Recurrence-free Survival In Stage Research Articles

Combination of grade and spread through air spaces (STAS) predicts recurrence in early stage lung adenocarcinoma: a retrospective cohort study.

Adenocarcinomas, a common subtype of lung cancer, exhibit diverse histological patterns. In 2020, The International Association for the Study of Lung Cancer (IASLC) introduced a grading system emphasizing high-grade components, which has shown prognostic value. Spread through air spaces (STAS) is recognized as a prognostic feature increasing the risk of recurrence in lung cancer. This study evaluates the combination of STAS status and the IASLC-grading system in surgically resected Stage I lung adenocarcinomas. This study is a retrospective analysis of 123 patients with Stage I lung adenocarcinoma who underwent lobectomy between 2011 and 2019. Histological patterns were assessed according to the IASLC criteria, and STAS status was documented. Patients were categorized based on their IASLC Grade and STAS status. Statistical analyses included Kaplan-Meier survival estimates, Cox proportional hazards models, and comparisons using Chi-square and t-tests. The cohort comprised 43 females and 80 males with a mean age of 61.8 ± 7.6years. STAS positivity was noted in 52.8% of patients. STAS positivity correlated significantly with Grade 3 tumors (p < 0.001). The 5-year recurrence-free survival was significantly lower in STAS-positive patients (70.7% vs. 88.7%, p = 0.026). Patients with Grade 3 and STAS positivity had significantly lower recurrence-free survival compared to other groups (p = 0.002). Grade 3 and STAS positivity were independent predictors of poor recurrence-free survival in multivariate analysis. IASLC Grade 3 tumors and STAS positivity are independent prognostic factors for poor recurrence-free survival in Stage I lung adenocarcinomas. Adjuvant treatment strategies should be considered for patients with these characteristics to improve outcomes.

Dissecting the clinicopathologic, genomic, and prognostic significance of anaplastic lymphoma kinase rearrangement in resected lung adenocarcinoma

ObjectivesThe ALINA trial introduced anaplastic lymphoma kinase (ALK) inhibitors in an early-stage context, generating notable interest. This study aims to investigate the characteristics and prognostic implications of ALK rearrangement in patients with resected lung adenocarcinoma (LUAD). MethodsWe retrospectively evaluated resected LUAD cases with documented ALK status from 2008 to 2020. The association between ALK positivity and clinicopathologic characteristics, molecular profiles, and outcomes was explored. ResultsAmong 4944 cases, 238 (4.8%) were ALK-positive, correlating with younger age and nonsmokers. ALK positivity was also significantly associated with pure-solid nodules, spread through air spaces, and solid-predominant adenocarcinoma. ALK-positive tumors exhibited an overall low frequency of co-mutations (eg, TP53, STK11). ALK positivity was associated with inferior recurrence-free survival (RFS) in patients with stage I who did not receive adjuvant chemotherapy whereas it was associated with prolonged RFS in patients with stage II and III who received adjuvant chemotherapy. Notably, 6 patients treated with adjuvant ALK inhibitors experienced no recurrence or metastasis during the follow-up period. In addition, the administration of ALK inhibitors significantly improved postrecurrence survival in patients positive for ALK. ConclusionsALK positivity was associated with specific aggressive pathologic features and inferior RFS in stage I LUAD. Patients positive for ALK seemed to benefit more from adjuvant chemotherapy. Active treatment with ALK inhibitors or chemotherapy should be considered for patients with ALK-positive LUAD, although further evidence is warranted to expand their utility in early-stage disease management.

A prognostic nomogram for predicting recurrence-free survival of stage I–III colon cancer based on immune-infiltrating Treg-related genes

PurposeA high postoperative recurrence rate seriously impedes colon cancer (CC) patients from achieving long-term survival. Here, we aimed to develop a Treg-related classifier that can help predict recurrence-free survival (RFS) and therapy benefits of stage I–III colon cancer.MethodsA Treg-related prognostic classifier was built through a variety of bioinformatic methods, whose performance was assessed by KM survival curves, time-dependent receiver operating characteristic (tROC), and Harrell’s concordance index (C-index). A prognostic nomogram was generated using this classifier and other traditional clinical parameters. Moreover, the predictive values of this classifier for immunotherapy and chemotherapy therapeutic efficacy were tested using multiple immunotherapy sets and R package “pRRophetic".ResultsA nine Treg-related classifier categorized CC patients into high- and low-risk groups with distinct RFS in the multiple datasets (all p < 0.05). The AUC values of 5-year RFS were 0.712, 0.588, 0.669, and 0.662 in the training, 1st, 2nd, and entire validation sets, respectively. Furthermore, this classifier was identified as an independent predictor of RFS. Finally, a nomogram combining this classifier and three clinical variables was generated, the analysis of tROC, C-index, calibration curves, and the comparative analysis with other signatures confirmed its predictive performance. Moreover, KM analysis exhibited an obvious discrepancy in the subgroups, especially in different TNM stages and with adjuvant chemotherapy. We detected the difference between the two risk subsets of immune cell sub-population and the response to immunotherapy and chemotherapy.ConclusionsWe built a robust Treg-related classifier and generated a prognostic nomogram that predicts recurrence-free survival in stage I–III colon cancer that can identify high-risk patients for more personalized and effective therapy.

