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1.
Am J Case Rep ; 25: e944002, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38825807

ABSTRACT

BACKGROUND Orbital metastasis originating from hepatocellular carcinoma (HCC), particularly as an initial manifestation in patients without a known history of HCC, is rare. Few reports exist on the treatment of patients having HCC with orbital metastasis using targeted therapy or immunotherapy. CASE REPORT We report a case of advanced-stage HCC in a 65-year-old man who first presented with progressive, painless blurred vision and proptosis of the right eye for 2 weeks. The patient had no history of chronic liver disease or cancer. Computed tomography revealed an enhancing hyperdense extraconal mass in the right orbit; a biopsy revealed metastatic HCC. Abdominal CT, which was performed to investigate the primary cancer, revealed a 1.2×1.6-cm arterial-enhancing nodule with venous washout in hepatic segment 5, associated with liver cirrhosis. The patient's serum alpha-fetoprotein level was 70.27 ng/dL. Chest computed tomography revealed lung metastasis. Thus, first-line systemic therapy combining durvalumab and tremelimumab was initiated alongside palliative radiotherapy targeting the right orbit, which began 1 week after the first dose of dual immunotherapy. The patient had significant clinical improvement, reduced proptosis, and serum alpha-fetoprotein levels. CONCLUSIONS Although orbital metastasis is a rare manifestation of HCC, physicians should recognize and consider aggressive investigations for early diagnosis, especially in patients with existing risk factors for HCC. Dual immunotherapy with durvalumab and tremelimumab in combination with radiotherapy can be considered a potential treatment option for managing advanced HCC with orbital metastasis.


Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Hepatocellular , Liver Neoplasms , Orbital Neoplasms , Humans , Male , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/secondary , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Aged , Orbital Neoplasms/secondary , Orbital Neoplasms/therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal/therapeutic use , Immunotherapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Tomography, X-Ray Computed , Antineoplastic Agents, Immunological/therapeutic use
2.
Oncologist ; 2024 May 30.
Article in English | MEDLINE | ID: mdl-38815152

ABSTRACT

BACKGROUND: In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported. MATERIALS AND METHODS: Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ-Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated. RESULTS: The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, -5.54; 95% CI, -10.93 to -0.16) and pain (LSM difference, -2.94; 95% CI, -5.86 to -0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95). CONCLUSION: The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer. CLINICALTRIALS.GOV ID: NCT03189719.

3.
J Pers Med ; 14(4)2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38673030

ABSTRACT

BACKGROUND: The ability of the survival nomogram developed in the EACH study and albumin-bilirubin (ALBI) grade to predict the survival of advanced hepatocellular carcinoma (HCC) patients receiving oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) remains unvalidated. Here, we comprehensively evaluated these prognostic tools. METHODS: The survival nomogram and ALBI grade of each patient were assessed, and the area under the receiver operating curve (AUROC) and Harrell's C-index for the risk classification model were calculated. RESULTS: Overall, 76 HCC patients who received FOLFOX4 between August 2017 and June 2023 were included. The survival nomogram classified patients into low-, intermediate-, and high-risk groups, with a median overall survival (OS) of 9.82, 10.64, and 3.70 months, respectively (p = 0.23). The AUROC was 0.621 and Harrell's C-index was 0.589. However, the ALBI grade categorized all patients into grade 1, 2, and 3, with a median OS of 9.82, 6.83, and 1.58 months, respectively (p = 0.00024). The AUROC was 0.663 and Harrell's C-index was 0.663. CONCLUSION: The ALBI grade can be a potential prognostic tool. However, the survival nomogram does not provide clear discrimination. Therefore, FOLFOX4 should be an option for patients with ALBI grade 1 who cannot receive immunotherapy or targeted therapy. Additional prospective studies with a larger cohort are warranted to validate the survival nomogram and ALBI grade as prognostic tools.

