Background

Cytological examination of urine is the most widely used noninvasive pathologic screen for bladder urothelial carcinoma (BLCA); however, inadequate diagnostic accuracy remains a major challenge.

Methods

We performed high-throughput proteomic analysis of ten paired BLCA and benign urothelial lesion (BUL) samples to identify ancillary proteomic markers for use in liquid-based cytology (LBC). Samples were analyzed mass spectrometry to identify differentially expressed proteins (DEP) between the two groups. A total of 4,839 proteins were identified and 111 DEP were confirmed as expressed at significantly different levels between the BLCA and BUL groups. Independent proteomic data generated from tissue samples (7,916 identified proteins and 784 DEP), along with comparative mRNA expression profiles from The Cancer Genome Atlas were analyzed for biomarker discovery. Six proteins, AHNAK, EPPK1, HSP90AB1, MYH14, OLFM4, and TUBB, were thereby identified as putative candidate and analyzed by immunostaining. To determine their immunocytochemical expression levels in LBC, protein expression was screened using data from The Human Protein Atlas and five proteins were finally selected for immunoreactivity validation in two independent LBC cohorts.

Results

These analyses confirmed AHNAK as a unique intracellular protein differing in immunohistochemical expression and subcellular localization between tumor and non-tumor cells. In conclusion, this study identified a new biomarker, AHNAK, applicable to discrimination between BLCA and BUL by LBC.

Conclusions

To our knowledge, the present study provides the first identification of a clinical biomarker for LBC based on in-depth proteomics.

Legal entity responsible for the study

Chnglim Hyun.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Tumor mutational burden (TMB) has emerged as a potent biomarker for cancer immunotherapy. In this study, we systematically analyzed the impact on TMB of both single-gene and co-occurring double-gene mutations in Chinese NSCLC and CRC patients.

Methods

FFPE tumor and matched blood samples of 291 NSCLC and 197 CRC patients were collected for NGS-based 450 cancer genes panel assay. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indel), copy number variations (CNV) and gene rearrangements in selected genes were assessed and tumor mutational burden (TMB) computed.

Results

37 and 81 genes were frequently mutated (each occurring in 15 or more patients) in our NSCLC and CRC cohorts, respectively, with 20 genes common to both. Mutations in most genes associated with higher TMB and exhibited similar trends between the two cohorts, examples including LRP1B, ARID1A, KMT2D, NOTCH1, FAT3, SPTA1, PRKDC etc. On the other hand, ALK- and EGFR-mutant patients possessed lower TMB in NSCLC (4.8 and 6.4, respectively) but higher in CRC. Interestingly, mutations in KRAS and TP53 saw significantly elevated TMB in NSCLC but not in CRC. In terms of double mutants, NSCLC patients with co-occurring KRAS-TP53 mutations had still higher level of TMB than either single mutant alone, consistent with reported clinical utility of immunotherapy for such patients. Our analysis produced a comprehensive list of such “synthetic rescue” pairs of genes where double mutants possessed significantly higher TMB. Finally, mutations in most gene pairs tended to be mutually dependent rather than exclusive, with consistent results between NSCLC and CRC (r = 0.41, p < e-16). A network of interactive co-mutations was assembled and functional clusters obtained.

Conclusions

Gene alterations have a clear and dramatic impact on TMB, offering mechanistic clues and suggesting potential for immunotherapy. Our comprehensive analyses of single- and double-gene mutations and their impact on TMB in two very different cancer types not only revealed novel insights, but also produced many fresh cases for further investigation. Our methods are very generic and easily adaptable to other cancers.

Legal entity responsible for the study

OrigiMed.

Funding

OrigiMed.

Disclosure

All authors have declared no conflicts of interest.

Background

The combined therapy of nedaplatin and amrubicin showed promising effect for advanced non-small-cell lung cancer patients in our previous phase I/II study (Ogawara et al. Chemotherapy. 2014;60(3):180-4.). In the phase I study, nedaplatin 100 mg/m² and amrubicin 25 mg/m² was recommended. In the phase II study, 17 out of 35 patients achieved a partial response, and the ORR was 48.6%. In the study, nedaplatin and amrubicin tend to be effective especially for the patients with squamous cell lung cancer (Sq-LC). Therefore, we assessed the efficacy and safety of the combination chemotherapy for patients with untreated, advanced or relapsed Sq-LC.

Methods

We did a single-armed, open-label, phase II study at 6 institutions in Nagasaki, Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20 to 75 years, Eastern Cooperative Oncology Group performance status of 0-1, adequate organ function. Primary endpoint was overall response rate (ORR) and the secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). This trial was registered with the UMIN Clinical Trials Registry, number UMIN000007587, and is closed to new participants.

Results

Between November 2012 and March 2016, 21 patients were enrolled. The patients were administered nedaplatin (100 mg/m², day 1) plus amrubicin (25mg/m², day 1-3) every 4 weeks. ORR was 33.3%, disease control rate was 71.4%, median duration of PFS was 4.2 months, median duration of OS was 14.6 months. Adverse events of grade 3/4 were neutropenia (38.1%), thrombocytopenia (9.5%), anemia (9.5%), febrile neutropenia (9.5%).

