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PrPc is expressed in various tumors and is associated with cancer progression, but previous studies have shown conflicting results regarding its relationship with patient prognosis—potentially due to differences in the antibodies used. This study aimed to clarify the relationship between PrPc expression and primary esophageal squamous cell carcinoma (ESCC) and primary hepatocellular carcinoma (HCC) using a novel anti-PrPc antibody, 4AA-m, noted for its high specificity and sensitivity. We used flow cytometry to detect PrPc expression in ESCC and HCC cell lines. Immunohistochemistry with 4AA-m was then performed on tissue microarrays from 179 patients with primary ESCC and 92 patients with primary HCC. PrPc expression was semi-quantitatively assessed using the Tumor-DAB-H-Score, and its association with tumor prognosis was analyzed. In ESCC, PrPc expression was negatively correlated with lymph node metastasis, and patients with high PrPc expression had better overall survival compared to those with low expression. PrPc expression was identified as an independent prognostic factor for overall survival in ESCC. In HCC, patients with positive PrPc expression had shorter recurrence-free survival (RFS) than those without PrPc expression. PrPc expression was also found to be an independent prognostic factor for RFS in HCC.

Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103 + CD39 + tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103 + CD39 + CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103 + CD39 + CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103 + CD39 + CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies. Identifying and enumerating tumor-specific CD8 T cells are important for assessing cancer prognosis and therapy efficacy. Here the authors show that CD39 and CD103 mark a subset of tumor-infiltrating CD8 T cells that are tumor-reactive and exhibit characteristics of exhausted or tissue-resident memory T cells.

[Display omitted] •Correlations between muscle alteration postradiotherapy and prognosis are unknown.•We pooled data for 258 patients with esophageal squamous cell cancer who underwent radiotherapy.•Developed or continued myosteatosis presented as independent prognostic markers.•Muscle status alteration throughout radiotherapy should be considered prognostic indicator. We assessed the impact and prognostic significance of alterations in muscle quality and quantity (myosteatosis and sarcopenia, respectively) in patients with esophageal cancer treated with radiotherapy (RT). We retrospectively pooled 258 patients with esophageal squamous cell cancer who underwent RT. Myosteatosis and sarcopenia were determined based on the skeletal muscle index derived from the muscle area and attenuation at the L3 level from computed tomography images. Subgroups were formed as 2 subgroups of non-sarcopenia/myosteatosis and sarcopenia/myosteatosis (with or without other muscle status) at either timepoint of RT, 3 subgroups of only-sarcopenia, only myosteatosis (without other muscle status), and the co-presence of sarcopenia and myosteatosis at either timepoint of RT, as well as 4 subgroups of continuous sarcopenia/myosteatosis, developed sarcopenia/myosteatosis, reduced sarcopenia/myosteatosis and non-sarcopenia/myosteatosis according to alterations of muscle status at both timepoints of RT. Overall survival (OS) was compared. Univariate and multivariate analyses based on Cox regression identified independent risk factors for prognosis. Either pre- or post-RT, patients with sarcopenia and myosteatosis (with or without other muscle status) had poor OS. Patients with only myosteatosis (without other muscle status) showed the best OS (1352 days pre-RT vs. 1648 days post-RT), while patients with concurrent myosteatosis and sarcopenia had the worst OS (907 days pre-RT vs. 706 days post-RT). The ascending order of OS for sarcopenia alterations was as follows: continuous sarcopenia (1093 days), non-sarcopenia (1740 days), developed sarcopenia (2187 days), and reduced sarcopenia (2208 days) (P = 0.002). The ascending order of OS for myosteatosis alterations was ranked as follows: continuous myosteatosis (1165 days), reduced myosteatosis (1275 days), developed myosteatosis (1783 days), and non-myosteatosis (1942 days) (P = 0.061). Univariate and multivariate Cox regression analyses revealed that increased age, longer tumor length, developed myosteatosis, and continuous myosteatosis were independent prognostic factors for OS. Muscle mass status at presentation and alterations in patients with esophageal cancer before and after RT should be considered prognostic indicators.

Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash—a class effect of EGFR antibodies—that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4–12·6]) vs 9·9 months [8·9–11·1]; stratified hazard ratio 0·84 [95% CI 0·74–0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3–4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Eli Lilly and Company.

Oral squamous cell carcinoma (OSCC) is the most common type of head and neck (H&N) cancers with an increasing worldwide incidence and a worsening prognosis. The abundance of tumour infiltrating lymphocytes (TILs) has been shown to be a key prognostic indicator in a range of cancers with emerging evidence of its role in OSCC progression and treatment response. However, the current methods of TIL analysis are subjective and open to variability in interpretation. An automated method for quantification of TIL abundance has the potential to facilitate better stratification and prognostication of oral cancer patients. We propose a novel method for objective quantification of TIL abundance in OSCC histology images. The proposed TIL abundance (TILAb) score is calculated by first segmenting the whole slide images (WSIs) into underlying tissue types (tumour, lymphocytes, etc.) and then quantifying the co-localization of lymphocytes and tumour areas in a novel fashion. We investigate the prognostic significance of TILAb score on digitized WSIs of Hematoxylin and Eosin (H&E) stained slides of OSCC patients. Our deep learning based tissue segmentation achieves high accuracy of 96.31%, which paves the way for reliable downstream analysis. We show that the TILAb score is a strong prognostic indicator ( p  = 0.0006) of disease free survival (DFS) on our OSCC test cohort. The automated TILAb score has a significantly higher prognostic value than the manual TIL score ( p  = 0.0024). In summary, the proposed TILAb score is a digital biomarker which is based on more accurate classification of tumour and lymphocytic regions, is motivated by the biological definition of TILs as tumour infiltrating lymphocytes, with the added advantages of objective and reproducible quantification.