4.
BMC Cancer ; 24(1): 281, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38429725

ABSTRACT

BACKGROUND: No widely used prognostic tool exists to demonstrate the benefit of oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) in patients with advanced hepatocellular carcinoma (HCC). We aimed to establish a prognostic score and demonstrate the real-world efficacy of FOLFOX4 chemotherapy in Thai patients. METHODS: Between August 2017 and December 2021, we identified 58 FOLFOX4-treated patients with HCC. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were assessed. The prognostic score was constructed by stepwise Cox proportional hazards regression analysis to select variables for the best model with the lowest Akaike information criterion from all potential variables. RESULTS: Forty-four patients (76%) received FOLFOX4 as first-line therapy. The ORR in the entire cohort was 8.6%, and the disease control rate was 29.3%. The PFS and OS were 3.7 and 4.8 months, respectively. Four clinically relevant variables were included in the new prognostic score to predict 6-month OS: L, the presence of lung metastasis; A, alcoholic cirrhosis; B, elevated total bilirubin level; and S, sorafenib-naïve status. Using the LABS score, patients were classified into low-, intermediate-, and high-risk groups, demonstrating OS values of 9.3, 4.2, and 2.1 months, respectively (p < 0.0001). The C-index and area under the receiver-operating characteristic curve of the score were 0.71 and 0.73, respectively. CONCLUSIONS: The proposed LABS score could discriminate patients who would derive benefit from FOLFOX4 chemotherapy. FOLFOX4 chemotherapy is an option for patients who cannot receive immunotherapy and targeted therapy, particularly those with a low-risk score. However, further validation of this model via larger cohorts is warranted.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Prognosis , Retrospective Studies , Liver Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Fluorouracil , Leucovorin , Treatment Outcome
5.
J Clin Med ; 13(6)2024 Mar 17.
Article in English | MEDLINE | ID: mdl-38541960

ABSTRACT

Background: Although cisplatin plus 5-fluorouracil (5-FU) is the standard first-line treatment for advanced-stage esophageal squamous cell carcinoma (ESCC), carboplatin was substituted for cisplatin in cisplatin-ineligible patients. The efficacy of carboplatin plus 5-FU for advanced-stage ESCC remains unreported. Methods: This retrospective study analyzed first-line treatment-carboplatin plus 5-FU, cisplatin plus 5-FU, or best supportive care (BSC)-in advanced-stage ESCC patients at a tertiary hospital in Thailand (2012-2022). Survival was assessed using the Kaplan-Meier method, compared via the log-rank test, and adjusted through propensity score matching. Significance was set at p < 0.05. Results: Of 256 patients, 39.9% received carboplatin plus 5-FU, 27.7% cisplatin plus 5-FU, and 32.4% BSC. Carboplatin was significantly associated with older age, poorer performance status, more comorbidities, chronic kidney disease, and lower creatinine clearance. Median overall survival (OS) for carboplatin plus 5-FU, cisplatin plus 5-FU, and BSC was 8.05 (HR 0.31 [0.23, 0.43] vs. BSC, p < 0.001; HR 1.06 [0.78, 1.44] vs. cisplatin plus 5-FU, p = 0.7), 8.43, and 3.64 months, respectively. No significant OS difference was observed between carboplatin and cisplatin treatments after propensity score matching. Median progression-free survival (PFS) and objective response rates (ORR) showed no significant difference between carboplatin and cisplatin treatments. Conclusions: Despite less favorable baseline characteristics of patients receiving carboplatin plus 5-FU, this combination exhibited comparable OS, PFS, and ORR to cisplatin plus 5-FU in real-world scenarios. Furthermore, it significantly improved OS over BSC. Consequently, carboplatin plus 5-FU should be considered as an alternative regimen, particularly for advanced-stage ESCC patients who are ineligible for cisplatin.