NeoIRX trial: Immunologic induction with peri-lymphatic cytokines to enhance pembrolizumab (pembro) response in stage II/III triple-negative breast cancer (TNBC).

604 Background: The addition of pembro to neoadjuvant chemotherapy (NACT) improves pathological complete response (pCR) rate and recurrence-free survival in stage II/III TNBC, albeit with substantial chemotherapy-attributed toxicity. We hypothesize that locoregional cytokine therapy could be combined with pembro to optimize immune response and clinical outcome. In a phase Ib early-stage breast cancer trial, we previously demonstrated that peri-lymphatic cytokine injection (IRX-2 regimen, comprised of physiologic doses of IL-2, IFNg, and other cytokines derived from activated donor lymphocytes, given with low-dose cyclophosphamide) is well tolerated and associated with increased intratumoral lymphocytes, T-cell activation, and PD-L1 expression. Here, we report preliminary outcomes of neoIRX, a phase II trial evaluating induction IRX-2 + pembro preceding NACT + pembro. Methods: Subjects with stage II/III TNBC were randomized to receive induction pembrolizumab (all subjects: 200mg IV) +/- peri-areolar IRX-2 (IRX-2 arm: 1 ml SQ x2 daily for 10 days + cyclophosphamide 300 mg/m2 IV x 1) preceding initiation of NACT + pembro. The primary endpoint was pCR rate following NACT + pembro (n = 15 subjects/arm planned); secondary endpoints were safety and tolerability. We explored post-induction/pre-NACT radiographic (ultrasound) and histologic outcomes (TILs, tumor regression) as a biomarker strategy to predict pCR. Results: The trial terminated after n = 12 subjects due to withdrawal of drug support for IRX-2. The IRX-2 arm achieved 83% pCR (n = 5/6, CI 36-100%) compared to 33% pCR with pembro alone (n = 2/6, CI 4-78%). The regimen was well-tolerated with minimal IRX-2-attributed toxicities (67% grade I skin bruise). Toxicities during NACT + pembro were similar to Keynote-522. 67% (n = 4/6) of IRX-2 subjects experienced week 3 radiographic regression, with evidence of brisk lymphocyte infiltration on week 3 biopsy, and with 100% pCR rate (n = 4/4) following NACT + pembro. n = 2/6 subjects receiving pembro+IRX-2 experienced pCR on week 3 biopsy, versus n = 0/3 evaluable in control arm. Conclusions: Induction IRX-2 + pembro is well tolerated and is associated with encouraging outcomes, supporting further study of peri-lymphatic induction cytokine therapy in stage II/III TBNC. Post-induction radiographic and histologic outcomes may identify patients with immune-responsive tumors, for whom NACT de-escalation may be a promising therapeutic approach to mitigate toxicity. Clinical trial information: NCT04373031 .

Overall survival after the introduction of adjuvant treatment in stage III melanoma: A nationwide registry based study.