Purpose Intramural metastasis (IM) is a poor prognostic factor for patients with esophageal squamous cell carcinoma (ESCC). We conducted this study to assess the prognostic impact of IM in an Uzbekistan cohort and to identify the factors associated with the poor prognosis of patients with ESCC and IM. Methods The subjects of this retrospective analysis were 1083 patients with thoracic ESCC, who underwent curative esophagectomy between 2001 and 2021 at the National Cancer Center of Uzbekistan. We compared the clinicopathological characteristics and survival outcomes of patients with versus those without IM and evaluated the factors associated with the poor prognosis of patients with IM. Results Patients with pathological IM ( n  = 59, 5.4%) were significantly older, had a higher percentage of lymphatic invasion and worse pathological N stage, and had shorter overall survival (OS) than patients without IM. Multivariable analysis of OS identified multiple IMs as the only independent prognostic factor in patients with IM (hazard ratio, 6.04; 95% confidence interval, 2.77–13.18; P  < 0.001). Patients with multiple IMs had shorter OS and recurrence-free survival than those with a single IM. Conclusion IM was a poor prognostic factor for patients with ESCC in this Uzbekistan cohort and multiple IMs were associated with worse outcomes.

Microangiogenesis and lymphangiogenesis are essential for tumor growth in the tumor microenvironment, contributing to tumor invasion and metastasis. Limited literature exists on these processes in esophageal squamous cell carcinoma (ESCC). Therefore, the purpose of this study is to explore the impacts of microangiogenesis and lymphangiogenesis on the occurrence, progression, and prognosis assessment of ESCC. Surgical specimens and paraffin-embedded human tissues were procured from ESCC patients, encompassing 100 ESCC tissues and 100 cancer-adjacent normal (CAN) tissues. CD34 and D2-40 were utilized as markers for microvessel endothelial cells and lymphatic vessel endothelial cells, respectively. Microvascular density (MVD) and lymphatic vessel density (LVD) were evaluated through immunohistochemical quantification. We found that tumor tissues in ESCC patients had significantly higher MVD and LVD than cancer-adjacent normal (CAN) tissues. High MVD and LVD were associated with lymph node metastasis and advanced tumor clinical stages. Additionally, both high MVD and high LVD were strongly linked to poorer prognosis among cancer patients. Furthermore, a positive correlation was found between high MVD and high LVD ( < 0.05). The presence of these markers individually indicated a worse prognosis, with their combined assessment showcasing enhanced prognostic value. Overall, the increased MVD and LVD indicates higher invasion and metastasis of ESCC, closely correlating with unfavorablefor poor prognosis of ESCC patients.

Patients with head and neck squamous cell carcinoma (HNSCC) are at a high risk of developing recurrence and secondary cancers. This study evaluates the prognostic and surveillance utilities of circulating tumour cells (CTCs) in HNSCC. A total of 154 HNSCC patients were recruited and followed up for 4.5 years. Blood samples were collected at baseline and follow-up. CTCs were isolated using a spiral microfluid device. Recurrence and death due to cancer were assessed during the follow-up period. In patients with HNSCC, the presence of CTCs at baseline was a predictor of recurrence (OR = 8.40, p  < 0.0001) and death (OR= ∞, p  < 0.0001). Patients with CTCs at baseline had poor survival outcomes ( p  < 0.0001). Additionally, our study found that patients with CTCs in a follow-up appointment were 2.5 times more likely to experience recurrence or death from HNSCC ( p  < 0.05) prior to their next clinical visit. Our study highlights the prognostic and monitoring utilities of CTCs’ in HNSCC patients. Early identification of CTCs facilitates precise risk assessment, guiding treatment choices and ultimately enhancing patient outcomes.

Background and Aim Following treatment of superficial esophageal squamous cell carcinoma (ESCC), surveillance for a second primary malignancy (SPM) is necessary. However, detailed evidence regarding the timing and prognosis of SPMs is insufficient. We aimed to clarify the details of SPMs and their effects on patient outcomes. Methods This retrospective, multicenter study involved 11 hospitals. Patients with superficial ESCC curatively resected using endoscopic submucosal dissection between May 2005 and December 2012, were included in this study. Results The 5‐year survival rate of 187 patients was 92.6% during a median follow‐up duration of 96.8 months. Thirty‐one patients died, 14 of whom died of SPMs. Compared to patients with SPMs detectable by esophagogastroduodenoscopy (EGD), patients with SPMs detectable only by modalities other than EGD had a significantly higher mortality rate (p < 0.001). Patients with second primary lung cancer (LC) had a high mortality rate (56.3%). Univariate and multivariate analyses showed that multiple Lugol‐voiding lesions (LVLs) tended to be associated with SPMs (p = 0.077, hazard ratio [HR] 4.43, 95% confidence interval [CI]: 0.91–6.50), and metachronous ESCC was an independent risk factor for the incidence of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08–11.41). Conclusions SPMs that cannot be detected by EGD, such as LC, must be considered after the curative resection of ESCC. We suggest strict screening by both EGD and computed tomography for patients with multiple LVLs or metachronous ESCC to detect SPMs in their early stages. Patients after treatment of superficial esophageal squamous cell carcinoma (ESCC) had a worse outcome if they had second primary malignancies (SPMs). Especially, patients with second primary lung cancer (LC) had a high mortality rate (56.3%). Multiple Lugol‐voiding lesions tended to be associated with SPMs (p = 0.077, hazard ratio [HR] 4.43, 95% confidence interval [CI]: 0.91–6.50), and metachronous ESCC was an independent risk factor for the incidence of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08–11.41).