Prognostic effects of cytokine levels on patients treated with taxane and zoledronic acid for metastatic breast cancer in bone (BEAT-ZO) (KCSG BR 10-13).

Advanced breast cancer frequently metastasizes to the skeleton causing major mobility issues and hazards to quality of life. To manage osteolytic bone metastasis, bone-modifying agents and chemotherapy are recommended as the standard of care. Here, we investigated serologic biomarkers that might be associated with prognosis in breast cancer patients treated with zoledronic acid (ZA) and taxane-based chemotherapy. We collected serum samples from breast cancer patients with bone metastasis who received taxane plus ZA as palliative treatment. Fourteen biomarkers of angiogenesis, immunogenicity, and apoptosis were assessed, and the correlation between serum cytokine levels and patient's prognosis was statistically analyzed. Sixty-six patients were enrolled, and samples from 40 patients were analyzed after laboratory quality control. Patients with low baseline PDGF-AA, high IFN-γ, low MCP-2, low TGF-ß1, and low TNF-α were significantly associated with longer progression-free survival (PFS). Decreasing VEGF and TNF-α and increasing FGF-2 and PDGF-AA in the early treatment phase indicated longer PFS. In univariate and multivariate analyses, low TGF-ß1 and TNF-α and high IFN-γ at baseline were associated with a significantly low hazard ratio for disease progression. Further, we designed a risk score with TGF-ß1, TNF-α, and IFN-γ levels, which could prognosticate patients for PFS. In conclusion, serum cytokine level, such as TGF-ß1, TNF-α, and IFN-γ, could be a potential prognostic biomarker for breast cancer patients with bone metastasis treated with ZA and taxane-based chemotherapy.

A Randomized Controlled Trial of Epidermal Growth Factor Ointment for Treating Epidermal Growth Factor Receptor Inhibitor-Induced Skin Toxicities.

BACKGROUND: The efficacy of epidermal growth factor (EGF) receptor (EGFR) inhibitors in patients with non-small cell lung cancer (NSCLC), pancreatic cancer (PC), or colorectal cancer (CRC) has been demonstrated. However, dermatological reactions to these inhibitors can cause significant physical and psychosocial discomfort. The objective of the present study was to evaluate the efficacy of EGF ointment for EGFR inhibitor-related skin adverse events (ERSEs). MATERIALS AND METHODS: This placebo-controlled, double-blind, multicenter, pilot phase III trial enrolled patients with NSCLC, PC, or CRC treated with EGFR inhibitors. Patients with grade ≥2 ERSEs were included. Patients were randomized to three treatment arms: arm 1, placebo; arm 2, 1 ppm of EGF ointment; and arm 3, 20 ppm of EGF ointment. Patients applied ointment to their skin lesions twice daily. RESULTS: Efficacy evaluation was available for 80 patients (9 for PC, 28 for NSCLC, and 43 for CRC). Responses were 44.4% in arm 1, 61.5% in arm 2, and 77.8% in arm 3. There was a linear correlation between EGF concentrations and responses (p = .012). Quality of life (QoL) was assessed for 74 patients. Maximum changes in composite scores by Skindex-16 after treatment were significantly different among arms (mean ± SD: -5.2 ± 8.6 for arm 1, -11.7 ± 14.2 for arm 2, and - 18.6 ± 17.7 for arm 3; p = .008). EGF arms showed significant improvement in emotions (p = .005) and functioning (p = .044) scores over the placebo arm. CONCLUSION: EGF ointment is effective for managing ERSEs. It can also improve patients' QoL compared with placebo. Clinical trial identification number. NCT02284139 IMPLICATIONS FOR PRACTICE: Patients with non-small cell lung cancer, pancreatic cancer, or colorectal cancer who are treated with epidermal growth factor (EGF) receptor (EGFR) inhibitors may experience dermatologic reactions to their treatment. This study investigated the benefit of an EGF ointment in the treatment of these adverse events and observed the ointment to be effective in managing EGFR inhibitor-related skin adverse events.

Randomised Phase 2 study of lapatinib and vinorelbine vs vinorelbine in patients with HER2 + metastatic breast cancer after lapatinib and trastuzumab treatment (KCSG BR11-16).

BACKGROUND: The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments. METHODS: A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m2 D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m2 D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks. RESULTS: The median number of previous anti-HER2 therapies was 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61-1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72-1.58). Toxicity profiles were similar in both arms and all were manageable. CONCLUSIONS: Lapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT01730677.