9570 Background: Adjuvant treatments with PD-1 and BRAF+MEK inhibitors significantly prolong recurrence-free survival in stage III cutaneous melanoma. However, the effect on overall survival is still unclear. After the approval of adjuvant treatments with PD-1 inhibitors and BRAF+MEK inhibitors, based on recurrence-free survival data, these treatments have been widely implemented. However, there are significant side effects and costs of the treatment, and the overall survival effect remains a highly anticipated outcome. Methods: Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry that covers nearly all (99%) primary cutaneous melanomas diagnosed. Information on deaths was received from the Cause of Death Registry, a virtually complete register of all deaths in Sweden. Patients diagnosed with stage III melanoma between 2016 and 2020 were included and divided depending on if they were diagnosed before or from July 2018, the timepoint when adjuvant treatment was introduced in Sweden (designated as pre- and post-cohorts). In Sweden, approved treatments are freely available for all residents and there is a high-adherence to national treatment guidelines. Data was retrieved for the age and sex of the patients, the site, histopathological subtype, Breslow thickness and ulceration of the primary melanoma, type of locoregional spread and numbers of affected lymph nodes. Patients were followed until the end of 2021. Melanoma-specific and overall survival were calculated using the Kaplan-Meier method and Cox regression analyses. Results: There were 1371 patients diagnosed with stage III melanoma in Sweden in 2016-2020. The median time of follow-up in the pre-cohort was 57 months (range 42-72 months) and in the post-cohort 27 months (range 12-42 months). The 2-year overall survival rates, comparing the 634 patients in the pre-cohort and the 737 in the post-cohort, were 84.3% (95% CI 81.4-87.3) and 86.1% (95% CI 83.4-89.0), respectively, with an adjusted HR 0.91 (95% CI 0.70-1.19, P= 0.51). Further, no significant overall or melanoma-specific survival differences were seen when comparing the pre- and the post-cohort in different subgroups depending on the age, sex or tumor characteristics. Conclusions: To our knowledge, this study is the first to assess the impact on overall survival from a national introduction of adjuvant treatment in stage III melanoma. In this nationwide, population and registry-based study, no survival benefit was detected in the cohort receiving adjuvant therapy. Considering also the significant side effects and costs, these findings encourage a careful assessment of the current recommendations on adjuvant treatment. To offer close follow-up, and only treat if relapse occurs, should be an option discussed with patients with fully resected stage III melanoma.

Survival after introduction of adjuvant treatment in stage III melanoma: a nationwide registry-based study.

Adjuvant treatments with PD-1 and BRAF+MEK inhibitors statistically significantly prolong recurrence-free survival in stage III cutaneous melanoma. Yet, the effect on overall survival is still unclear. Based on recurrence-free survival outcomes, these treatments have been approved and widely implemented. The treatments have considerable side effects and costs, and overall survival effect remains a highly anticipated outcome. Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry for patients diagnosed with stage III melanoma between 2016 and 2020. The patients were divided depending on if they were diagnosed before or from July 2018, based on the timepoint when adjuvant treatment was introduced in Sweden. Patients were followed up until the end of 2021. In this cohort study, melanoma-specific and overall survival were calculated using the Kaplan-Meier method and Cox-regression analyses. There were 1371 patients diagnosed with stage III primary melanoma in Sweden in 2016-2020. The 2-year overall survival rates, comparing the 634 patients in the precohort and the 737 in the postcohort, were 84.3% (95% confidence interval [CI] = 81.4% to 87.3%) and 86.1% (95% CI = 83.4% to 89.0%), respectively, with an adjusted hazard ratio of 0.91 (95% CI = 0.70 to 1.19, P = .51). Further, no statistically significant overall or melanoma-specific survival differences were seen when comparing the precohort and the postcohort in different subgroups for age, sex, or tumor characteristics. In this nationwide population-based and registry-based study, no survival benefit was detected in patients diagnosed before or after the implementation of adjuvant treatment in stage III melanoma. These findings encourage a careful assessment of the current recommendations on adjuvant treatment.

805P Predicting recurrence-free survival for patients with stage II melanoma: A validated tool to guide selection for adjuvant systemic therapy

Keynote 716 has recently shown improved recurrence-free survival (RFS) for sentinel node-negative Stage IIB/C melanoma patients given adjuvant pembrolizumab. Accordingly, identification of patients most likely to benefit from adjuvant systemic therapy requires accurate, personalised risk prediction. The current AJCC 8th Edition (AJCC-8) estimates melanoma-specific survival (MSS). We developed and externally validated a tool for predicting RFS in stage II melanoma patients.

Oxaliplatin-induced neuropathy and colo-rectal cancer patient's quality of life: Practical lessons from a prospective cross-sectional, real-world study.