6.
J Int Med Res ; 51(8): 3000605231193583, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37592923

ABSTRACT

OBJECTIVE: Combination fluoropyrimidine-based chemotherapy is the standard first-line treatment for metastatic colorectal cancer (CRC). We performed a propensity score (PS)-based analysis to report our real-world experience with long-term follow-up of this regimen for metastatic CRC. METHODS: In this retrospective study, 170 patients with newly diagnosed metastatic CRC treated with first-line combination chemotherapy between January 2003 and March 2021 were identified. Cox proportional hazards regression analysis and PS-based approaches with the logistic regression model were adopted, and the results were compared. RESULTS: The hazard ratio for overall survival (OS) in the oxaliplatin- and irinotecan-based groups was 0.79 (95% confidence interval = 0.56-1.11), and the median OS times in these groups were 16.8 and 13.0 months, respectively. The median time to progression (TTP) for these regimens were 9.0 and 8.9 months, respectively. The objective response rates for the oxaliplatin- and irinotecan-based groups were 42.7% and 34.6%, respectively. OS and TTP did not differ between these regimens in all PS matching models. CONCLUSIONS: First-line treatment using fluoropyrimidine-based chemotherapy regimens in combination with oxaliplatin or irinotecan in patients with metastatic CRC provided comparable efficacy and tolerable toxicity profiles in a real-world setting with long-term follow-up.


Subject(s)
Colonic Neoplasms , Rectal Neoplasms , Humans , Irinotecan/therapeutic use , Oxaliplatin/therapeutic use , Propensity Score , Retrospective Studies , Thailand , Drug Therapy, Combination
7.
Nat Med ; 29(8): 2133-2141, 2023 08.
Article in English | MEDLINE | ID: mdl-37524953

ABSTRACT

There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544-0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615-0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. ClinicalTrials.gov identifier: NCT03653507 .


Subject(s)
Adenocarcinoma , Stomach Neoplasms , Humans , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine/therapeutic use , Claudins/therapeutic use , Esophagogastric Junction/pathology , Oxaliplatin/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology
8.
Transl Cancer Res ; 11(5): 1033-1044, 2022 May.
Article in English | MEDLINE | ID: mdl-35706805

ABSTRACT

Background: c-Myc regulates multiple genes involved in cell proliferation in various cancer types including non-small cell lung cancer (NSCLC). Copy number gains of cytoband 17q25.3, along with chromosome 17, have been reported in NSCLC patients, emphasizing the clinical significance as a potential molecular target for therapy. The upregulation of c-Myc has been found to accelerate tumor development associated with duplication of the syntenic human cytoband 17q25.3. This study aimed to explore and compare the correlations of chromosome 17 copy number and c-Myc expression in NSCLC with the paired-normal respiratory epithelium and to examine their role as potential molecular targets for NSCLC therapy. Methods: A total of 66 NSCLC tissue samples with paired-normal respiratory epithelium were examined. The copy number of chromosome 17 was determined by human epidermal growth factor receptor 2 (HER2)/centromeric enumeration probe of chromosome 17 (CEP17) dual in situ hybridization (DISH). Results: Copy number gains of chromosome 17 were identified in 8 of 60 (13.3%) available NSCLC specimens. No copy number gains of chromosome 17 were demonstrated in the paired-normal respiratory epithelium. The mean HER2 (1.2±0.3) and CEP17 (1.4±0.3) copy numbers of the normal respiratory epithelium were significantly lower than those of the NSCLC tissue [1.8±1.0 vs. 2.0±0.8, respectively (P<0.001)]. Twelve of 66 (18.2%) NSCLC patients had overexpression of c-Myc. Five (41.7%) of the patients whose tumors positive for c-Myc had HER2 gene amplification [1] or copy number gain of chromosome 17 [4]. HER2 gene amplification or copy number gain of chromosome 17 and high expression of c-Myc were associated with decreased overall survival. Conclusions: Both biomarkers deserve further investigation to identify NSCLC patients with poorer survival outcomes requiring better therapeutic approaches.

9.
Case Rep Oncol ; 15(1): 191-198, 2022.
Article in English | MEDLINE | ID: mdl-35431867

ABSTRACT

Testicular neuroendocrine tumor associated with teratoma is a rare disease. Very few cases have been reported in the literature, particularly cases involving visceral metastasis. Teratoma with somatic malignant transformation (SMT) is associated with a worse prognosis compared to teratoma without SMT. Previous data have suggested that chemotherapy regimens should be directed toward the transformed histology; however, those suggestions were based on patients with rhabdomyosarcoma, adenocarcinoma, and primitive neuroectodermal subtypes. To the best of our knowledge, only 2 cases with visceral metastasis have been reported, and a better outcome with the bleomycin/etoposide/cisplatin regimen, which responds strongly to germ cell tumors, has been reported in these cases. In contrast, 2 others with lymph node metastasis did not respond to these regimens. Here, we report a case of a patient with testicular neuroendocrine carcinoma associated with teratoma who achieved a good response to chemotherapy.

