Squamous Cell Carcinoma Histology Research Articles

The Spectrum of HPV-independent Penile Intraepithelial Neoplasia: A Proposal for Subclassification.

Compared with vulva, precursor lesions of human papillomavirus (HPV)-independent invasive squamous cell carcinoma (SCC) of the penis are insufficiently characterized. We analyzed the histologic and immunohistochemical characteristics of 70 peritumoral precursor lesions and correlated them with the histology and mutational profile of the adjacent HPV-negative invasive penile SCC. Atypical basal keratinocyte proliferation with variously elongated epithelial rete with premature squamatiziation, but regular superficial cornification, termed differentiated penile intraepithelial neoplasia (d-PeIN), were identified adjacent to 42/70 (60%) SCC (36/42 keratinizing (P<0.001); 3 papillary, and 1 each verrucous, clear cell, sarcomatoid SCC). d-PeIN were associated with chronic inflammatory dermatoses (32/42; P<0.001), p53 overexpression (26/42; P<0.001), and hotspot mutations in TP53 (32/42; P<0.001), CDKN2A (26/42; P<0.001) or both (21/42; P=0.003) in the adjacent SCC. Cytoplasmic p16ink4a overexpression in 5/42 d-PeIN correlated with CDKN2A missense mutations in the adjacent SCC. In all, 21/70 (30%) cornified verrucous or glycogenated verruciform precursors with minimal atypia and wild-type p53 (18/21; P<0.001) occurred adjacent to verrucous or papillary SCC (17/21; P<0.001) and keratinizing (4/21) SCC, which harbored mutations in HRAS and/or PIK3CA (12/21; P<0.004). Undifferentiated p16ink4a-negative full-thickness precursors were identified in 7/70 (10%) SCC. Four histologically different HPV-independent penile precursor lesions can be assigned to 2 major genetic/biological pathways with characteristic highly differentiated precursors requiring different clinical management decisions. These include d-PeIN in chronic inflammatory dermatoses, with p53 overexpression and TP53/CDKN2A mutations, and the p53 wild-type verrucous and verruciform precursors unassociated with dermatoses, but with mutations in oncogenes PIK3CA and HRAS.

Detection of early (T1) lung cancers and lepidic adenocarcinomas in sputum and bronchial cytology

BackgroundThe lung is an extensively epithelialized organ, producing ample exfoliated material for sputum and bronchial cytology. In view of the updates in the World Health Organization classification of early (T1/≤ 3 cm) lung cancer with respect to adenocarcinomas with lepidic pattern, this study retrospectively reviews sputum and bronchial cytology paired with resection-confirmed lung cancers. MethodsA computerized search for all lung resection specimens of carcinomas over a 20-year period was performed. Cytologic diagnoses of corresponding sputum and bronchial cytology were classified into five-tiered categories (C1-insufficient/inadequate, C2-benign, C3-atypia, C4-suspicious and C5-malignant). Reports and slides of the resection specimen were reviewed for reclassification of T1 cancers. ResultsTotally 472 and 383 sputum and bronchial cytology specimens respectively were included. Sensitivity for T1 lesions on sputum cytology were 10.6 %, 2.1 % and 0.5 % at cutoffs of atypia/C3, suspicious/C4 and malignant/C5 categories, lower than bronchial cytology (35.1 %, 15.5 %, 8.1 %; p < 0.001). T1 lesions correlated with lower detection rates, whereas squamous cell carcinoma histology, larger size and bronchial invasion were associated with increased detection rates in sputum and bronchial cytology (p < 0.050). Detection rates for abrasive bronchial cytology (brushing) were overall higher (p = 0.018- < 0.001), but on subgroup comparison, non-abrasive (aspiration, lavage and washing) cytology demonstrated favorable trends (p = 0.063–0.088) in detecting T1 lesions. Adenocarcinomas with lepidic pattern had lower suspicious/C4 (p = 0.040) or above and malignant/C5 (p = 0.019), but not atypia/C3 or above (p = 0.517) rates. ConclusionsMost adenocarcinomas with lepidic pattern are only diagnosed as atypia/C3 on cytology. With its modest sensitivity, interpretation of negative and indeterminate cytology results mandates caution.

Machine-Learning-Aided Prediction of Brain Metastases Development in Non–Small-Cell Lung Cancers