BACKGROUNDColon cancer is one the most common forms of cancer in both sexes. Due to important progress in the field of early detection and effective treatment, colon and rectal cancer survivors currently account for 10% of cancer survivors worldwide. However, the effects of anti-cancer treatments, especially oxaliplatin-based chemotherapy, on the quality of life (QoL) have been less evaluated. Although the incidence of severe chemotherapy-induced neuropathy (CIPN) in clinical studies is below 20%, data from real-world studies is scarce, and CIPN is probably under-reported due to patient selection and the patients’ fear that reporting side-effects might lead to treatment cessation.AIMTo determine the impact of CIPN on QoL in colorectal cancer patients with a recent history of oxaliplatin-based chemotherapy.METHODSWe performed a prospective cross-sectional study in two major Romanian oncology tertiary hospitals—the Regional Institute of Oncology Iași (Iasi, Romania) and the Fundeni Clinical Oncology Institute (Bucharest, Romania). All consecutive patients with colon or rectal cancer, undergoing Oxaliplatin-based chemotherapy that consented to enroll in the study, were assessed by means of two questionnaires—the EORTC QQ-CR29 (quality of life in colon and rectal cancer patients) and the QLQ-CIPN20 (assessment of neuropathy). Several demographical, social, clinical and treatment data were also collected. Statistical analysis was performed by means of SPSS v20. The student t test was used to assess the relationship between the QLQ-CIPN20 and QLQ-CR29 results. Kaplan Meyer-curves were used to report 3-year progression-free survival (PFS) in patients that discontinued chemotherapy vs those that completed the recommended course.RESULTSOf the 267 patients that fulfilled the inclusion criteria in the pre-specified time frame, 101 (37.8%) agreed to participate in the clinical study. At the time of the enrolment in the study, over 50% of the patients had recently interrupted their oxaliplatin-based chemotherapy, most often due to neuropathy. Almost 85% of the responders reported having tingling or numbness in their fingers or hands, symptoms that were associated with pain in over 20% of the cases. When comparing the scores in the two questionnaires, a statistically significant relationship (P < 0.001) was found between the presence of neuropathic symptoms and a decreased quality of life. This correlation was consistent when the patients were stratified by sex, disease stage, comorbidities and the presence of stoma or treatment type, suggesting that neuropathy in itself may be a reason for a decreased quality of life. At the 3 year final assessment, median recurrence-free survival in stage III patients was 26.88 mo. When stratified by completion of chemotherapy, median recurrence free-survival of stage III patients that completed chemotherapy was 28.27 mo vs 24.33 mo in patients that discontinued chemotherapy due to toxicity, a difference that did not reach statistical significance.CONCLUSIONCIPN significantly impacts QoL in colorectal cancer patients. CIPN is also the most frequent reason for treatment discontinuation. Physicians should actively assess for CIPN in order to prevent chronic neuropathy.

Why do some patients with stage 1A and 1B endometrial endometrioid carcinoma experience recurrence? A retrospective study in search of prognostic factors.

Endometrial endometrioid carcinoma (EEC) is the most encountered subtype of endometrial cancer (EC). Our study aimed to investigate the factors affecting recurrence in patients with stage 1A and 1B EEC. Our study included 284 patients diagnosed with the International Federation of Gynecology and Obstetrics stage 1A/1B EEC in our center from 2010 to 2018. The clinicopathological characteristics of the patients were obtained retrospectively from their electronic files. The median age of the patients was 60 years (range 31-89). The median follow-up time of the patients was 63.6 months (range 3.3-185.6). Twenty-two (7.74%) patients relapsed during follow-up. Among the relapsed patients, 59.1% were at stage 1A ECC, and 40.9% were at stage 1B. In our study, the one-, three-, and five-year recurrence-free survival (RFS) rates were 98.9%, 95.4%, and 92.9%, respectively. In the multivariate analysis, grade and tumor size were found to be independent parameters of RFS in all stage 1 EEC patients. Furthermore, the Ki-67 index was found to affect RFS in stage 1A EEC patients, and tumor grade affected RFS in stage 1B EEC patients. In the time-dependent receiver operating characteristic curve analysis, the statistically significant cut-off values were determined for tumor size and Ki-67 index in stage 1 EEC patients. Stage 1-EEC patients in the higher risk group in terms of tumor size, Ki-67, and grade should be closely monitored for recurrence. Defining the prognostic factors for recurrence in stage 1 EEC patients may lead to changes in follow-up algorithms.

An Individualized EMT-Related Gene Signature to Predict Recurrence-Free Survival in Stage II/III Colorectal Cancer Patients.