Conclusions

Combination therapy of nedaplatin and amrubicin could be an effective and tolerable first-line treatment option for patients with advanced or relapsed Sq-LC.

Clinical trial identification

UMIN000007587.

Legal entity responsible for the study

Nagasaki University Hospital.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Head & neck cancer patients treated with radical/adjuvant radiotherapy suffer from weight loss, the cause of which can be multifactorial. In this study we have evaluated weight loss pattern in H&N cancer patients receiving either conventional or conformal chemoradiotherapy (CCRT)/adjuvant radiotherapy (RT) and to find out possible factors.

Methods

A retrospective study was done using data of already treated head & neck cancer patients. Inclusion criteria- 1) Primary site: oral cavity, oropharynx, larynx, & hypopharynx. 2) Treated with either radical CCRT(with Inj. Cisplatin) or adjuvant RT. Exclusion criteria- 1) palliative radiotherapy, 2)treatment gap >6 days. Basic parameters were collected, weight at beginning & at end of Radiotherapy noted. As general rule, Ryle’s tube insertion was done only when needed (difficulty to swallow liquid).

Results

160 patients’ data were collected: 80 patients- Conformal RT (40 patients radical CCRT & 40 patients adjuvant RT), 80 patients- Conventional RT (40 patients radical CCRT & 40 patients adjuvant RT). Only 5 patients (2 conformal CCRT & 3 conformal RT) out of total 160 patients gained weight during course of RT. Hence, 155 patients suffered weight loss. We compared variables with absolute weight loss of ≤ 5kg & >5kg using Chi square (χ2) test. Also, variables were compared with relative weight loss of ≤ 10% & >10%. The variables affecting both absolute and relative weight loss were initial low KPS status, use of conventional RT technique and use of chemotherapy & higher radiation dose (>60Gy). It was also found that ryle’s tube insertion was significantly more in patients with >5kg/>10% weight loss.Table: 312P

Variables affecting absolute and relative weight loss: χ2 Assessment (P Value) (* indicates significant)

Conclusions

Weight loss in H&N cancer patients during CCRT/RT is expected. Conformal RT (which corresponds to reduced treatment volume & toxicities), better KPS status can limit the extent of weight loss. Addition of chemotherapy and higher radiation dose (>60Gy) will increase weight loss. Ryle’s tube insertion as prophylaxis may be considered, specially in patients with expected weight loss >5kg/>10%.

Legal entity responsible for the study

Subhadip Das, Debarshi Lahiri, Syamsundar Mandal, Priyanka Biswas.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Standard chemotherapy for extrapulmonary neuroendocrine carcinomas (EPNEC) is not established. Treatment for small cell lung cancer is also used for EPNEC. The efficacy of chemotherapy for elderly patients with EPNEC is not clear. The aim of this study is to estimate the efficacy of chemotherapy in the elderly with EPNEC.

Methods

We retrospectively investigated the patients of EPNEC who received 1^st line platinum-based chemotherapy between April 2007 to June 2018. The time to treatment failure (TTF), the overall survival time (OST) and the efficacy of chemotherapy were compared between two groups; the elderly patients group in which patients’ age was over 70 years old (group A) and the younger patients group that age under 70 years old (group B).

Results

Among 35 patients with EPNEC, 14 patients were group A and 21 patients were group B. Median age was 75 (70-86) years old in group A, which was 60 (41-69) years old in group B. Primary site included pancreas (n = 3), gastrointestinal (n = 6), prostate (n = 2), and primary unknown (n = 3) in group A, which included pancreas (n = 4), biliary duct (n = 1), gastrointestinal (n = 8), prostate (n = 1), urothelial duct (n = 2), salivary grand (n = 1), and primary unknown (n = 4) in group B. Primary chemotherapy contained cisplatin (CDDP) + etoposide (ETP) (n = 1), carboplatin (CBDCA) + ETP (n = 7), CDDP + irinotecan (CPT-11) (n = 6) in group A, which contained CDDP + ETP (n = 5), CBDCA + ETP (n = 2), CDDP + CPT-11 (n = 14) in group B. The initial dose of chemotherapy reduced in 43% of the patients in group A, which reduced in 23% of that in group B. The Median TTF was 71.5 (25-343) days in group A and 123.0 (41-154) days in group B (p = 0.50) and the median OST was 712 (101-888) days in group A, which was 333 (165-671) days in group B (p = 0.46). One patient (7%) had complete response and 3 patients (21%) had partial response in group A, 0 patient had complete response and 13 patients (61%) had partial response in group B, and disease control rate was 69% in group A, which was 76% in group B.