10.
Clin Med Insights Oncol ; 16: 11795549221092747, 2022.
Article in English | MEDLINE | ID: mdl-35479767

ABSTRACT

Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer death worldwide, for which better knowledge in molecular prognostic factors is needed to improve clinical outcome. This study aimed to investigate the clinical significance of c-Myc, ALK, ROS1, BRAF, and PD-L1 in NSCLC patients. Methods: Formalin-fixed paraffin-embedded tissue specimens were obtained from 124 NSCLC patients. Of these, 66 matched specimens of normal respiratory epithelial and tumor tissue from patients with stages I-III, who underwent surgical resection, and 58 NSCLC specimens from stage IV patients were recruited into this analysis. Immunohistochemistry staining along with semiquantitative criteria were used to evaluate the expression of the interested proteins. Results: Of the 66 patients with stages I-III, positive expression of c-Myc was detected in 12 specimens (18.2%) of NSCLC tissue, whereas none of the normal respiratory epithelial tissue was found to have c-Myc expression (P < .001). Of the 66 NSCLC patients, 28 (43.8%) had PD-L1-positive staining on 1%-49% tumor cells and 7 (10.9%) patients expressed PD-L1 in ⩾50% tumor cells. One (2.3%) adenocarcinoma patient was found to have ROS1 rearrangement. Patients with no expression of c-Myc and PD-L1 (co-negative expression) tended to have a better prognosis than other subgroups. Conclusions: NSCLC tissue significantly expressed more c-Myc and PD-L1, compared with the matched normal respiratory epithelium, emphasizing the important role of these key drivers in tumorigenesis. Therapeutic approach to precisely inhibit the targetable molecular pathways should be considered on an individual patient basis to improve survival outcome.

11.
Lancet ; 398(10302): 759-771, 2021 08 28.
Article in English | MEDLINE | ID: mdl-34454674

ABSTRACT

BACKGROUND: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer. METHODS: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment. FINDINGS: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group. INTERPRETATION: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population. FUNDING: Merck Sharp & Dohme.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/therapeutic use , Esophageal Neoplasms/drug therapy , Fluorouracil/therapeutic use , Squamous Cell Carcinoma of Head and Neck/drug therapy , Double-Blind Method , Female , Humans , Male , Middle Aged , Survival
12.
J Gastrointest Cancer ; 51(3): 947-951, 2020 Sep.
Article in English | MEDLINE | ID: mdl-31758468

ABSTRACT

PURPOSE: A multimodality approach using concurrent chemoradiotherapy (CRT) followed by esophagectomy has been the standard treatment in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Computed tomography (CT) is widely utilized to evaluate esophageal cancer before and after CRT. This study evaluated the utility of pretreatment maximal esophageal wall thickness on CT scans to predict treatment outcomes after CRT in patients with locally advanced ESCC. METHODS: Eighty-one patients with T3 locally advanced ESCC, whom were treated completely with CRT with and without surgery, and had available CT scans before and after CRT at a university hospital between 2005 and 2015, were retrospectively reviewed. RESULT: Twenty patients (24.7%) had esophagectomy after neoadjuvant CRT and sixty-one patients (75.3%) had definitive CRT. The maximal esophageal wall thicknesses were measured retrospectively and correlated with the response and survival after treatment. A total of 40% of neoadjuvant CRT patients achieved a pCR. There was a significant difference in pretreatment maximal esophageal wall thickness between the pCR and non-pCR groups (mean 11.9 ± 5.3 mm versus 16.9 ± 3 mm; p = 0.01). Pretreatment maximal esophageal wall thickness < 10 mm was significantly related to better overall survival than ≥ 10 mm (median survival 79 months versus 15 months; HR 3.21, 95%CI 1.14-9; p = 0.02). The neoadjuvant CRT group had significantly better survival than the definitive CRT group (median survival 51 months versus 14.5 months; HR 0.46; 95%CI 0.25-0.85; p = 0.01). CONCLUSION: In our study, pretreatment esophageal wall thickness of T3 locally advanced ESCC is a useful indicator for predicting survival and pCR after treatment.


