 631 of tumor) were for training and 293 images (151 of no tumor and 142 of tumor) for testing. The area under the receiver operating characteristic for training and testing was 0.83. LIMITATIONS: The study had a limited number of images in each set and was conducted at a single institution. CONCLUSIONS: The convolutional neural network method is moderately accurate in distinguishing tumor from no tumor. Further research should focus on validating the convolutional neural network on a large image set. See Video Abstract at http://links.lww.com/DCR/B959 . MODELO BASADO EN APRENDIZAJE PROFUNDO PARA IDENTIFICAR TUMORES EN IMGENES ENDOSCPICAS DE PACIENTES CON CNCER DE RECTO LOCALMENTE AVANZADO TRATADOS CON TERAPIA NEOADYUVANTE TOTAL: ANTECEDENTES:Una barrera para la aceptación generalizada del tratamiento de Observar y Esperar para el cáncer de recto localmente avanzado, es la imprecisión y la variabilidad en la identificación de la respuesta tumoral endoscópica, en pacientes que completaron la terapia neoadyuvante total (quimiorradioterapia y quimioterapia sistémica).OBJETIVO:Desarrollar un método novedoso para identificar la presencia o ausencia de un tumor en imágenes endoscópicas utilizando una clasificación automática basada en redes neuronales convolucionales profundas y evaluar la precisión del método.DISEÑO:Las imágenes endoscópicas obtenidas antes, durante y después de la terapia neoadyuvante total se agruparon en base de la presencia del tumor. Se modificó una red neuronal convolucional para la clasificación probabilística de tumor versus no tumor y se entrenó con un conjunto de imágenes endoscópicas. Después del entrenamiento, se aplicó a la red un conjunto de imágenes endoscópicas de prueba.ENTORNO CLINICO:El estudio se realizó en un centro oncológico integral.PACIENTES:Analizamos imágenes de 109 pacientes que fueron diagnosticados de cáncer de recto localmente avanzado entre diciembre de 2012 y julio de 2017 y que se sometieron a terapia neoadyuvante total.PRINCIPALES MEDIDAS DE VALORACION:La precisión en la identificación de la presencia o ausencia de tumores en imágenes endoscópicas medidas como el área bajo la curva de funcionamiento del receptor para los conjuntos de imágenes de entrenamiento y prueba.RESULTADOS:Se incluyeron mil trescientas noventa y dos imágenes: 1099 (468 sin tumor y 631 con tumor) para entrenamiento y 293 (151 sin tumor y 142 con tumor) para prueba. El área bajo la curva operativa del receptor para entrenamiento y prueba fue de 0,83.LIMITACIONES:El estudio tuvo un número limitado de imágenes en cada conjunto y se realizó en una sola institución.CONCLUSIÓN:El método de la red neuronal convolucional es moderadamente preciso para distinguir el tumor de ningún tumor. La investigación adicional debería centrarse en validar la red neuronal convolucional en un conjunto de imágenes mayor. Consulte Video Resumen en http://links.lww.com/DCR/B959 . (Traducción -Dr. Fidel Ruiz Healy ).

Gut Microbiota and Therapy in Metastatic Melanoma: Focus on MAPK Pathway Inhibition.

Gut microbiome (GM) and its either pro-tumorigenic or anti-tumorigenic role is intriguing and constitutes an evolving landscape in translational oncology. It has been suggested that these microorganisms may be involved in carcinogenesis, cancer treatment response and resistance, as well as predisposition to adverse effects. In melanoma patients, one of the most immunogenic cancers, immune checkpoint inhibitors (ICI) and MAPK-targeted therapy-BRAF/MEK inhibitors-have revolutionized prognosis, and the study of the microbiome as a modulating factor is thus appealing. Although BRAF/MEK inhibitors constitute one of the main backbones of treatment in melanoma, little is known about their impact on GM and how this might correlate with immune re-induction. On the contrary, ICI and their relationship to GM has become an interesting field of research due to the already-known impact of immunotherapy in modulating the immune system. Immune reprogramming in the tumor microenvironment has been established as one of the main targets of microbiome, since it can induce immunosuppressive phenotypes, promote inflammatory responses or conduct anti-tumor responses. As a result, ongoing clinical trials are evaluating the role of fecal microbiota transplant (FMT), as well as the impact of using dietary supplements, antibiotics and probiotics in the prediction of response to therapy. In this review, we provide an overview of GM's link to cancer, its relationship with the immune system and how this may impact response to treatments in melanoma patients. We also discuss insights about novel therapeutic approaches including FMT, changes in diet and use of probiotics, prebiotics and symbiotics. Finally, we hypothesize on the possible pathways through which GM may impact anti-tumor efficacy in melanoma patients treated with targeted therapy, an appealing subject of which little is known.