Approximately 30% of stage II and 50-60% of stage III colorectal cancer (CRC) patients who have undergone surgery will develop recurrence within 5years. Thus, more reliable prognostic biomarkers are urgently needed to identify the high-risk subset of patients who will benefit from postoperative adjuvant therapy. We retrospectively analyzed 911 stage II/III CRC patients in multiple cohorts. Using a series of bioinformatic and statistical approaches, an individualized prognostic signature was established in the training cohort and validated in four other independent cohorts. An integrated decision tree was generated to improve risk stratification, and a nomogram was built to quantify risk assessment for individual patients. Epithelial-mesenchymal transition (EMT) was identified as a dominant risk factor for recurrence-free survival (RFS) in stage II/III CRC patients. The EMT-related gene signature could discriminate high-risk subsets in a training cohort and four independent validation cohorts (with 473, 89, 130, 74 and 145 patients, respectively). Survival analyses demonstrated that the EMT-related gene signature served as an independent risk factor for RFS in different subgroups. The decision tree could optimize the risk stratification, and the nomogram could predict the 5-year RFS probability accurately. The proposed EMT-related prognostic signature is a useful biomarker to predict RFS and identify the high-risk subset in stage II/III CRC patients.

Clear Cell Carcinoma (CCC) of the Cervix Is a Human Papillomavirus (HPV)-independent Tumor Associated With Poor Outcome: A Comprehensive Analysis of 58 Cases.

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus-independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.

Clinicopathological Features and Survival Outcomes of Primary Pulmonary Invasive Mucinous Adenocarcinoma.

Simple SummaryPulmonary invasive mucinous adenocarcinoma (IMA) is a recognized variant of lung adenocarcinoma (ADC) that has unique histological patterns. Comprehensively clinical studies and pathological analyses on IMAs have been limited because IMA is rarely diagnosed compared with other subtypes. We compared the clinical characteristics, pathological features, and survival outcomes of 77 IMA patients with 520 non-IMA-type ADC patients. Currently, IMAs lack a simple pathological prognostic grading system to predict survival. We therefore proposed a simple two-tier grading system, which was modified from the low- and high-grade PanIN grading system, to evaluate its prognostic value. We found that IMAs have more distinct clinicopathological characteristics compared to non-IMA-type ADCs. For patients with stage I–IIIA IMA, a new two-tier grading system might be useful in predicting recurrence-free survival. We demonstrated that stage I and II IMAs have better overall survival compared with non-IMA-type ADCs.Pulmonary invasive mucinous adenocarcinoma (IMA) has unique histological patterns. This study aimed to comprehensively evaluate the clinicopathological features, prognosis, and survival outcomes of IMAs. We retrospectively identified 77 patients with pulmonary IMA and reviewed their clinical and pathological features. Another 520 patients with non-IMA-type ADC were retrieved for comparison with patients with IMA. A new two-tier grading system (high-grade and low-grade IMAs) modified from the pancreatic intraepithelial neoplasia classification system was used for survival analyses. Compared to patients with non-IMA-type ADC, patients with IMA tended to have never smoked (p = 0.01) and had early-stage IMA at initial diagnosis (p < 0.001). For stage I–II diseases, the five-year overall survival (OS) rates were 76% in IMAs and 50% in non-IMA-type ADCs, and a longer OS was observed in patients with IMA (p = 0.002). KRAS mutations were the most commonly detected driver mutations, which occurred in 12 of the 28 (43%) patients. High-grade IMAs were associated with a shorter recurrence-free survival (RFS) for stage I–IIIA diseases (p = 0.010) than low-grade IMAs but not for OS. In conclusion, patients with stage I and II IMA had better OS than those with non-IMA-type ADC. A new two-tier grading system might be useful for predicting RFS in stage I–IIIA IMAs.

Mid-term results of completely portal robotic lobectomy for stage I & II non-small cell lung cancer.

BackgroundMinimally invasive robotic-assisted thoracic surgery is an increasingly popular platform for oncological thoracic resection. The aim of this study is to evaluate the feasibility of completely portal robotic lobectomy for patients with early non-small cell lung cancer (NSCLC), analysing the perioperative and mid-term results.MethodsThis is a single-institution retrospective cohort study of consecutive patients who underwent completely portal robotic lobectomy for early stage NSCLC over a 53-month period.ResultsA total of 59 consecutive patients were included in this study. Median operative time was 155 min (range, 80–313 min). Conversion rate was 13.6%. Median intensive care/high dependency unit stay, chest tube duration and length of hospital stay were 1 day (range, 0–4 days), 2 days (range, 1–20 days) and 4 days (range, 2–30 days) respectively; 98.2% of patients achieved R0 resection. Overall, 23.7% had minor complications. There was no perioperative (30-day) mortality in this study. Final pathological staging distribution was 55.9% stage 1A, 23.7% stage 1B, 10.2% stage 2A and 10.2% stage 2B; 23% were upstaged after pathological staging. Median follow-up was 33 months (range, 3–70 months). The 3-year overall survival and recurrence-free survival were 86.2% (95% CI, 72.0–96.8) and 69% (95% CI, 56.1–81.9) respectively. The 3-year overall survival and recurrence free survival for stage 1 patients were 88.4% (95% CI, 77.4–99.4) and 75.6% (95% CI, 62.3–88.9) respectively.ConclusionsBy clearly defining completely portal robotic lobectomy, it is possible to delivery promising perioperative and mid-term results for early stage primary lung cancer, even in a geographical location that has yet to assimilate this technology.