PurposeNon–small-cell lung cancer (NSCLC) shows a high incidence of brain metastases (BM). Early detection is crucial to improve clinical prospects. We trained and validated classifier models to identify patients with a high risk of developing BM, as they could potentially benefit from surveillance brain MRI. MethodsConsecutive patients with an initial diagnosis of NSCLC from January 2011 to April 2019 and an in-house chest-CT scan (staging) were retrospectively recruited at a German lung cancer center. Brain imaging was performed at initial diagnosis and in case of neurological symptoms (follow-up). Subjects lost to follow-up or still alive without BM at the data cut-off point (12/2020) were excluded. Covariates included clinical and/or 3D-radiomics-features of the primary tumor from staging chest-CT. Four machine learning models for prediction (80/20 training) were compared. Gini Importance and SHAP were used as measures of importance; sensitivity, specificity, area under the precision-recall curve, and Matthew's Correlation Coefficient as evaluation metrics. ResultsThree hundred and ninety-five patients compromised the clinical cohort. Predictive models based on clinical features offered the best performance (tuned to maximize recall: sensitivity∼70%, specificity∼60%). Radiomics features failed to provide sufficient information, likely due to the heterogeneity of imaging data. Adenocarcinoma histology, lymph node invasion, and histological tumor grade were positively correlated with the prediction of BM, age, and squamous cell carcinoma histology were negatively correlated. A subgroup discovery analysis identified 2 candidate patient subpopulations appearing to present a higher risk of BM (female patients + adenocarcinoma histology, adenocarcinoma patients + no other distant metastases). ConclusionAnalysis of the importance of input features suggests that the models are learning the relevant relationships between clinical features/development of BM. A higher number of samples is to be prioritized to improve performance. Employed prospectively at initial diagnosis, such models can help select high-risk subgroups for surveillance brain MRI.

The Effect of Nasogastric Feeding after Surgery in Patients with Head and Neck Cancers – Retrospective Single Center Experience

This study aimed to assess clinical factors that could predict the need for nasogastric feeding after surgery in patients with head and neck cancer (HNC) and evaluate the effect of tube feeding on selected laboratory parameters. This single-center retrospective study included 153 patients who underwent surgery for HNC. Data on patient and tumor characteristics were collected, along with laboratory measurements. Logistic regression was used to identify the predictors of the need for nasogastric feeding. Laboratory parameters were compared between patients who required nasogastric feeding vs those who did not. Nasogastric feeding was required in 90 patients (59%). Significant predictors of nasogastric feeding in HNC patients after surgery, which were revealed by univariate regression analysis, included low body mass index (odds ratio [OR] = 0.84), squamous cell carcinoma histology (OR = 8.05), T2 tumor stage (OR = 2.27), red blood cell count (M/µL) (OR = 0.44), hemoglobin levels (g/dL) (OR = 0.80), and mean corpuscular volume (fL) (OR = 1.10). Multivariate analysis showed that low BMI (OR = 0.87) and red blood cell count (M/µL) (OR = 0.32) were prognostic factors for nasogastric feeding. A significant percentage increase in white blood cell count from admission to discharge was noted in patients who required nasogastric feeding vs those who did not (p = 0.003). Determining factors that predict the need for nasogastric feeding in HNC patients after surgery may support more personalized treatment planning to optimize clinical outcomes.

Carcinoma cervix: A single institute experience from Kashmir, Northern India.

Carcinoma cervix is the fourth most commonly diagnosed cancer worldwide, with an estimated 604,000 new cases and 342,000 deaths worldwide in 2020. Carcinoma cervix is an uncommon malignancy in Kashmir. In this retrospective study, we have tried to find clinicopathological characteristics of carcinoma cervix along with the survival rates at our tertiary care hospital. Case records of cervical cancer patients registered from January 1, 2015, to January 1, 2019, were retrieved. A total of 138 patients was registered. 22 had undergone surgery, and out of these 17 had received postoperative radiotherapy. 109 patients were treated with definitive chemoradiation and 13 with palliative radiotherapy. Descriptive statistics were used to summarize patient and treatment-related variables, and Kaplan-Meier analysis was performed for survival analysis. A total of 138 cases that were registered from 2015 to 2019 were included in this study. The median age at the presentation was 56 years. Most of the patients had a performance status of 1 (98 patients (71.01)). Most of the patients 110 (79.71%) were married before 20 years of age, only 1 patient was unmarried, and 85 (61.59) patients were multiparous in our study group. Only 14 (10.14%) patients in our study group had a history of oral contraceptive use and most of them were non-smokers [124 (89.80%)]. Multiple marriages were present in 8 (5.79%) patients only. The most common presenting symptom was bleeding per vagina (78.26%), and the maximum number of patients fall in the post-menopausal group (67.39%). 116 patients had squamous cell carcinoma histology while 10 patients had adenocarcinoma histology. Most of the patients had stage II and stage III disease (85 patients). At last, follow up out of 138 patients 75 (54.35) were alive. 3 year disease-free survival was 54.34% and 3-year overall survival was 72.46%. Carcinoma cervix is an uncommon malignancy in Kashmir because of different socio-cultural and religious practices but the response to treatment, toxicity profile, and survival are similar to the rest of the world.