Conclusions

Though the effect of chemotherapy for the elderly EPNEC patients was insufficient compared with the younger patients, the prognosis was similar to that of the younger. Many of the elderly received CBDCA + ETP and CDDP + CPT-11 regimen, these may be acceptable for the elderly EPNEC.

Legal entity responsible for the study

Chikako Funasaka.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Case Summary

Leptomeningeal carcinomatosis (LMC) is a terminal event in advanced cancer, its incidence in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is increasing due to recent advances in systemic therapy and prolongation of survival.

Osimertinib is a third generation EGFR-tyrosine kinase inhibitor (TKI) with preclinical and early clinical studies showing activity against LMC resistant to previous TKI treatments and acquired T790M mutation.

We report a case of osimertinib in the treatment of LMC in a T790M-negative, EGFR-mutated NSCLC with significant clinical benefit and no toxicity.

Osimertinib is a potentially effective treatment for LMC associated with EGFR-mutated NSCLC regardless of T790M status and a well-tolerated treatment for poor performance status patients.

Background

Inhibition of the PD-1/PD-L1 pathway may induce anticancer immune responses in non-small cell lung cancer (NSCLC). Here, we analyzed the correlation between PD-L1 expression and clinicopathological characteristics, stromal tumor-infiltrating lymphocyts (sTILs), pulmonary major driver gene alteration in NSCLC.

Methods

PD-L1 expression characterizations by immunohistochemistry using the clone 22C3 antibody were performed on 1156 NSCLC (329 archived and 827 recently acquired tumor) and 198 small biopsy.

Results

PD-L1 high expression was observed in 9.7%, 6.5%, and 27.4% in recently acquired NSCLC, adenocarcinoma (ADC), and squamous cell carcinoma (SqCC) cohort, respectively, which showed higher than in archive cohorts previously reported in our group (4.9%, 0.5%, and 13.9% in NSCLC, ADC, and SqCC, respectively). In subgroup analysis, PD-L1 high expression was significantly associated with male sex (p = 0.002), larger tumor size (p < 0.001), pleural invasion (p = 0.001), venous and lymphatic invasion (p < 0.001), smoking history (p < 0.001), solid predominant histology (p < 0.001), and advanced pathological stage (p < 0.001) in ADC cohort. It tended to be more common in poorer differentiation (p = 0.011) and absence pleural invasion (p = 0.001) in SqCC. In the small biopsy specimens, PD-L1 high expression was found in 29.3% cases in NSCLC. PD-L1 high expression was significantly associated with high sTILs (p = 0.029). Both PD-L1 high and low expressions were more frequent in EGFR-wild type than in mutated type (p < 0.001).

Conclusions

PD-L1 high expression was significantly associated with poor differentiation and ≥50% sTILs. It was more frequently observed in EGFR-wild tumors. The prevalence of PD-L1 expression in recently acquired sample was higher than in archived sample, which suggests that PD-L1 expression should be evaluated as soon as possible after operation, otherwise will be reduced.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

In the 2016 Japanese Society guidelines for cancer of the colon and rectum, it is recommended to measure carcinoembryonic antigen (CEA) of the patient with colorectal cancer (CRC) after curative surgery every 1 to 3 months, as it is helpful to judge for recurrence of the disease. Although, it is reported that postoperative CEA level is more informative than preoperative CEA level for predicting prognosis (Tsuyoshi K, Yoshifumi S, Meier H et al. Association of Preoperative and Postoperative Serum Carcinoembryonic Antigen and Colon Cancer Outcome. JAMA Oncology. Publish online December 21, 2017), the association between persistently elevated CEA level after surgical resection and prognosis is still unclear. This study aimed to evaluate whether perioperative CEA level was useful for estimation of the prognosis in stage III CRC.

Methods

This retrospective study was conducted at the Cancer Institute Hospital of Japanese foundation of cancer research. A total of 505 consecutive patients who underwent curative resection for stage III CRC from March 2005 to December 2010 were identified. Postoperative CEA was measured within 12 weeks after surgery. High CEA level was defined as more than 5ng/ml. We examined disease-free survival (DFS), overall survival (OS) and the association of prognostic variables with DFS and OS.

Results

A total of 505 patients [272 (54%) male; median age 62 (23-85) years] were enrolled in this study. Patients with high CEA level of preoperatively and postoperatively were 5.5% (28/505) and 30% (153/505), respectively. The 3-year DFS rate for all patients was 74.5% and the 5-year OS rate for all patients was 87.5%. The 3-year DFS rate in patients with normal postoperative CEA level tended to be higher than in patients with high postoperative CEA level. Furthermore, the 5-year OS rate in patients with normal postoperative CEA level was significantly higher than in patients with high postoperative CEA level. In the multivariate analysis, N-stage, pathology and venous invasion were predictive factors of DFS. And pathology and postoperative CEA level were predictive factors of OS.

Conclusions

High postoperative CEA level may be a negative predictive factor for OS in patients who underwent curative resection for stage III CRC.

Legal entity responsible for the study

Ryotaro Kozuki.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.