The development of analytical techniques to study therapeutic monoclonal antibodies is expected to be useful for pharmacokinetic analysis and for the development of therapeutic indexes to determine ...dosage standards. To date, the blood concentration of antibody drugs has been analyzed by the enzyme-linked immunosorbent assay (ELISA). However, with the development of mass spectrometry and microfluidization technologies, the assay implication is drastically changing. We have developed an analytical validation method for many monoclonal antibodies and Fc-fusion proteins using Fab-selective proteolysis nSMOL coupled with liquid chromatography-mass spectrometry (LC-MS/MS). However, the correlation between the analyzed data characterization and the referable value from individual measurement techniques has not been adequately discussed. Therefore, in this study, we discussed in detail the relationship of the bioanalytical data from three different techniques, LC-MS/MS, ELISA, and microfluidic immunoassay, using 245 clinical plasma samples from non-small cell lung cancer patients treated with bevacizumab. The quantified concentration data of bevacizumab in human plasma indicated that the results obtained were almost the same correlation regardless of which technique was used. And the referable value from LC-MS/MS and microfluidic immunoassay were similar and correlated compared with ELISA.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Intraductal papillary mucinous neoplasm (IPMN) involves adenoma (IPMA), a precancerous lesion, cancer (IPMC) including high-grade dysplasia (HGD), and invasive carcinoma (IC). DNA markers ...of IPMN are required for detection of invasive disease, and
cysteine dioxygenase 1
(
CDO1
) gene promoter hypermethylation is a potential candidate. However, it has never been investigated in the context of IPMN.
Patients and Methods
A total of 107 IPMN tumor tissues, including 41 IPMC and 66 IPMA, were studied.
CDO1
promoter methylation was quantified using TaqMan quantitative methylation-specific polymerase chain reaction (qMSP) in patients with IPMN and other pancreatic cystic disorders after pancreatectomy.
Results
The methylation values (TaqMeth Vs) of
CDO1
increased when noncancerous pancreas tissues were compared with IPMA and HGD (
p
< 0.0001). Among IPMC, the TaqMeth Vs in IC were not significantly higher than in HGD. The TaqMeth Vs of the solid tumors were higher than those of the cystic tumors (
p
= 0.0016), which were in turn higher than the corresponding noncancerous tissues (
p
< 0.0001). Prognostic analysis revealed that high TaqMeth Vs (≥ 14.1) resulted in a poorer prognosis than low TaqMeth Vs (< 14.1) (
p
< 0.0001). In other pancreatic cystic diseases, only malignant mucinous cystic neoplasm showed DNA hypermethylation of its promoter. A pilot study in pancreatic juice confirmed methylation in all IPMN samples but not in benign pancreatic diseases (
p
= 0.0277).
Conclusions
CDO1
promoter hypermethylation is extremely specific to IPMN and may accumulate with IPMN tumor progression during the adenoma–carcinoma sequence. It might be a promising candidate as a diagnostic marker of pancreatic cystic diseases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The G8 questionnaire is a quick and easy-to-use screening tool. Several studies reported that the G8 questionnaire had a high sensitivity for predicting abnormalities in the full comprehensive ...geriatric assessment and predicted functional decline and survival in elderly cancer patients. The present study aimed to evaluate the role of the G8 questionnaire for predicting clinical outcomes and overall survival (OS) in elderly patients with lung cancer, who received chemotherapy or chemoradiotherapy. The data of 101 lung cancer patients aged ≥70 years, who were hospitalized between September 2011 and August 2014, were analyzed. Of these patients (median age, 77 years), 83 (82%) had impaired G8 scores. The proportion of patients with an impaired G8 score was significantly higher in patients aged ≥80 years than those aged <80 years (p = 0.04). All 18 patients with a normal G8 score possessed an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and none of the patients with a normal G8 score had an ECOG PS of ≥2 (p < 0.0001). An impaired G8 score tended to correlate with a relative dose intensity of <0.65 in patients who received chemotherapy or chemoradiotherapy (p = 0.05, odds ratio = 5.40). In the univariate analysis, an ECOG PS of ≥2 and an impaired G8 score were significantly associated with a poor OS (p = 0.009 and p = 0.003, respectively). Moreover, in the multivariate analysis, an ECOG PS of ≥2 (HR 2.55; 95% CI, 1.23-5.30; p = 0.01) and an impaired G8 score (HR 3.86; 95% CI, 1.44-13.36; p = 0.006) were remained independent prognostic factor for OS. G8 screening tool is useful for the prognostication of elderly lung cancer patients treated with chemotherapy. These finding suggest that the G8 questionnaire could be a useful tool in treatment decision-making to predict prognosis and prevent patients from receiving inappropriate anti-cancer treatment near the end of life.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immune checkpoint inhibitor has greatly altered the standard of care for patients with advanced non–small-cell lung cancer (NSCLC). This prospective study reported the benefits of nivolumab in a ...routine clinical practice. Furthermore, neutrophil-to-lymphocyte ratio was identified as a candidate of predictive markers in nivolumab-treated NSCLC patients.