Phase II trial of epidermal growth factor ointment for patients with Erlotinib-related skin effects.

PURPOSE: The efficacy of erlotinib, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated in patients with non-small cell lung cancer (NSCLC) and pancreatic cancer (PC). In the present study, we evaluated the effect of epidermal growth factor (EGF) ointment on erlotinib-related skin effects (ERSEs). METHODS: This was an open-label, non-comparative, multicenter, phase II trial. The patients included those diagnosed with NSCLC or PC who were treated with erlotinib. The effectiveness of the ointment was defined as follows: (1) grade 2, 3, or 4 ERSEs downgraded to ≤ grade 1 or (2) grade 3 or 4 ERSEs downgraded to grade 2 and persisted for at least 2 weeks. RESULTS: Fifty-two patients from seven institutes in Korea were enrolled with informed consent. The final assessment included 46 patients (30 males, 16 females). According to the definition of effectiveness, the EGF ointment was effective in 36 (69.2%) intention to treat patients. There were no statistically significant differences in the effectiveness of the EGF ointment by gender (p = 0.465), age (p = 0.547), tumor type (p = 0.085), erlotinib dosage (p = 0.117), and number of prior chemotherapy sessions (p = 0.547). The grading for the average National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) rating of rash/acne and itching improved from 2.02 ± 0.83 to 1.13 ± 0.89 and 1.52 ± 0.84 to 0.67 ± 0.90, respectively (p < 0.001). The most common reason for discontinuing the study was progression of cancer (37%). CONCLUSIONS: Based on the results, the EGF ointment is effective for ERSEs, regardless of gender, age, type of tumor, and dosage of erlotinib. The EGF ointment evenly improved all kinds of symptoms of ERSEs. CLINICAL TRIAL REGISTRATION NO: ClinicalTrials.gov identifier: NCT01593995.

Phase II Trial of Nilotinib in Patients With Metastatic Malignant Melanoma Harboring KIT Gene Aberration: A Multicenter Trial of Korean Cancer Study Group (UN10-06).

BACKGROUND: KIT has been suggested to be a potential therapeutic target for malignant melanoma. We evaluated the antitumor activity and safety of the KIT inhibitor nilotinib in metastatic melanoma patients harboring KIT gene mutations or amplifications. METHODS: We conducted a phase II multicenter trial of nilotinib in metastatic malignant melanoma with KIT mutations or amplifications. Patients received 400 mg oral nilotinib twice daily. The primary endpoint was response rate, and if seven or more responders were observed from the cumulative 36 patients, nilotinib would be considered worthy of further testing in this study population. RESULTS: Between October 2009 and June 2013, 176 patients underwent molecular screening for KIT gene aberrations, and 42 patients harboring KIT gene mutations and/or amplification were enrolled in the study. Overall, 25 (59.5%), 15 (35.7%), and 2 (4.8%) patients had KIT mutations, KIT amplifications, and both KIT mutations and amplification, respectively. Of the 42 enrolled patients, 1 patient achieved complete response, 6 patients achieved partial response, and 17 patients achieved stable disease, resulting in an overall response rate of 16.7% (95% confidence interval [CI]: 5.4%-28.0%) and a disease control rate of 57.1% (95% CI: 42.1%-72.1%). The median duration of response was 34 weeks (range: 5-55 weeks). Of the 7 responders, 6 patients had KIT mutations (exon 11: 5 patients; exon 17: 1 patient), and 1 patient had KIT amplification only. CONCLUSION: Although this study did not meet its primary endpoint of response rate, nilotinib showed durable response in a subset of metastatic melanoma patients with specific KIT mutations. IMPLICATIONS FOR PRACTICE: KIT aberration can be detected in a subset of metastatic melanoma patients. This phase II trial showed that nilotinib demonstrates durable response in a subset of patients with KIT mutations. The safety profile was very tolerable. This study suggests that a KIT inhibitor may benefit a small subset of metastatic melanoma patients with KIT mutations.

Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04).

PURPOSE: In the treatment of non-small-cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. MATERIALS AND METHODS: We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). RESULTS: A total of 228 patients with activating EGFR mutation (n = 215) or ALK translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% v 41.9%, P < .001) and median PFS (8.48 v 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; P = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 v 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm. CONCLUSION: To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with EGFR- or ALK-mutated NSCLC who have progressed on relevant targeted therapy.

Prognostic significance of neutrophil lymphocyte ratio and platelet lymphocyte ratio in advanced gastric cancer patients treated with FOLFOX chemotherapy.