Abstract B10: High-dimensional (30-plex) imaging mass cytometry on tissue microarray identifies novel PD-L1-inclusive immunophenotypes associated with overall survival in stage III melanoma

Abstract We sought to determine the subcellular distribution of 30+ immune-related markers including PD-L1 in stage III melanoma tumor tissues (nuclear, cytoplasmic, surface) using novel imaging mass cytometry technology that enables simultaneous detection of over 30 immune and tumor markers. Metal-tagged antibodies were used to stain stage III melanoma tissues similarly to an IHC-based protocol, followed by laser ablation and mass cytometry using the Helios® and Hyperion® technology (Fluidigm). Markers for immune subsets included CD45, CD3, CD4, CD8, PD-1, Granzyme B, FoxP3, CD11b, CD11c, CD107, CD20, Vista, and CD68. Markers for tumor cell phenotyping included PD-L1 (intracellular and extracellular domain specific), E-cadherin, B-catenin, PD-L2, and keratin 8/18. Structural, inflammatory, survival, and signaling markers included Ki67, p53, p-tyrosine, Bcl-2, Cl-caspase 3, histone H3, collagen-1, actin, and arginase-1. We further validated subcellular distribution of PD-L1 in the same patient tumor cores using fluorochrome-labeled antibodies and 100X confocal microscopy to show difference in surface-only, cytoplasmic-only, and nuclear PD-L1. We then assessed the association between subcellular PD-L1 and immune populations in the tumor microenvironment, along with overall and recurrence-free survival. We wrote custom algorithms for data processing to identify novel immune subsets, ran SPADE and viSNE analyses for cross-validation, and employed Imaris Bitplane software to validate our own algorithms for immune population identification. Overall, we found that intracellular-only PD-L1 in tumor tissues has the highest correlation (Pearson r) to CD11b, FoxP3, PD-1, arginase, Ki67, PD-L2 and nuclear stain iridium, while extracellular (surface) PD-L1 in tumors has the highest correlation (Pearson r) to FoxP3, PD-1, arginase, Ki67, PD-L2 and Vista. We identified two novel immunophenotypes (histone-3+/p-tyrosinehi /Vistalo / PD-L1-ICDlo / PD-L1-ECDlo and CD11bhi / PD-L1-ICDhi / PD-L1-ECDhi) that are positively associated with overall patient survival. Of note, only phospho-Tyrhi was significantly associated with RFS. This work highlights the use of cutting-edge technology that can employ the highest multiplexing available for assessing novel interactions of 30+ tumor tissue markers for identification of novel immunophenotypes and biomarker in stage III melanoma patients. Our novel study showcases a novel methodologic approach to high-throughput analysis of retrospective profiling of the melanoma tumor immune microenvironment on a single IHC slide, followed by appropriate and rigorous cross-validation using Fluidigm’s novel CyTOF imaging technology. Our study provides a groundwork for this powerful, novel technology in translational and clinical research for biomarker identification and identification of novel combinatorial markers that may predict overall and recurrence-free survival in stage III melanoma. Citation Format: Heather G. Hambright, Anand V.R. Kornepati, Dai Ogata, Roland R.L. Bassett, Suhendan Ekmekcioglu, Elizabeth A. Grimm, Tyler J. Curiel. High-dimensional (30-plex) imaging mass cytometry on tissue microarray identifies novel PD-L1-inclusive immunophenotypes associated with overall survival in stage III melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B10.

Guidelines for Reporting of Figures and Tables for Clinical Research in Urology.