The immune checkpoint inhibitor nivolumab is entering routine oncologic practice. We investigated the safety and efficacy of nivolumab in the real world and alternative predictive factors for survival in patients with advanced non–small-cell lung cancer (NSCLC).
We performed a prospective observational study to evaluate the activity of nivolumab treatment for chemotherapy-refractory NSCLC. Patients were treated with nivolumab once every 2 weeks, and the efficacy was assessed every 8 ± 2 weeks.
Fifty-two patients were enrolled after nivolumab approval in Japan. These patients received a median of 4 (range, 1-43) cycles of nivolumab. Overall objective response was observed in 12 patients (23.1%). Median progression-free survival was 2.1 (95% confidence interval, 1.0-3.2) months, and 1-year overall survival rate was 59.9%. A total of 23 immune-related adverse events occurred in 20 patients, as follows: 7 cases of pneumonitis, 6 of oral mucositis, 5 of hypothyroidism, 2 of colitis, 2 of liver dysfunction, and 1 of arthritis. All patients recovered after appropriate management. A pretreatment neutrophil-to-lymphocyte ratio (NLR) of ≥ 5 was significantly associated with poor prognosis compared to NLR < 5 (hazard ratio, 4.52; 95% confidence interval, 1.84-11.14; P = .013), independently.
Nivolumab showed promising activity with a manageable safety profile in clinical practice, consistent with effects of previous clinical trials. This drug could affect a specific population of patients with advanced NSCLC, and pretreatment NLR was a candidate for surrogate markers for survival benefit of patients with NSCLC treated with nivolumab.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cancer chemotherapy indications for patients with poor performance status and advanced lung cancer are limited. Molecular targeted drugs, including epidermal growth factor receptor (EGFR)-tyrosine ...kinase inhibitors, can be used in patients with poor performance status owing to their high efficacy and safety. The third-generation EGFR-tyrosine kinase inhibitor osimertinib has demonstrated effectiveness in the initial treatment of advanced EGFR mutation-positive non-small cell lung cancer in patients with good performance status; however, no evidence exists of the drug's effectiveness in patients with poor performance status in a prospective study. We designed a study that aims to investigate the efficacy and safety of first-line osimertinib treatment in patients with advanced non-small cell lung cancer harboring sensitive EGFR mutations and with poor performance status.
The OPEN/TORG2040 study is a multicenter, single-arm, phase II trial for patients with unresectable, advanced EGFR mutation-positive non-small cell lung cancer with a poor performance status (≥ 2). Eligible patients will receive osimertinib until disease progression or unacceptable toxicity. The primary endpoint is the objective response rate of the first-line osimertinib treatment. Considering a threshold value of 45%, expected value of 70% for objective response rate, one-sided significance level of 5%, statistical power of 80%, and ineligible patients, the sample size was set to 30. The secondary endpoints are disease control rate, performance status improvement rate, and safety and patient-reported outcomes using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Quality of Life Questionnaire and Lung Cancer 13. Time to treatment failure, progression-free survival, and overall survival will also be assessed.
Our study can determine the clinical benefits of osimertinib treatment in patients with poor performance status, since the clinical outcomes of patients with EGFR mutation-positive non-small cell lung cancer with poor performance status treated with this drug as a first-line treatment have not been sufficiently evaluated.
Japan Registry of Clinical Trials: jRCTs041200100 (registration date: February 12, 2021).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this study is to examine the factors related to oncologists’ use of the disease treatment and employment support guidance fee in Japan. A cross-sectional online survey was conducted in ...January 2021 among all the diplomates of the subspecialty board of medical oncology in the Japanese Society of Medical Oncology (n = 1,452), using the official mailing list. Logistic regression analysis was used to investigate the association between demographic and other factors and use of the disease treatment and employment support guidance fee. In total, 146 individuals participated in the study (response rate 10.0%). Experience of using the fee was associated with medical specialty and knowledge of the Guideline for Workplace Patient Coordination and Disease Treatment. It may be possible to increase the use of the disease treatment and employment support guidance fee among oncologists by raising awareness of the Guideline for Workplace Patient Coordination and Disease Treatment.