Prognostic Impact of the Immune-Cell Infiltrate in N1-Positive Non–Small-Cell Lung Cancer

IntroductionThe tumoral immune milieu plays a crucial role for the development of non–small-cell lung cancer (NSCLC) and may influence individual prognosis. We analyzed the predictive role of immune cell infiltrates after curative lung cancer surgery. Materials and MethodsThe tumoral immune-cell infiltrate from 174 patients with pN1 NSCLC and adjuvant chemotherapy was characterized using immunofluorescence staining. The density and distribution of specific immune cells in tumor center (TU), invasive front (IF) and normal tissue (NORM) were correlated with clinical parameters and survival data. ResultsTumor specific survival (TSS) of all patients was 69.9% at 5 years. The density of tumor infiltrating lymphocytes (TIL) was higher in TU and IF than in NORM. High TIL density in TU (low vs. high: 62.0% vs. 86.7%; p = .011) and the presence of cytotoxic T-Lymphocytes (CTLs) in TU and IF were associated with improved TSS (positive vs. negative: 90.6% vs. 64.7% p = .024). High TIL-density correlated with programmed death-ligand 1 expression levels ≥50% (p < .001). Multivariate analysis identified accumulation of TIL (p = .016) and low Treg density (p = .003) in TU as negative prognostic predictors in squamous cell carcinoma (p = .025), whereas M1-like tumor- associated macrophages (p = .019) and high programmed death-ligand 1 status (p = .038) were associated with better survival in adenocarcinoma. ConclusionThe assessment of specific intratumoral immune cells may serve as a prognostic predictor in pN1 NSCLC. However differences were observed related to adenocarcinoma or squamous cell carcinoma histology. Prospective assessment of the immune-cell infiltrate and further clarification of its prognostic relevance could assist patient selection for upcoming perioperative immunotherapies.

Conservative treatment of cervical cancer: A single center experience over a two-decade period

ObjectiveTo report the surgical, oncological, and obstetrical outcomes of the different surgical techniques used for the fertility-sparing treatment of patients with early-stage cervical cancer. MethodsWe retrospectively analyzed all fertility-sparing procedures performed between 2004 and 2020. The study included patients desiring to preserve fertility who had squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma histology, all grades, and FIGO 2009 stage IA2-IB1 tumors. Results48 patients met the inclusion criteria. Eight patients (16.7%) had stage IA2, and 40 (83.3%) had stage IB1 tumors. Conization with pelvic lymph node assessment was performed in 5 (10.4%) patients, an open radical trachelectomy in 21 (43.8%), and a laparoscopic radical trachelectomy in 22 (45.8%). No major intraoperative complications were registered. Two patients required surgery due to an early postoperative complication. Late postoperative complications were seen in 15 patients (31.2%), with cervical stenosis being the most frequent (60%). The rate of DFS at 2 and 5 years was 89% (95% CI, 76–95%), and the 5- year OS was 96% (95% CI, 83–98%). Univariate analysis demonstrated a relationship between tumor size and recurrence, but not for other prognostic tumor factors or surgical approach. One patient (4.8%) developed recurrent disease in the open radical trachelectomy group, and five (22.7%) in the laparoscopic radical trachelectomy group. The pregnancy rate was 41.4%, and the live birth rate 88.2%. ConclusionFertility-sparing treatment for patients with early-stage cervical cancer is ever-evolving. This study adds information to the literature about the outcomes of these quite uncommon procedures, and allows a critical analysis of many of the topics which are under discussion.

Treatment trends and prognostic factors related to histology of squamous cell carcinoma of the prostate: A SEER review.

e17120 Background: Excluding skin cancers, prostate cancer is the most common malignancy in males. Over 93% of prostate cancers are adenocarcinomas, and as such, an abundance of literature exists with regards to its screening, treatment, and prognosis. Often overlooked, however, data is lacking with regards to squamous cell carcinoma (SCC) of the prostate, a rare alternative form of prostatic cancer comprising fewer than 1% of malignancies. Given the rarity of SCC of the prostate there are neither accepted treatment guidelines nor consistent characterizations of the disease’s histogenesis and histopathology. This study seeks to improve existing guidelines on the treatment of prostate SCC by supplementing current literature with a novel method of longitudinal data collection in the form of the SEER database. Methods: This was a retrospective cohort study utilizing the Surveillance, Epidemiology and End Results (SEER) database sponsored by the National Cancer Institute (NCI). Investigated variables entailed patient demographics such as race and age, tumor characteristics including grade, tumor type, and histopathologic characteristics. Treatment modalities (surgical resection, radiation therapy, and systemic therapy) as well as disease characteristics were considered in generating Kaplan Meier overall survival (OS) curves compared using log rank test. Results: The most abundantly utilized treatment was surgery (58.6%), either alone or in conjunction with systemic and radiotherapy. Surgery alone was utilized for 24 patients and chemotherapy alone was utilized for 7 patients. Interestingly, only 14% of patients received multimodality treatment. Prostatic squamous cell carcinoma was the ultimate cause of death in 63.8% of cases. Kaplan Meier analysis demonstrated a median OS of 13 months. When stratifying by histopathologic characteristics, our results showed a significant difference in overall survival between patients with papillary carcinoma, with the median survival time of four years, and non-keratinizing squamous cell carcinoma, with a median survival time of one year (p = 0.005). Conclusions: Further studies are warranted regarding this exceedingly rare and understudied malignancy. The current analysis suggests subclassification of SSC of the prostate into papillary versus non-keratinizing squamous cell carcinoma may yield valuable prognostic information. Further research may emphasize this distinction as well as the role of multimodal treatment which appears to be underrepresented in SSC of the prostate when compared to other similar malignancies.