Subject(s)
Chemoradiotherapy/mortality , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/pathology , Esophagectomy/mortality , Neoadjuvant Therapy/mortality , Aged , Combined Modality Therapy , Esophageal Neoplasms/therapy , Esophageal Squamous Cell Carcinoma/therapy , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Survival Rate
13.
BMC Cancer ; 19(1): 1174, 2019 Dec 03.
Article in English | MEDLINE | ID: mdl-31795956

ABSTRACT

BACKGROUND: The prognoses of head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC) are poor, especially when both tumors occur at the same time. We examined the clonal relatedness of HNSCCs with synchronous ESCCs to confirm whether the second tumors were metastasis or separate second primary malignancies (SPMs) using loss of heterozygosity (LOH) analysis. METHODS: Twenty-one pairs of formalin-fixed paraffin-embedded tissue from HNSCC patients with synchronous esophageal cancer were analyzed by single nucleotide polymorphism (SNP) array using the Illumina HumanCytoSNP FFPE-12 BeadChip (San Diego, CA), which contains approximately 300,000 probes. LOH was identified using Nexus Copy Number software (El Segundo, CA). RESULTS: Comparing the LOH pattern between HNSCC and paired ESCC, we found that 20 out of 21 paired tissues had a high number of discordant LOHs (LOH identified solely in the primary HNSCC but not in synchronous ESCC at the same genomic location) and a low number of concordant LOHs (LOH at the same genomic location in both HNSCC and ESCC). Only one case fell into the undetermined category. Therefore, these 20 ESCCs were classified as SPMs or second field tumors (SFTs). Moreover, the HNSCC patients with molecularly confirmed esophageal SPM had significantly poorer survival than the other patients. CONCLUSIONS: We propose the use of a genome-wide SNP array as a tool to differentiate metastatic tumors from SPM/SFT. The SNP array offers genome-wide LOH information that earlier microsatellite analysis studies lack. The ability to accurately identify SPM should contribute to a better treatment plan and follow-up care of these patients.


Subject(s)
Esophageal Neoplasms/genetics , Esophageal Squamous Cell Carcinoma/genetics , Head and Neck Neoplasms/genetics , Neoplasms, Multiple Primary/genetics , Squamous Cell Carcinoma of Head and Neck/genetics , Aged , Clonal Evolution , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/pathology , Female , Head and Neck Neoplasms/pathology , Humans , Loss of Heterozygosity , Male , Neoplasms, Multiple Primary/pathology , Polymorphism, Single Nucleotide , Squamous Cell Carcinoma of Head and Neck/pathology
14.
Lung Cancer ; 104: 119-125, 2017 02.
Article in English | MEDLINE | ID: mdl-28212993

ABSTRACT

OBJECTIVE: The Phase III, randomized, open-label IPASS study (NCT00322452) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) gefitinib versus carboplatin/paclitaxel for Asian patients with advanced non-small-cell lung cancer (NSCLC) showed that investigator-assessed progression-free survival (PFS) and objective response rate (ORR) were significantly prolonged in patients with EGFR mutation-positive NSCLC who received gefitinib versus patients with EGFR mutation-negative NSCLC. We report post-hoc analyses of IPASS data by blind independent central review (BICR), performed at the request of the US FDA, in a subset of patients with EGFR mutation-positive NSCLC. PATIENTS AND METHODS: Eligible patients (aged ≥18 years; histologically/cytologically confirmed Stage IIB/IV adenocarcinoma NSCLC; non- or former light-smokers; treatment-naïve) were randomly assigned 1:1 to gefitinib (250mg/day) or carboplatin (dose calculated to produce an area under the curve of 5 or 6 mg/mL/minute)/paclitaxel (200mg/m2). Primary endpoint: PFS. BICR analyses included PFS, ORR, and duration of response (DoR). RESULTS: Scans from 186 IPASS patients (gefitinib n=88, carboplatin/paclitaxel n=98) with EGFR mutation-positive NSCLC were available for BICR. Consistent with investigator-assessed results, in patients with EGFR mutation-positive NSCLC: PFS (hazard ratio 0.54; 95% confidence interval [CI] 0.38, 0.79; p=0.0012) and ORR (odds ratio 3.00; 95% CI 1.63, 5.54; p=0.0004) were significantly longer with gefitinib versus carboplatin/paclitaxel. The median DoR by BICR was 9.6 months with gefitinib and 5.5 months with carboplatin/paclitaxel. CONCLUSION: BICR analysis of IPASS data support the original, investigator-assessed results. EGFR mutation-positive status remains a significant predictor of response to first-line TKI therapy.