BACKGROUND: Several inflammatory response materials could be used for prediction of prognosis of cancer patients. The neutrophil lymphocyte ratio (NLR), and the platelet lymphocyte ratio (PLR) have been introduced for prognostic scoring system in various cancers. The objective of this study was to determine whether the NLR or the PLR would predict the clinical outcomes in advanced gastric cancer patients treated with oxaliplatin/ 5-fluorouracil (FOLFOX). METHODS: The study population consisted of 174 advanced gastric cancer patients. Patients were treated with 85 mg/m2 of oxaliplatin as a 2-h infusion at day 1 plus 20 mg/m2 of leucovorin over 10 min, followed by 5-FU bolus 400 mg/m2 and 22-h continuous infusion of 600 mg/m2 at days 1-2. Treatment was repeated in 2-week intervals. The NLR and PLR were calculated from complete blood counts in laboratory test before and after first cycle of chemotherapy. RESULTS: NLR was a useful prognostic biomarker for predicting inferior overall survival (OS) (p = 0.005), but was not associated with progression free survival (PFS) (p = 0.461). The normalization of NLR after one cycle of chemotherapy was found to be in association with significant improvement in PFS (5.3 months vs. 2.4 months, p < 0.001), and OS (11.9 months vs. 4.6 months, p < 0.001). The normalization of PLR was also associated with longer PFS (5.6 months vs. 3.4 months, p = 0.006), and OS (16.9 months vs. 10.9 months, p = 0.002). In multivariate analysis, changes in NLR were associated with PFS (Hazard ratio (HR): 2.297, 95% confidence interval (CI): 1.429-3.693, p = 0.001). The NLR, (HR: 0.245, 95% CI: 0.092-0.633, p = 0.004), PLR (HR: 0.347, 95% CI: 0.142-0.847, p = 0.020), changes in NLR (HR: 2.468, 95% CI: 1.567-3.886, p < 0.001), and changes in PLR (HR: 1.473, 95% CI: 1.038-2.090, p = 0.030) were independent prognostic markers for OS. CONCLUSION: This study demonstrates that NLR, PLR, and changes in NLR or PLR are independent prognostic factor for OS in patients with advanced gastric cancer treated with chemotherapy. These specific factors may also help in identifying the patients, who are more sensitive to FOLFOX regimen.

The relationship of vascular endothelial growth factor gene polymorphisms and clinical outcome in advanced gastric cancer patients treated with FOLFOX: VEGF polymorphism in gastric cancer.

BACKGROUND: The aim of this study is to evaluate the associations between vascular endothelial growth factor (VEGF) Single-nucleotide polymorphisms (SNPs) and clinical outcome in advanced gastric cancer patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). METHODS: Genomic DNA was isolated from whole blood, and six VEGF (-2578C/A, -2489C/T, -1498 T/C, -634 G/C, +936C/T, and +1612 G/A) gene polymorphisms were analyzed by PCR. Levels of serum VEGF were measured using enzyme-linked immunoassays. RESULTS: Patients with G/G genotype for VEGF -634 G/C gene polymorphism showed a lower response rate (22.2%) than those with G/C or C/C genotype (32.3%, 51.1%; P = 0.034). Patients with the VEGF -634 G/C polymorphism G/C + C/C genotype had a longer progression free survival (PFS) of 4.9 months, compared with the PFS of 3.5 months for those with the G/G (P = 0.043, log-rank test). By multivariate analysis, this G/G genotype of VEGF -634 G/C polymorphism was identified as an independent prognostic factor (Hazard ratio 1.497, P = 0.017). CONCLUSION: Our data suggest that G/G genotype of VEGF -634 G/C polymorphism is related to the higher serum levels of VEGF, and poor clinical outcome in advanced gastric cancer patients.

Prognostic value of metabolic tumor volume on PET / CT in primary gastrointestinal diffuse large B cell lymphoma.