The genomic, transcriptomic, and immunological landscape of SGLT2 in lung cancer.

9027 Background: Retrospective data suggest that SGLT2 inhibitors, commonly used in diabetes, are associated with a lower incidence of cancer development and in vivo data indicate SGLT2 plays a role in the development of NSCLC. We investigated the genomic and immunological landscape of NSCLC [adenocarcinoma (AC) or squamous cell carcinoma (SCC) histology] with high and low expression of the SGLT2-coding gene SLC5A2 and the relationship with clinical outcomes. Methods: NSCLC tumors of AC (N = 11,725) or SCC (N = 4,158) histology were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or whole exome) and RNA (whole transcriptome). PD-L1 expression (22C3; Positive (+): TPS ≥1%) was assessed by IHC. High tumor mutational burden (TMB-H) was defined as ≥10 mutations/MB. Mutations were defined as pathogenic SNVs/indels . SLC5A2-H and -L expression (transcripts per million) was defined as top and bottom quartile, respectively. A transcriptomic signature predictive of response to immunotherapy was applied (T cell-inflamed). The Mann-Whitney U test was applied as appropriate, with P-values adjusted for multiple comparisons (p &lt; .05). Real-world overall survival (OS) data was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined subpopulations of patients (N = 13,505). Results: In AC tumors, SLC5A2-H was associated with higher rates of EGFR (20.8 vs 13.5%, p &lt; .05) and STK11 mutations (20.1 vs 12.9%, p &lt; .05), but lower rates of TP53 (50.8 vs 69.5%, p &lt; .05) and ARID1A (8.7 vs 4.6%, p &lt; .05) mutations. There was no significant difference in the KRAS mutation rate (35.6 vs 37.1%, p = 1). AC and SCC SLC5A2-H tumors had a lower prevalence of PD-L1+ (AC: 47 vs 68%, SCC: 50 vs 67%, p &lt; .05). AC SLC5A2-H tumors had a lower prevalence of TMB-H (30 vs 39%, p &lt; .05), but not in SCC (40 vs 41%, p = .6). SLC5A2-H tumors were associated with a higher prevalence of T cell-inflamed tumors (AC: 40 vs 19%, SCC: 33 vs 11%, p &lt; .05). SLC5A2-H AC had longer OS as compared to SLC5A2-L AC tumors (HR = 0.787 [.73-.85], p &lt; .001) but no significant difference in time on treatment (TOT) with pembrolizumab was observed (HR .90 [.78-1.03], p = .13). SLC5A2-H SCC tumors had significantly longer OS (HR .88, [.78-1.00], p = .045) and they had significantly longer TOT with pembrolizumab (HR .72 [.56-.94], p = .01). Finally, SLC5A2-H, KRAS mutant AC tumors had significantly longer OS (HR .64 [.57-.73], p &lt; .001) whereas SLC5A2-H KRAS mutant SCC tumors (HR 1.46 [.83-2.57], p = .19) trended towards shorter OS. Conclusions: SLC5A2 expression was associated with a highly altered genomic landscape in AC. In specific mutational and histological subgroups, differences in SLC5A2 expression were associated with OS and responsiveness to immunotherapy. These mutational and histological subtypes should be further investigated as research on SGLT2 inhibitors progresses.

A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) SWOG S1609: The vulvar cancers.

5517 Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be effective in several malignancies but their potential role in various rare solid cancers is yet to be established. The efficacy of immunotherapy in vulvar cancer patients has not been explored. This study presents the first results of ipilimumab and nivolumab in vulvar cancers (cohort 35) of the SWOG S1609 Dual Anti-CTLA-4 &amp; Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease (SD) &gt; 6 months, and toxicity are secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years) were analyzed. 14 cases were of squamous cell carcinoma histology and 2 were of poorly differentiated carcinoma. ORR was 18.8% (3/16, 25% when including one unconfirmed PR). There was 1 CR (SCC; PFS of 465 days) and 2 PR (both SCC; one with 57% regression with PFS of 1022 days, another with 53% regression with PFS of 501 days). Of note, there was one SCC patient with unconfirmed PR that showed 69% regression with PFS of 209 days. Overall clinical benefit rate (CBR; no progression &gt; 6months) was 31.3% (5/16). The median PFS was 2.2 months, 6-month PFS 33%, 1-year PFS 20%. The median OS was 7.6 months, 6-month OS 62%, 1-year OS 44%. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n = 4 each). Grade 3-4 adverse events occurred in 25% of patients (n = 4). There was 1 grade 3-4 adverse event (6.7%) that led to discontinuation, and 1 (6.7%) grade 5 death adverse event. Conclusions: Ipilimumab plus nivolumab in vulvar cancers resulted in an ORR of 18.8% and CBR of 31.3%, with durable responses seen. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies exploring the role of immunotherapy in vulvar cancers are warranted. Clinical trial information: NCT02834013 .