In an effort to improve the presentation of and information within tables and figures in clinical urology research, we propose a set of appropriate guidelines. We introduce six principles: (1) include graphs only if they improve the reader's ability to understand the study findings; (2) think through how a graph might best convey information, do not just select a graph from preselected options on statistical software; (3) do not use graphs to replace reporting key numbers in the text of a paper; (4) graphs should give an immediate visual impression of the data; (5) make it beautiful; and (6) make the labels and legend clear and complete. We present a list of quick "dos and don'ts" for both tables and figures. Investigators should feel free to break any of the guidelines if it would result in a beautiful figure or a clear table that communicates data effectively. That said, we believe that the quality of tables and figures in the medical literature would improve if these guidelines were to be followed. Patient summary: A set of guidelines were developed for presenting figures and tables in urology research. The guidelines were developed by a broad group of statistical experts with special interest in urology.

Reverse engineering a predictive signature characterized by proliferation, DNA damage, and immune escape from stage I lung adenocarcinoma recurrence.

Identifying early-stage cancer patients at risk for progression is a major goal of biomarker research. This report describes a novel 19-gene signature (19-GCS) that predicts stage I lung adenocarcinoma (LAC) recurrence and response to therapy and performs comparably in pancreatic adenocarcinoma (PAC), which shares LAC molecular traits. Kaplan-Meier, Cox regression, and cross-validation analyses were used to build the signature from training, test, and validation sets comprising 831 stage I LAC transcriptomes from multiple independent data sets. A statistical analysis was performed using the R language. Pathway and gene set enrichment were used to identify underlying mechanisms. 19-GCS strongly predicts overall survival and recurrence-free survival in stage I LAC (P=0.002 and P<0.001, respectively) and in stage I-II PAC (P<0.0001 and P<0.0005, respectively). A multivariate cox regression analysis demonstrated the independence of 19-GCS from significant clinical factors. Pathway analyses revealed that 19-GCS high-risk LAC and PAC tumors are characterized by increased proliferation, enhanced stemness, DNA repair deficiency, and compromised MHC class I and II antigen presentation along with decreased immune infiltration. Importantly, high-risk LAC patients do not appear to benefit from adjuvant cisplatin while PAC patients derive additional benefit from FOLFIRINOX compared with gemcitabine-based regimens. When validated prospectively, this proof-of-concept biomarker may contribute to tailoring treatment, recurrence reduction, and survival improvements in early-stage lung and pancreatic cancers.

Invasive Stratified Mucinous Carcinoma (iSMC) of the Cervix Often Presents With High-risk Features That Are Determinants of Poor Outcome: An International Multicenter Study.

Invasive stratified mucinous carcinoma (iSMC) has been suggested to represent an aggressive subtype of endocervical adenocarcinoma. We sought to investigate the outcomes of iSMC and determine which clinical and pathologic parameters may influence the prognosis. Slides from 52 cases of iSMC were collected and classified as follows: pure iSMC (>90% of the entire tumor) and iSMC mixed with other human papillomavirus-associated adenocarcinoma components (miSMC) (>10%, but <90% of the entire tumor). Clinical and pathologic parameters were evaluated and compared with overall survival (OS) and recurrence-free survival (RFS). One third of patients with iSMC presented with lymph node metastases (LNM) and 25% developed local recurrences, whereas 4 (7.7%) developed distant recurrences. 29 cases (55.8%) were pure iSMC, whereas 23 cases (44.23%) were miSMC. OS was 74.7% in pure iSMC versus 85.2% in miSMC (P=0.287). RFS was 56.5% in pure iSMC and 72.9% in miSMC (P=0.185). At 5 years, OS in stage I was 88.9% versus stage II to IV 30% (P=0.004), whereas RFS in stage I was 73.9% versus stage II to IV 38.1% (P=0.02). OS was influenced by International Federation of Gynecology and Obstetrics (FIGO) stage (P=0.013), tumor size (P=0.02), LNM (P=0.015), and local recurrence (P=0.022), whereas RFS was influenced by FIGO stage (P=0.031), tumor size (P=0.001), local recurrence (P=0.009), LNM (P=0.008), and type of surgical treatment (P=0.044). iSMC is an aggressive cervical tumor biologically different from other human papillomavirus-associated adenocarcinomas due to the propensity for LNM, local/distant recurrence. FIGO stage, tumor size, LNM, and presence of local/pelvic recurrences are determinants of outcome in iSMCs.

Impact of cumulative cisplatin dose and adjuvant chemotherapy in locally-advanced nasopharyngeal carcinoma treated with definitive chemoradiotherapy.