Primary gastrointestinal (PGI) diffuse large B cell lymphoma (DLBCL) is a relatively common disease. Recent studies indicate that measurement of maximum standardized uptake value (SUV(max)) on pretreatment for (18)F-fluorodeoxyglucose PET is an important prognostic factor in PGI DLBCL. However, there is still an association between initial tumor burden and prognosis. Thus, in the present study, we investigated whether tumor volume by PET could have a potential prognostic value to predict the outcome. From 2006 to 2009, 165 Stage I E/II E PGI DLBCL patients were enrolled in the study. One hundred and five patients received cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP) only, whereas 60 patients underwent surgery plus R-CHOP. Metabolic tumor volume (MTV) was defined initial tumor burden as target GI lesion above SUV, 2.5 by PET as a contouring border. Over a median follow-up period of 36.6 months, receiver operating characteristic (ROC) analysis indicated that the best cut-off values for MTV and SUV(max) were 160.1 cm(3) and 12.0, respectively. The estimated area under the ROC curve was higher for MTV than SUV(max). Thus, MTV was a better predictor for survival than SUV(max). In patients with a low MTV (<160.1 cm(3)), there were no significant differences in survival between patients undergoing R-CHOP alone and surgery plus R-CHOP (P = 0.347 for progression-free survival [PFS]; P = 0.148 for overall survival [OS]). Conversely, in patients with a high MTV (>160.1 cm(3)), survival was longer in those who underwent surgery plus R-CHOP than in those treated with R-CHOP alone (P < 0.001 for PFS; P < 0.001 for OS). Multivariate analysis revealed that high MTV is an independent factor for predicting survival. Even in the era of rituximab, treatment of PGI DLBCL is not easy in patients with a high MTV.

A phase II trial of Erlotinib in combination with gemcitabine and cisplatin in advanced pancreatic cancer.

BACKGROUND: Gemcitabine has been recognized as a standard chemotherapy in advanced pancreas cancer(APC). We conducted a phase II study of a triple combination regimen (GPT) consisting of gemcitabine (G), cisplatin(P) and erlotinib (T) in patients with APC. PATIENTS AND METHODS: Chemotherapy-naïve patients with locally advanced or metastatic, histologically confirmed adenocarcinoma of the pancreas were treated with erlotinib 100 mg daily, 1,000 mg/m2 of gemcitabine and 25 mg/m2 of cisplatin administered on days 1 and 8, respectively, every 3 weeks.The primary end point was objective response. Secondary end points included progression-free survival, overall survival and toxicity. The study was designed according to the optimal two-stage design. RESULTS: Twenty-two patients were enrolled between June 2009 and August 2010. No complete response was achieved and partial response was observed in 5 patients (26%), Stable disease in 7 (37%), and progressive disease in 7 (37%). The median time to progression was 4.0 months (95% CI: 2.9­5.1 months), and the median overall survival 6.8 months (95% CI: 3.7­9.9 months). The response rate in stage I reached the target (≥3/22,p0010%) established for movement to stage II but this study was determined to close earlier than planned because of unexpected treatment-related deaths (3 patients). CONCLUSION: The triple regimen of GPT is effective for APC. Treatment related mortalities factored early closure of this GPT protocol. Considering effect and toxicity, this triple regimen seems to offer few benefits to the patients compared with gemcitabine based doublets. (ClinicalTrials.gov number, NCT00922896).

Clinical significance of metabolic tumor volume by PET/CT in stages II and III of diffuse large B cell lymphoma without extranodal site involvement.

The objective of this study was to investigate whether metabolic tumor volume (MTV) by positron emission tomography (PET) can be a potential prognostic tool when compared with Ann Arbor stage, in stages II and III nodal diffuse large B cell lymphoma (DLBCL). We evaluated 169 patients with nodal stages II and III DLBCL who underwent measurements with PET prior to rituximab combined with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Cutoff point of MTV was measured using the receiver operating characteristic (ROC) curve. During a median period of 36 months, stage II was 59.2% and III was 40.8%. Using the ROC curve, the MTV of 220 cm(3) was the cutoff value. The low MTV group (<220 cm(3)) had longer progression-free survival (PFS) and overall survival (OS), compared with the high MTV group (≥220 cm(3)) (p < 0.001, p < 0.001). Stage II patients had longer survival than those in stage III (PFS, p = 0.011; OS, p = 0.001). The high MTV group had lower PFS and OS patterns, regardless of stage, compared with the low MTV group (p < 0.001, p < 0.001). Multivariate analysis revealed an association of the high MTV group with lower PFS and OS (PFS, hazard ratio (HR) = 5.300, p < 0.001; OS, HR = 7.009, p < 0.001), but not stage III (PFS, p = 0.187; OS, p = 0.054). Assessment of MTV by PET had more potential predictive power than Ann Arbor stage in the patients that received R-CHOP.

Clinical significance of preoperative neutrophil-lymphocyte versus platelet-lymphocyte ratio in patients with operable colorectal cancer.