Comprehensive genomic and immunohistochemical profiles and outcomes of immunotherapy in patients with recurrent or advanced cervical cancer.

This study aimed to investigate genomic and immunohistochemical (IHC) profiles and immunotherapy outcomes in patients with cervical cancer. Patients with recurrent cervical cancer who underwent tumor next-generation sequencing (NGS) with the TruSight Oncology 500 panel at Yonsei Cancer Center between June 2019 and February 2022, were identified. Patients who received treatment with checkpoint inhibitors during the same period were also identified. Clinical information, including histology, stage, human papillomavirus (HPV) genotype, IHCs profile, and therapy outcome, was reviewed. We identified 115 patients treated for recurrent cervical cancer, including 74 patients who underwent tumor NGS. Most of these 74 patients were initially diagnosed with advanced stage (63.6%) and had squamous cell histology (52.7%), and high-risk HPV (76.9%). Based on IHC analysis, the programmed death-ligand 1 combined positive score (PD-L1 CPS) was higher in patients with squamous cell carcinoma (SCC) than in those with adeno or mucinous types (P=0.020). HER2 receptor expression of 2+ and 3+ were identified in 5 and 1 patients, respectively, and significantly varied based on histology (p=0.002). Among the 74 patients, single nucleotide variants (SNVs) and copy number variations (CNVs) were identified in 60 (81.1%) and 13 patients (17.6%), respectively. The most common SNVs were PIK3CA, TP53, STK11, FAT1, and FBXW7 mutations. Mutations in PIK3CA, with two hotspot mutations, were frequently observed in patients with SCC histology, whereas mutations in TP53 were frequently observed in patients with non-SCC histology. Additionally, variations in FAT1 were exclusively identified in patients with SCC histology. Mutations in homologous recombination repair-associated genes were identified in 18 patients (24.3%). The most frequent CNV alteration was CCNE1 amplification. Moreover, among the 36 patients who underwent NGS and received immunotherapy, the tumor mutational burden and microsatellite instability were significantly correlated with immunotherapy duration. During this timeframe, 73 patients received pembrolizumab monotherapy, among whom a small portion showed a durable response. Comprehensive genomic and IHC profiling may help identify potential candidates for targeted immunotherapy in patients with cervical cancer.

Beneficial effects of postoperative radiotherapy for IIIA‑N2 non‑small cell lung cancer after radical resection analysed using the propensity score‑matching method.

The objective of the present study was to investigate the role of postoperative radiotherapy (PORT) after radical resection of stage IIIA-N2 non-small cell lung cancer (NSCLC). Subgroups of patients who benefited from PORT were evaluated. A retrospective review of 288 consecutive patients with resected pIIIA-N2 NSCLC at Beijing Chest Hospital (Beijing, China) was performed. Of these patients, 61 received PORT. The 288 patients were divided into PORT and non-PORT groups according to the treatment received. The baseline characteristics of the two patient groups were balanced using propensity score-matching (PSM; 1:1 matching). In total, 60 patients in the PORT group and 60 patients in the non-PORT group were matched. After PSM, the median survival time of the matched patients was 53 months. The 1-, 3- and 5-year overall survival (OS) rates of the PORT patient group were 95.0, 63.2 and 48.2%, respectively, while those of the non-PORT group were 86.7, 58.3 and 34.5%, respectively, and there was no significant difference between the two groups (P=0.056). The 5-year local recurrence-free survival (LRFS) rate in the PORT group was significantly improved (P=0.001). The effects of PORT on OS and LRFS rates were analysed in patients with different clinicopathological features. For subgroups with multiple N2 stations, N2 positive lymph nodes ≥4 and squamous cell carcinoma, PORT significantly increased the OS and LRFS rates (P<0.05). In conclusion, there was no statistically significant improvement in the 5-year OS rate with PORT overall, but there may be subgroups, such as patients with multiple N2 stations, N2 positive nodes ≥4 and squamous cell carcinoma histology, that could be explored as potentially benefitting from improved 5-year OS and LRFS rates with PORT.