Subject(s)
Asian People , Carboplatin/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Mutation , Paclitaxel/pharmacology , Quinazolines/pharmacology , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , Female , Gefitinib , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Protein Kinase Inhibitors/pharmacology , Quinazolines/administration & dosage , Randomized Controlled Trials as Topic , Smoking/epidemiology
15.
Clin Lung Cancer ; 18(1): 34-42.e2, 2017 01.
Article in English | MEDLINE | ID: mdl-27686971

ABSTRACT

INTRODUCTION: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non-small-cell lung cancer with EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes. PATIENTS AND METHODS: We performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR-mutation positive, advanced non-small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival. RESULTS: After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results. CONCLUSION: Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Mutation/genetics , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Double-Blind Method , Erlotinib Hydrochloride/administration & dosage , Female , Follow-Up Studies , Humans , Imidazoles/administration & dosage , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Pyrazines/administration & dosage , Survival Rate
16.
Oncol Res Treat ; 39(11): 688-694, 2016.
Article in English | MEDLINE | ID: mdl-27855414

ABSTRACT

BACKGROUND: Cisplatin-based chemotherapy followed by surgical resection of the residual tumor remains the standard of care for patients with mediastinal germ cell tumors (MGCTs). To prevent pulmonary complications, a non-bleomycin-containing regimen is generally preferred. This study aims to review the clinical characteristics and outcomes of these patients. METHODS: A retrospective chart review was undertaken in patients treated for MGCTs between 2003 and 2013. RESULTS: A total of 40 patients were enrolled; 7 patients were diagnosed with seminoma, while 33 patients had non-seminoma. 92% of patients received chemotherapy as a first treatment modality: 87% bleomycin, etoposide and cisplatin; 13% etoposide and cisplatin, with an objective response rate of 61.3%. Among these, 44% achieved a complete serological response. 17 patients underwent surgical resection of the residual tumor. No patient suffered from pulmonary complications after surgery. The 5-year overall survival (OS) was 71.4 and 27.3% in seminoma and non-seminoma patients, respectively (p = 0.051). For those who received chemotherapy followed by surgical resection with no viable tumor or only mature teratoma detected, the 5-year OS was 72.7% compared with 20.7% in patients not treated with surgery (p = 0.02). CONCLUSION: Our study confirmed the importance of a multimodality approach with primary chemotherapy followed by surgical resection of the residual tumor. A bleomycin-containing regimen can be safely used in this setting.


Subject(s)
Bleomycin/administration & dosage , Mediastinal Neoplasms/drug therapy , Mediastinal Neoplasms/mortality , Neoplasm Recurrence, Local/mortality , Neoplasms, Germ Cell and Embryonal/drug therapy , Neoplasms, Germ Cell and Embryonal/mortality , Adolescent , Adult , Antibiotics, Antineoplastic/administration & dosage , Combined Modality Therapy/mortality , Female , Humans , Longitudinal Studies , Male , Mediastinal Neoplasms/diagnosis , Neoplasm Recurrence, Local/prevention & control , Neoplasms, Germ Cell and Embryonal/diagnosis , Prevalence , Prognosis , Retrospective Studies , Risk Factors , Survival Rate , Thailand/epidemiology , Treatment Outcome , Young Adult
17.
J Med Assoc Thai ; 99(3): 331-7, 2016 Mar.
Article in English | MEDLINE | ID: mdl-27276745