The objective of this study was to clarify whether the neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR) are significant prognostic markers in patients with resectable colorectal cancer (CRC). A total of 200 patients who underwent curative resection for CRC were enrolled. The NLR and PLR were positively correlated (p < 0.001). Both the NLR and PLR were shown to be good prognostic biomarkers of overall survival (OS) (p=0.002 and p=0.001, respectively). The PLR was an independent prognostic factor of OS based on multivariate analysis (hazard ratio, 1.971; 95% confidence interval, 1.102-3.335; p=0.021).

Primary thyroid marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type: clinical manifestation and outcome of a rare disease - consortium for improving survival of lymphoma study.

PURPOSE: Primary thyroid marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type (pTY-MZL) is an extremely uncommon form of lymphoma. Due to its rarity, the natural history and optimal treatment modality for this disease have yet to be clearly established. METHODS: A total of 27 patients with histologically confirmed pTY-MZL were retrospectively analyzed. RESULTS: The median age of our subjects was 53 years (range 25-82). This study involved 17 females (63.0%) and 10 males (37.0%). Twenty-four out of 27 patients (88.9%) initially presented with localized disease, defined by Ann Arbor stage I/II. Bone marrow involvement was detected in 8.3% of the patients (2 patients), and 91.7% of the patients (25 of 27) were categorized into the low or low-intermediate risk group, according to the International Prognostic Index criteria. Accompanying Hashimoto's thyroiditis was detected in 72% of the patients, whereas thyroglobulin antibody levels were elevated in 70% of the patients. Twenty-six patients were treated with surgery, radiotherapy or chemotherapy, and 25 patients achieved complete remission. During the follow-up period, only 2 patients evidenced progression, and no deaths occurred over the course of the study. CONCLUSION: pTY-MZL tends to be an indolent disease. However, unlike other mucosa-associated lymphoid tissue site MZLs, pTY-MZL was well controlled via several treatment modalities, and the patients' responses were sustained for a prolonged period.

Prognostic significance of serum levels of vascular endothelial growth factor and insulin-like growth factor-1 in advanced gastric cancer patients treated with FOLFOX chemotherapy.

BACKGROUND: Tumor vascular endothelial growth factor (VEGF) is a key angiogenic factor and may have an impact on tumor progression and response to chemotherapy. The insulin-like growth factor (IGF) system is related to cell proliferation and tumor growth. However, there is limited available data regarding the clinical and prognostic significance of VEGF or IGF-1 in advanced gastric cancer. The aim of this study was to evaluate the prognostic significance of serum VEGF and IGF-1 levels in advanced gastric cancer patients who were treated with oxaliplatin/5-fluorouracil (FOLFOX). METHODS: The study population consisted of 100 advanced gastric cancer patients (median age 56 years). Patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1 plus leucovorin 20 mg/m(2) over 10 min, followed by a 5-fluorouracil (5-FU) bolus 400 mg/m(2) and 22 h of continuous infusion of 600 mg/m(2) on days 1-2. Treatment was repeated in 2-week intervals. The levels of serum VEGF and IGF-1 were measured using enzyme-linked immunoassays. RESULTS: There was a significant correlation between the serum level of VEGF and Lauren's classification (p = 0.030) and previous operations (p = 0.010). IGF-1 was associated with the number of metastases (p = 0.012). The median level of serum VEGF was decreased after FOLFOX chemotherapy (p = 0.034). However, none of the measured serum markers were significantly correlated with response. In univariate analysis, overall survival (p < 0.001) was significantly shorter in patients with high serum levels of VEGF. Multivariate analysis revealed that VEGF was an independent factor for overall survival (HR 2.221; 95% CI 1.377-3.583, p = 0.001). Furthermore, IGF-1 had no significant influence on the clinical outcome. CONCLUSION: A high level of serum VEGF is an independent prognostic factor in patients with advanced gastric cancer treated with chemotherapy. This may help to identify the patients who are more sensitive to the FOLFOX regimen.

Treatment outcomes between concurrent chemoradiotherapy and combination of surgery, radiotherapy, and/or chemotherapy in stage III and IV maxillary sinus cancer: multi-institutional retrospective analysis.