Abstract 3330: Development of a genome-wide multiomic atlas of early-stage lung cancer enables identification of novel methylation biomarkers for disease detection beyond TCGA

Abstract Lung cancer is the leading cause of cancer mortality, mainly due to diagnosis at advanced stages. Early detection reduces mortality and screening by CT is recommended for a high-risk population, however, uptake is low. Biomarkers for early-stage detection may enhance screening. Liquid biopsy and blood circulating tumor DNA (ctDNA) are established plasma surrogates of tumor tissue but their use in early detection remains challenging due to the high noise level of current techniques. We constructed a novel multiomic atlas through whole genome sequencing (WGS) to map all genetic and epigenetic changes associated with early-stage lung cancer as a tool to identify markers. Biospecimens from 48 early-stage lung cancer cases (58% stage I) and 29 cancer-free controls, all high-risk by USPSTF, were acquired from academic (UBC, Vanderbilt, Cleveland Clinic) and commercial biobanks. Cases had tumor and normal lung tissue, whole blood (WB) and plasma samples. Controls had WB and plasma samples. EpiCheck sequencing (ECS) which combines methylation-sensitive restriction endonuclease digestion to detect differential methylation with WGS for multiomic analyses was performed on each sample. Extracted DNA was digested, underwent standard library preparation and sequenced at an average depth of 600x for cfDNA and 80x for tissue and WB. A subset also underwent WG bisulfite sequencing (BS) and standard WGS for comparison. Data analysis was performed using customized software. ECS outperformed BS. Mapping rate was 99.6%, 99.7% and 85.7% and unique mapping rate was 94.1%, 94.3% and 81.4% for WGS, ECS, and BS samples, respectively. Copy number integrity showed Pearson correlations of 0.9 for ECS and 0.67 for BS. Somatic mutation analysis in tissue identified a subset of cases with relatively high ctDNA shedding in plasma that were associated with larger tumors, older age and squamous cell carcinoma histology. This subset was further used to identify tumor derived plasma-based markers and assess fragmentation with high confidence. Shorter ctDNA fragments were observed in some, but not all cases. Additional analysis of WB and plasma identified host derived blood-based markers using methylation and copy number. This orthogonal approach enabled detection of small, low shedding tumors. A discovery panel of 87 markers showed 100% sensitivity and 97% specificity to discriminate cases vs controls. Only 11% of these markers are represented in the TCGA data. ECS generates high integrity sequencing data superior to BS, enabling genome-wide multiomic analyses (methylation, mutation, copy number, fragmentomics), with methylation signatures beyond the scope of TCGA. Results, which require validation, underscore the potential of the EpiCheck lung cancer atlas as a development platform of novel blood biomarkers for early-stage lung cancer detection. Citation Format: Revital Knirsh, Stephen Lam, Anna McGuire, Peter J. Mazzone, Stephen Deppen, Eric Grogan, Fabien Maldonado, Orna Savin, Shacade Danan, Sarah Zaouch, Nimrod Axelrad, Dvir Netanely, Aharona Shuali, Catherine A. Schnabel, Adam Wasserstrom, Danny Frumkin. Development of a genome-wide multiomic atlas of early-stage lung cancer enables identification of novel methylation biomarkers for disease detection beyond TCGA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3330.

Relationship between Systemic Inflammatory Markers, GLUT1 Expression, and Maximum 18F-Fluorodeoxyglucose Uptake in Non-Small Cell Lung Carcinoma and Their Prognostic Significance

Factors involved in inflammation and cancer interact in various ways with each other, and biomarkers of systemic inflammation may have a prognostic value in cancer. Glucose transporter 1 (GLUT1) plays a pivotal role in glucose transport and metabolism and it is aberrantly expressed in various cancer types. We evaluated the differential expression of GLUT1, along with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in non-small-cell lung cancer (NSCLC), and then analyzed their prognostic significance. A total of 163 patients with resectable NSCLC were included in this study. Tumor sections were immunohistochemically stained for GLUT1 and GLUT3. Maximum standardized uptake value (SUVmax) was measured by preoperative FDG-PET, and neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) were derived from pretreatment blood count. GLUT1 and GLUT3 was positively expressed in 74.8% and 6.1% of the NSCLC tissues, respectively. GLUT1 expression was significantly correlated with squamous cell carcinoma histology, poor differentiation, high pathologic stage, old age, male, smoking, and high SUVmax (>7) (all p < 0.05). The squamous cell carcinoma and smoker group also showed significantly higher SUVmax (both p < 0.001). Systemic inflammation markers, including NLR, PLR, and LMR, were positively correlated with high SUVmax (all p < 0.05). High GLUT1 expression, high SUVmax, high NLR, and low LMR, were significantly associated with poor overall survival in patients with NSCLC. However, in the multivariate survival analysis, LMR was an independent prognostic factor overall (HR 1.86, 95% CI 1.05-3.3) and for the stage I/II cohort (HR 2.3, 95% CI 1.24-4.3) (all p < 0.05). Systemic inflammatory markers-NLR, PLR, and LMR are strongly correlated with the SUVmax and are indicators of aggressive tumor behavior. Specifically, LMR is a promising prognostic biomarker in NSCLC patients.

Utility of Elective Neck Dissection in Clinically Node-Negative Parotid Malignancy.