ABSTRACT

BACKGROUND: Squamous cell carcinoma antigen (SCCA) and CYFRA 21-1 have been reported as useful tumor markers for esophageal squamous cell carcinoma (ESCC), but no information has yet been reported about the relationship between these serum tumor markers and tissue proliferative activity (Ki-67) in ESCC patients. OBJECTIVE: To study the correlation between SCCA, CYFRA 21-1, Ki-67, and clinicopathological factors in ESCC patients. MATERIAL AND METHOD: Pretreatment SCCA and CYFRA 21-1 serum levels were measured, while the expression of Ki-67 was assessed on tumor tissue. The associations between these biomarkers, clinicopathological factors, and overall survival were analyzed. RESULTS: One hundred sixty six patients participated in this study. Elevated SCCA and CYFRA 21-1 were found in 78.9% and 50.0% of the patients, respectively, while 42.8% had both serum markers elevated. The SCCA and CYFRA 21-1 levels were not correlated (p = 0.128) to each other nor to age, sex, T N, M location, grade, or Ki-67. High Ki-67 expression levels were significantly correlated with T4 (p = 0.010), M1 (p = 0.010), and poor grade (p = 0.015) but not to age, sex, N, or location. Levels of SCCA, CYFRA 21-1, and Ki-67, alone or in any combination, were not correlated to survival of patients. CONCLUSION: The authors showed that Ki-67 in tumor tissue is probably a more reliable marker than serum SCCA and CYFRA 21-1 in predicting the clinical course of ESCC.


Subject(s)
Antigens, Neoplasm/blood , Carcinoma, Squamous Cell/pathology , Esophageal Neoplasms/pathology , Keratin-19/blood , Ki-67 Antigen/metabolism , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/blood , Esophageal Neoplasms/blood , Esophageal Squamous Cell Carcinoma , Female , Humans , Male , Middle Aged , Serpins/blood
18.
J Cancer Res Clin Oncol ; 142(4): 749-56, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26621152

ABSTRACT

PURPOSE: To identify potential biomarkers that may provide new therapeutic targets or prognostic indicators for non-small cell lung cancer (NSCLC), we investigated the three-dimensional (3D) organization of telomeres and cytoband 17q25.3 copy number in NSCLC tissues. METHODS: NSCLC paraffin-embedded tissue specimens from 18 patients were assessed for 3D telomere organization by 3D nuclear telomere imaging followed by quantitative analysis. Patients were stratified by smoking, histology, and EGFR status. Cytoband 17q25.3 was examined by fluorescent in situ hybridization. Data from comparative genomic hybridization and/or single nucleotide polymorphism arrays for cytoband 17q25.3 were obtained and correlated with Q-FISH and 3D telomere results. RESULTS: 3D telomeric profiling demonstrated that the smokers, EGFR-negative, and squamous cell carcinoma subgroups tended to have higher numbers of lower-intensity telomeres, indicative of shorter telomeres, as well as higher numbers of telomeric aggregations compared to non-smokers, EGFR-positive, and adenocarcinomas, respectively. Gains of cytoband 17q25.3 in conjunction with an increase in the control region 17p11.2 were observed in 7 of 18 (38.9 %) patients, reflecting a gain of chromosome 17. Clonal gains of cytoband 17q25.3 were observed in 11 of 18 (61 %) patients, highlighting a potential biological significance for the genes in this region in NSCLC tumourigenesis. CONCLUSIONS: The 3D telomere profiles may differentiate NSCLC patients with different histologies, EGFR, and smoking statuses, rendering them a potential biomarker for distinguishing these clinically relevant histological and molecular subtypes of lung cancer. Highly frequent clonal gain of cytoband 17q25.3 was also demonstrated, suggesting an important biological role for the genes in this region.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Chromosomes, Human, Pair 17 , DNA Copy Number Variations , ErbB Receptors/genetics , Lung Neoplasms/genetics , Polymorphism, Single Nucleotide , Smoking/adverse effects , Telomere/metabolism , Adenocarcinoma/genetics , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , Comparative Genomic Hybridization , Female , Humans , In Situ Hybridization, Fluorescence , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Survival Analysis , Telomere/genetics
19.
Nutr Cancer ; 66(1): 1-5, 2014.
Article in English | MEDLINE | ID: mdl-24274379