Comparative Study of the Efficacy and Safety of Radical Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy in Locally Advanced Gastric Cancer: A Propensity Score-Matching Analysis.

BACKGROUND: The effectiveness and safety of preventive hyperthermic intraperitoneal chemotherapy (HIPEC) for gastric cancer (GC) remain controversial. This study aimed to describe the safety and efficacy of radical surgery (RS) with or without HIPEC for patients with locally advanced GC (LAGC). METHODS: The study identified 394 patients with LAGC who underwent RS with or without HIPEC in China. RESULTS: Of the 394 patients, 146 received RS+HIPEC, and 248 received RS alone. The RS-HIPEC procedure improved the relapse-free survival (RFS) of the GC patients (2-year RFS, 62.9 % vs 37.8 %; χ2 = 4.468; P = 0.035) compared with those who received RS alone. The incidence of postoperative myelosuppression (Z = 4.077; P = 0.043) was higher in the RS+HIPEC group, whereas the incidence of wound complications was lower (Z = 4.077; P = 0.043). In the subgroup analysis, HIPEC improved the OS (2-year OS, 69.9 % vs 40.8 %; χ2 = 5.537; P =0.019) and RFS (2-year RFS, 65.6 % vs 33.3 %; χ2 = 7.380, P = 0.007) of the patients with nerve invasion and the RFS of the patients with vascular invasion (2-year RFS, 60.7 % vs 31.6 %; χ2 = 3.891; P = 0.049). In addition, the prognosis of the patients who underwent HIPEC was better when the tumor diameter was smaller than 5 cm (2-year RFS, 68.6 % vs 37.9 %; χ2 = 3.957; P = 0.047). CONCLUSIONS: The RS + HIPEC procedure improved the RFS of the patients with LAGC compared with RS alone, especially the patients with nerve or vascular invasion and the patients with tumor smaller than 5 cm. Moreover, it reduced the incidence of wound complications and did not induce more perioperative complications in addition to myelosuppression.

Use of First-Line Immune Checkpoint Inhibitors and Association With Overall Survival Among Patients With Metastatic Melanoma in the Anti-PD-1 Era.

Importance: In 2015, first-line programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) were Food and Drug Administration (FDA)-approved and National Comprehensive Cancer Network (NCCN)-recommended for patients with stage IV melanoma. Few studies have assessed the overall survival (OS) and usage rate associated with first-line ICI following 2015. Objective: To determine the rates of ICI use for metastatic melanoma following FDA approval in 2015 and characterize OS associated with first-line ICI use in this patient population. Design, Setting, and Participants: In this retrospective, nationwide cohort study, adult patients (≥20 years of age) with newly diagnosed stage IV cutaneous melanoma from 2010 to 2019 were identified using the US National Cancer Database (NCDB). Data were released by NCDB in March 2022 and analyzed in June 2022. Interventions: Patients were compared based on first-line ICI receipt vs not. Main Outcomes and Measures: The OS and use of first-line ICI in 2016 to 2019 were assessed using multivariable Cox and logistic regression, respectively. To account for immortal time bias in receiving ICI, landmark time points were used (the 50th and 75th percentile times from diagnosis to ICI initiation). Results: Among 16 831 patients with stage IV melanoma, 11 435 (67.9%) of patients were male; 116 (0.69%) were Asian or Pacific Islander, 475 (2.82%) were Hispanic, 270 (1.60%) were non-Hispanic Black, 15 711 (93.55%) were non-Hispanic White, and 145 (0.86%) were other race and ethnicity; the median (IQR) age at diagnosis was 64 (54-73) years. First-line immunotherapy use increased from 8.9% (127 of 1429) in 2010 to 38.8% (685 of 1766) in 2015, and 62.5% (1223 of 1958) in 2019. Median OS improved from 7.7 months (95% CI, 7.1-8.6 months) in 2010 to 17.5 months (95% CI, 14.9-19.8 months) in 2018. For patients diagnosed in 2016 or later, OS improved with first-line ICI (median OS using the 78-day landmark: 43.7 months [95% CI, 38.1-49.1 months] vs 16.1 months [95% CI, 13.5-19.3 months] for targeted therapy or chemotherapy; adjusted P < .001)-even after adjusting for patient, disease, and treatment factors. Results were similar for the 48-day landmark. This included patients presenting with brain metastases (first-line ICI median OS using the 78-day landmark: 19.9 months [95% CI, 17.2-25.0 months] vs 10.7 months for targeted therapy [95% CI, 9.5-12.3 months], adjusted P = .001). First-line ICI use varied by patients' age, insurance status, zip code-level household income, and treating hospital type. Conclusions and Relevance: Following anti-PD-1 approval in 2015, first-line ICI was associated with substantial OS improvements for patients with stage IV melanoma, including those with brain metastases. As of 2019, 38% of patients still were not receiving first-line ICI in the US, with use varying by patients' socioeconomic factors.