Both adjuvant chemotherapy and higher cumulative cisplatin dose (CDDP-D) given as part of multimodality therapy for locally-advanced nasopharyngeal carcinoma (LA-NPC) have improved survival in Asian series. We evaluated their impact in a contemporary single-institution Canadian cohort of LA-NPC. Patients with EBV-related stage II-IV LA-NPC by 7th edition TNM (TNM-7) treated with IMRT plus high-dose CDDP followed by adjuvant chemotherapy with CDDP/Carboplatin - 5-FU (maximum total/adjuvant CDDP-D=540/240mg/m2) between 2003 and 2016 were analyzed. 5-year overall survival (OS) and recurrence-free survival (RFS) were calculated and compared using log-rank test by stage, adjuvant chemotherapy (yes/no) and total CDDP-D (>300 vs ≤300mg/m2). Multivariable analysis (MVA) was performed to identify survival predictors. A total of 312 patients were evaluated: TNM-7 stage II/III/IV=2%/51%/47%; T4=36%; N3=17%; adjuvant chemotherapy=83% (79% 21% CDDP/carboplatin); median total/adjuvant CDDP-D=380/160mg/m2; median follow-up 76years (range 06-149). 5-year OS differed by stage II-III vs IV (95% vs 80%, p<0.001) and by total CDDP-D >300 (n=210) vs ≤300 (n=102) mg/m2 (89% vs 83%, p=0.02). Adjuvant chemotherapy and total CDDP-D impacted on 5-year OS in stage IV but not stage II-III. 5-year RFS was higher in stage IV patients with total CDDP-D >300 vs ≤300mg/m2 (74% vs 59%, p=0.03), with a trend seen in locoregional (LRC) (91% vs 80%, p=0.05) but not distant control (DC) (78% vs 72%, p=0.36). Adjuvant chemotherapy and total CDDP-D >300mg/m2 improved OS and RFS in stage IV but not stage II-III LA-NPC, mainly due to effect on LRC rather than DC.

Utility of circulating tumor cells in stage II colorectal cancer patients undergoing curative resection.

BackgroundThe aim of this study was to determine whether circulating tumor cells (CTCs) have utility as a prognostic biomarker in stage II colorectal cancer (CRC), as well as a biomarker for the selection of patients for adjuvant chemotherapy.MethodsCTCs were detected in peripheral blood samples obtained from 73 stage II CRC patients, using a negative enrichment and immune-fluorescence in situ hybridization (imFISH) staining method. The follow-up time ranged from 3.5 to 35.9 months, and the clinic-pathologic characteristics and recurrence free survival (RFS) were collected and analyzed.ResultsSeventy-three stage II CRC patients were included in this study. The positive rate of CTCs was 65.8% in all patients, 87.5% in recurrent patients and 59.6% in no recurrence patients. The mean RFS was 30.6 months for all patients, 28.7 months for CTC-positive patients and 34.0 months for CTC-negative patients (P=0.043). The mean RFS of CTC-positive and CTC-negative patients with adjuvant chemotherapy were not reached, and those without adjuvant chemotherapy were 27.7 and 33.4 months, respectively.ConclusionsThe level of CTCs may be an effective prognostic factor to predict RFS in stage II CRC patients, and has potential in selecting stage II CRC patients for adjuvant chemotherapy.

Radiomics Signature Predicts the Recurrence-Free Survival in Stage I Non-Small Cell Lung Cancer

We aimed to explore the predictive value of radiomics signature for the recurrence-free survival (RFS) in patients with resected stage I non-small cell lung cancer. From January 2009 to December 2011, patients with resected stage I non-small cell lung cancer were divided into sub-solid and pure-solid groups according to presence of ground glass opacity in computed tomography. A total of 107 extracted radiomics features were reduced to 8 features by using LASSO Cox analysis to develop a radiomics signature for RFS prediction. Univariate and multivariate survival analyses were applied to identify independent prognostic variables, the Harrell concordance index (C-index) was measured to assess their prediction performance. Our study included 378 patients with a median follow-up time of 63.2 months. The radiomics signature could stratify all patients into high-risk (180 of 378) and low-risk group (198 of 378) with different RFS (P < .001). In the sub-solid group (n= 115), 3 patients who occurred relapse were categorized into the high-risk group by the radiomics signature. In the pure-solid group, patients with low risk (141 of 263) had a better outcome than those with high risk (122 of 263) (P < .001). Multivariate analyses revealed that the histology (P < .001) and the developed radiomics signature (P < .001) remained independent prognostic factors for RFS. Radiomics signature may be an independent imaging biomarker for predicting the survival, which may guide for personalizing treatment option in patients with stage I non-small cell lung cancer.