We sought to investigate the utility of elective neck dissection (END) in clinically node-negative parotid malignancy through the evaluation of factors that are associated with receiving END and survival analysis of patients who received END. Retrospective cohort database study. The National Cancer Database (NCDB). The NCDB was used to extract patients with clinically node-negative parotid malignancy. END was defined as having 5or more lymph nodes examined pathologically, as previously defined in the literature. Univariate and multivariate analyses were used to compare predictors of receiving END, rates of occult metastasis, and survival. Of the 9405 included patients, 3396 (36.1%) underwent an END. END was most frequently performed for squamous cell carcinoma (SCC) and salivary duct histology. All other histologies were significantly less likely to undergo END compared to SCC (p < .05). Salivary ductal carcinoma and adenocarcinoma had the greatest rates of occult node disease (39.8% and 30.0%, respectively), followed by SCC (29.8%). Kaplan-Meier survival analysis showed a statistically significant increase in 5-year overall survival in patients who received END with poorly differentiated mucoepidermoid (56.2% vs 48.5%, p = .004) along with moderately and poorly differentiated SCC (43.2% vs 34.9%, p = .002; 48.9% vs 36.2%, p < .001, respectively). Histological classification is a benchmark for determining which patients should receive an END. We demonstrated an increase in overall survival in patients who undergo END with poorly differentiated tumors of mucoepidermoid and SCC histology. As such, histology should be considered along with clinical T-stage and rate of occult nodal metastasis to determine eligibility for END.

Comparison of Recurrence Patterns between Adenocarcinoma and Squamous Cell Carcinoma after Stereotactic Body Radiotherapy for Early-Stage Lung Cancer.

We compared recurrence patterns between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) after stereotactic body radiotherapy (SBRT) for early-stage lung cancer. Patients with ADC and SCC histology, who were treated with SBRT for clinical stage IA1-IIA lung cancer at our institution, were included in the analysis. The rates of disease-free survival (DFS), overall survival (OS), local recurrence (LR), lymph node metastasis (LNM), and distant metastasis (DM) were calculated using the Kaplan-Meier method or the cumulative incidence function. Among the 204 patients analyzed, 138 and 66 were in the ADC and SCC groups, respectively. The median follow-up period was 60 months. The five-year DFS and OS rates were 57% vs. 41% and 69% vs. 48% in the ADC and SCC groups, respectively (p = 0.015 and 0.019, respectively). In the multivariate analysis, the histological type was not associated with DFS or OS. Five-year LR, LNM, and DM rates were 10% vs. 24%, 12% vs. 20%, and 25% vs. 27% in the ADC and SCC groups, respectively (p = 0.0067, 0.074, and 0.67, respectively). The multivariate analysis identified the histological type of SCC as an independent factor for LR (hazard ratio, 2.41; 95% confidence interval, 1.21-4.77; p = 0.012). The present results suggest that the risk of LR after SBRT is higher for SCC than for ADC.

Hematologic Paraneoplastic Syndrome in Newly Diagnosed Patients with Lung Cancer

Introduction: Lung cancer could have signs and symptoms generated by paraneoplastic syndromes. This study aimed to describe and analyze hematologic paraneoplastic syndrome in patients with lung cancer in Indonesia. Methods: This was a cross-sectional analytic study conducted in Persahabatan National Respiratory Referral Hospital, Jakarta, between September 2018 and February 2019, on all newly diagnosed patients with lung cancer whose diagnosis was established and who fulfilled the inclusion and exclusion criteria. Results: The mean age of subjects was 56.7 ± 11.4 years old. Most subjects were male, had normal nutritional status (42.6%), had a smoking history (75%), and had a moderate Brinkman Index (BI) value (52%). The most common type of histology was squamous cell carcinoma (SCC) (39.7%), with advanced stage (83.8%) and performance status &lt;2 (94.1%). Paraneoplastic anemia was 40.4%, associated with poor nutritional status and commonly normocytic normochromic anemia. The proportion of paraneoplastic leukocytosis was 39%, associated with males and smoking history. The proportion of paraneoplastic neutrophilia was 51.5%, and it was related to males, smoking history, and SCC histology type. Paraneoplastic hypereosinophilia and thrombocytosis proportions were 2.9% and 18.4%, respectively. The proportion of paraneoplastic hypercoagulability was 91.2%, which was caused by the elevated D-dimer level. Conclusion: The most common hematologic paraneoplastic syndromes in patients with lung cancer were hypercoagulability, neutrophilia, and anemia. The low hemoglobin (Hb) level of paraneoplastic anemia was associated with low body mass index (BMI). Male and smoking history in lung cancer patients were associated with paraneoplastic leukocytosis and/or neutrophilia.

Survival Outcomes of Metastatic Non-small Cell Lung Cancer Patients With Limited Access to Immunotherapy and Targeted Therapy in a Cancer Center of a Low- and Middle-Income Country.