ABSTRACT

Concurrent chemoradiotherapy (CCRT) induces toxicities from inflammation and immunological suppression. Omega-3 fatty acids, glutamine, and arginine are therapeutic factors that can attenuate such inflammation and promote cellular immunity. The question is whether immunonutrition (IN) during CCRT reduces inflammation and improves the immune function in patients with esophageal squamous cell carcinoma (ESCC). Seventy-one locally advanced ESCC patients being treated with CCRT (5-FU and cisplatin) were randomized into 2 groups. The IN group received a combination of omega-3 fatty acids, glutamine, and arginine, whereas the control group received standard formula. The levels of C-reactive protein (CRP), tumor necrosis factor (TNF), interferon-gamma (IFN), interleukin (IL-6, IL-10), CD3, CD4, CD8, white blood cells, neutrophils, and total lymphocytes were measured before and during treatment. The levels of CRP (P = 0.001) and TNF (P = 0.014) increased more during treatment in the control group than the treatment group, whereas IFN, IL-6, and IL-10 were similar but not significantly. CD3, CD4, CD8, white blood cells, neutrophils, and total lymphocytes decreased more in the control group than in the treatment group, but not significantly. Enteral IN during CCRT reduced the increase of inflammatory cytokine levels.


Subject(s)
Carcinoma, Squamous Cell/therapy , Chemoradiotherapy/methods , Enteral Nutrition , Esophageal Neoplasms/therapy , Inflammation Mediators/blood , Adult , Aged , Arginine/administration & dosage , C-Reactive Protein/metabolism , Chemoradiotherapy/adverse effects , Cisplatin/therapeutic use , Esophageal Squamous Cell Carcinoma , Fatty Acids, Omega-3/administration & dosage , Female , Fluorouracil/therapeutic use , Glutamine/administration & dosage , Humans , Immunity, Cellular/drug effects , Interferon-gamma/blood , Interleukin-10/blood , Interleukin-6/blood , Male , Middle Aged , Tumor Necrosis Factor-alpha/blood , Young Adult
20.
Breast Cancer Res Treat ; 142(1): 89-99, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24129974

ABSTRACT

Although the incidence of cancer increases with age, older patients are under-represented in cancer treatment trials, resulting in limited data availability in this patient population. Here we present results from pre-defined subgroup analyses conducted by age group (<65 vs ≥ 65 years) from a randomized, double-blind, placebo-controlled phase III trial in patients with HER2-positive metastatic breast cancer. Patients who had not received previous chemotherapy or biological therapy for HER2-positive locally recurrent, unresectable or metastatic breast cancer were randomly assigned to treatment with placebo, trastuzumab, and docetaxel or with pertuzumab, trastuzumab, and docetaxel. Primary endpoint was independently assessed progression-free survival. We performed pre-specified subgroup analyses of progression-free survival according to age. The study is registered with ClinicalTrials.gov, NCT00567190. 808 patients were enrolled. Of those, 127 patients were 65 years of age or older (placebo arm: 67, pertuzumab arm: 60). Patients in both age groups experienced progression-free survival benefit with treatment in the pertuzumab arm (<65 years: HR: 0.65; 95 % CI 0.53-0.80; ≥65 years: HR: 0.52; 95 % CI 0.31-0.86). Diarrhoea, fatigue, asthenia, decreased appetite, vomiting, and dysgeusia were reported more frequently in patients 65 years of age or older compared with younger patients. Neutropenia and febrile neutropenia were reported less frequently in the older age group. The efficacy and safety data reported in CLEOPATRA suggest that the combined use of pertuzumab, trastuzumab, and docetaxel should not be limited by patient age.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Adult , Age Factors , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Docetaxel , Female , Humans , Middle Aged , Neoplasm Metastasis , Receptor, ErbB-2/metabolism , Taxoids/administration & dosage , Trastuzumab , Treatment Outcome
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