Oligometastasis is a state in which cancer patients have a limited number of metastatic tumors; patients with oligometastases survive longer than those with polymetastases. Extensive disease ...(ED)-small cell lung cancer (SCLC) is considered a systemic disease and a poor survival. This study investigated whether the concept of oligometastases is prognostic factor also applicable to patients with ED-SCLC.
We performed a retrospective study of 141 consecutive patients with ED-SCLC between 2008 and 2016. The patients were divided into four subgroups: group 1; patients with solitary metastatic site in one organ (n = 31), group 2; patients with 2-5 metastatic sites in one organ (n = 18), group 3; patients with over 6 metastases in one organ (n = 15), and group 4; patients with 2 or more metastatic organs (n = 77).
It was identified that 49 patients with ED-SCLC had oligometastases (groups 1 + 2) and 92 had polymetastases (groups 3 + 4). The prognoses of patients with ED-SCLC and oligometastases, defined as ≤5 metastases in a single organ, were significantly superior to those of patients with polymetastases 16.0 (95% CI, 11.0-21.0) months vs. 6.9 (95% CI, 6.0-7.8) months; p<0.001. 43 of 49 patients with ED-SCLC and oligometastases were relapsed after initial chemotherapy, and 38 (88%) experienced local recurrence.
Patients with ED-SCLC and oligometastases may have improved survival than those with polymetastases. As oligometastatic ED-SCLC tends to recur locally, local therapy combined with systemic chemotherapy may be a treatment option.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CD44 and CD133 are stem cell markers in colorectal cancer (CRC). CD44 has distinctive isoforms with different oncological properties like total CD44 (CD44T) and variant CD44 (CD44V). Clinical ...significance of such markers remains elusive.
Sixty colon cancer were examined for CD44T/CD44V and CD133 at mRNA level in a quantitative PCR, and clarified for their association with clinicopathological factors.
(1) Both CD44T and CD44V showed higher expression in primary colon tumors than in non-cancerous mucosas (p<0.0001), while CD133 was expressed even in non-cancerous mucosa and rather decreased in the tumors (p = 0.048). (2) CD44V expression was significantly associated with CD44T expression (R = 0.62, p<0.0001), while they were not correlated to CD133 at all in the primary tumors. (3) CD44V/CD44T expressions were significantly higher in right colon cancer than in left colon cancer (p = 0.035/p = 0.012, respectively), while CD133 expression were not (p = 0.20). (4) In primary tumors, unexpectedly, CD44V/CD44T/CD133 mRNA expressions were not correlated with aggressive phenotypes, but CD44V/CD44T rather significantly with less aggressive lymph node metastasis/distant metastasis (p = 0.040/p = 0.039, respectively). Moreover, both CD44V and CD133 expressions were significantly decreased in liver metastasis as compared to primary tumors (p = 0.0005 and p = 0.0006, respectively).
Our transcript expression analysis of cancer stem cell markers did not conclude that their expression could represent aggressive phenotypes of primary and metastatic tumors, and rather represented less demand on stem cell marker-positive cancer cells.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
. The optimal second and subsequent lines of chemotherapy for patients with non-small cell lung cancer (NSCLC) who have preexisting interstitial lung disease (ILD) are unclear. ...Hence, we examined the clinical efficacy and safety of second-line chemotherapy in such patients, including any exacerbation of preexisting ILD.
Methods.
The medical records of patients with NSCLC and preexisting ILD who received both first- and second-line chemotherapy were retrospectively reviewed.
Results.
Twenty-four patients with a median age of 71 years who were treated between April 2013 and March 2021 were included. The response rate after second-line chemotherapy with S-1 (n = 13), docetaxel (n = 8), pemetrexed (n = 2), or docetaxel plus ramucirumab (n = 1) was 12.5%, with a median progression-free survival (2nd line PFS) of 3.8 months. The overall survival from a start of first-line chemotherapy (1
st
line OS) and post-progression survival (PPS) post-first-line chemotherapy were 18.7 and 9.7 months, respectively. Spearman rank correlation and linear regression analyses showed that PPS was strongly correlated with 1st line OS (R = 0.85, P < 0.00001). Importantly, the 2nd line PFS was also significantly correlated with 1st line OS (R = 0.71, P = 0.0001). While second-line chemotherapy-related acute exacerbation of ILD was observed in 7 patients (29.2%), there were no treatment-related fatalities.
Conslusions.
Second-line chemotherapy has a strong positive impact on the OS of patients with NSCLC who have preexisting ILD. Given the findings of this study, second-line chemotherapy may be valuable in terms of prolonging long-term OS.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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