To describe the survival outcomes of metastatic non-small cell lung cancer patients with limited access to immunotherapy and targeted therapy in a cancer reference center in Colombia. A retrospective analysis of metastatic non-small cell lung cancer patients treated between 2013 and 2018 was performed, majority diagnosed with adenocarcinoma. It was carried out in a public cancer reference center that provides care to patients of low and middle socioeconomic status. Overall survival and progression-free survival were evaluated by Kaplan-Meier analysis and log-rank test. A Cox regression model was performed for univariate and multivariate analysis. 209 patients were included with majority of adenocarcinoma (79.5%). First-line treatment was cytotoxic chemotherapy (50.2%), EGFR-targeted therapy (14.8%), chemoimmunotherapy (1.9%), and ALK-targeted therapy (1.4%). 31.6% received best supportive care. Median time of follow-up was 13 months, median overall survival was 11.2 months (95% CI, 7.9-14.4), 13 months for adenocarcinoma (95% CI, 8.1-17.9), and 2.5 months for squamous cell carcinoma (95% CI, 0.6-4.4) (P < .001). Median progression-free survival was 9.3 months (95% CI, 7.9-10.7) without differences according to the type of first-line therapy. Median time-to-treatment was 55 days and only 54% of patients with a tested actionable mutation in EGFR received an EGFR-targeted therapy as the first-line treatment. Multivariate analysis showed that squamous cell carcinoma histology and receiving best supportive care were independent factors for worse overall survival ((HR:1.8, 95% CI, 1.076-3.082, P=.026) and (HR:14.6, 95% CI, 8.921-24.049, P < .001), respectively). Meanwhile, squamous cell carcinoma histology was an independent factor for worse progression-free survival (HR:3.4, 95% CI, 1.540-7.464, P=.002). Despite advances in precision medicine, during the study period, cytotoxic chemotherapy was the most used treatment in our patients. Furthermore, about a third of them received best supportive care. The use of targeted therapies has been restricted by access to molecular diagnosis and remained low until 2018. Access to immunotherapy should be prioritized.

Safety and Efficacy of Concurrent or Sequential Radiotherapy Plus (PD-1) Inhibitors in Oligometastatic Esophageal Cancer.

We assess real-world outcomes, including safety and efficacy, of concurrent or sequential treatment with radiotherapy plus programmed cell death protein 1 (PD-1) inhibitors in patients with oligometastatic esophageal cancer (OMEC). This cohort study retrospectively collected clinical data of patients with synchronous or metachronous OMEC. All patients underwent concurrent or sequential treatment with radiotherapy plus PD-1 inhibitors. Each patient had up to five measurable metastatic lesions and up to three organs involved. Study endpoints were progression-free survival (PFS), treatment-related toxicities, locoregional progression-free survival (LRPFS), objective response rate (ORR), and disease control rate (DCR). Description statistics and Kaplan-Meier models were used for statistical analysis. A total of 86 patients were included, most of whom were diagnosed with squamous cell carcinoma histology (98%) and presented with synchronous OMEC (64%). The median follow-up period was 17 months (range: 6-32 months), the median PFS was 15.2 months (95% confidence interval: 12.1-18.2 months); and the 1- and 2-year PFS rates were 61.4% and 26.7%, respectively. The 1- and 2-year LRPFS were 91.3% and 57.3%, respectively. The ORR and DCR were 46.5% and 91.8%, respectively. Forty-two patients (48.8%) experienced grade 3 or higher treatment-related adverse events (TRAEs); a grade 5 treatment-related adverse event was observed in one patient (1.2%) who died of immune-related pneumonitis. Combining radiotherapy with PD-1 inhibitors is a safe and effective treatment option for patients with OMEC. No new safety concerns were identified in this study. However, due to the potential risk of cumulative toxicity, an individual risk-benefit assessment for each patient is required prior to treatment initiation.

Comparison of LNM and survival in T1 stage esophageal cancer patients based on histological classification: A large population-based study

Limited evidence and contradictory results have been reported regarding the impact of squamous cell carcinoma (SCC) and adenocarcinoma (AC) classification on lymph node metastasis (LNM) and prognosis in esophageal cancer (EC). We aimed to compare 2 histology types in terms of LNM and prognosis using a comprehensive statistical analysis of a large population. The Surveillance, Epidemiology, and End Results (SEER) database was used to extract patient information. Univariate and multivariate logistic or Cox regression, a multivariate competing risk model and propensity score matching (PSM) were used to explore the association between LNM or survival and the 2 histology types. Information for 4764 patients, including 1712 SCC and 3052 AC patients, was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate logistic regression analysis revealed a correlation between LNM and histology (odds ratio [OR] = 0.654, P = .037). We found that patients with AC had a better prognosis than SCC patients through both the multivariate Cox regression (hazard ratio [HR] = 0.866) and the multivariate competing risk model (subdistribution hazard ratio [SHR] = 0.704). However, no positive relation was found between LNM and histology type (P = .844) based on propensity score matching (PSM), and the prognosis remained poorer for the patients with SCC (P < .001). T1-stage EC with a histology of SCC may have a comparable risk of LNM as the AC type, while SCC has a poorer prognosis than the AC type.