PURPOSE: The incidence of maxillary sinus cancer (MSC) is extremely rare, representing less than 1% of all cancers. Because of its rarity, the management of locally advanced MSC is a challenging issue. The objective of the present study was to retrospectively compare the efficacy of 2 traditional treatment strategies, concurrent chemoradiotherapy (CCRT) versus combination of surgery and radiotherapy and/or chemotherapy (SRCT) in MSC. PATIENTS AND METHODS: From 1989 to 2010, 65 patients with histologically confirmed stage III or IVA/IVB were retrospectively analyzed. RESULTS: The median age of our subjects was 60 years (range 36 to 81). The present study involved 18 women (27.7%) and 47 men (72.3%). Of the 65 patients, 52 (80.0%) had squamous cell carcinoma. The TNM stage was stage III, as determined by the American Joint Committee on Cancer, 6th edition, in 27 patients (41.5%). Stage IVA or IVB was observed in 38 patients (58.5%). Of the 65 patients, 41 underwent treatment. Of these 41 patients, 26 and 15 patients underwent SRCT and CCRT, respectively. During the 75.6 months (range 6.4 to 249.4) of median follow-up, the median progression-free survival duration was 45.1 months (95% confidence interval 0.0 to 142.7). The 5-year overall survival rate was 64.8%. However, the patients who had undergone surgery had better progression-free survival (hazard ratio 2.363, 95% confidence interval 1.098 to 5.085, P = .028) and overall survival (hazard ratio 4.989, 95% confidence interval 1.646 to 15.118, P = .004). The SRCT group had a better progression-free survival (P = .043) and overall survival (P = .029) duration than did the CCRT group. CONCLUSION: SRCT might be superior to CCRT for locally advanced MSC. Additional studies comparing the treatment outcomes of CCRT with SRCT are warranted.

Changes of Immune Cell Fractions in Patients Treated with Immune Checkpoint Inhibitors.

BACKGROUND: With the development of immunology, immune checkpoint inhibitors (ICIs) have been widely used in various cancer treatments. Although some patients can benefit from ICIs, other patients have no response to ICIs or suffer from hyperprogression. There has been no biomarker for predicting the efficacy of ICIs. Thus, the objective of this study was to find biomarkers for predicting the efficacy of ICIs using peripheral blood. METHODS: Adults patients planned to be treated with ICIs were enrolled in this study. Blood sampling was carried out before and after administration of ICIs. Changes of immune cell fraction were analyzed for each patient. RESULTS: Among 182 patients enrolled, immune cell analysis was performed for 90 patients. The objective response rate was 14.4% (n = 13/90). The median progression-free survival (PFS) was 6.0 months (95% CI: 3.1-8.9 months), and the median overall survival (OS) was 13.9 months (95% CI: 5.6-22.2 months). Significant benefits in ORR and OS were shown for patients with increased NKp46-/CD56+ NK cells (p = 0.033 and p = 0.013, respectively). The PFS tended to be longer in these patients, although the difference was not statistically significant (p = 0.050). CONCLUSION: Changes of immune cell fraction before and after administration of ICIs could be a novel biomarker for predicting the efficacy of immunotherapy.

Clinicopathologic significance of ERCC1, thymidylate synthase and glutathione S-transferase P1 expression for advanced gastric cancer patients receiving adjuvant 5-FU and cisplatin chemotherapy.

The objective of this study was to determine whether the expressions of the excision cross-complementing (ERCC1), thymidylate synthase (TS) and glutathione S-transferase P1 (GSTP1) are predictive of clinical outcomes in advanced gastric cancer (AGC) patients receiving treatment with adjuvant 5-fluorouracil (5-FU) and cisplatin (FP) chemotherapy. One hundred forty nine patients were included in this study. ERCC1 and GSTP1 expression was correlated significantly with tumor size (p = 0.040, p = 0.018, respectively). Stage and positive lymph node ratio were associated independently with disease free survival (DFS) and overall survival (OS). Both ERCC1 and GSTP1 expression had a significant impact on OS (hazard ratio = 0.069, p = 0.021). TS expression was not related to DFS and OS.

Relationship between heavy metal exposure and type 2 diabetes: a large-scale retrospective cohort study using occupational health examinations.

OBJECTIVES: To investigate the associations between heavy metal exposure and serum ferritin levels, physical measurements and type 2 diabetes mellitus (DM). DESIGN: A retrospective cohort study. SETTING: Changwon, the location of this study, is a Korean representative industrial city. Data were obtained from medical check-ups between 2002 and 2018. PARTICIPANTS: A total of 34 814 male subjects were included. Of them, 1035 subjects with lead exposure, 200 subjects with cadmium exposure and the 33 579 remaining were assigned to cohort A, cohort B and the control cohort, respectively. Data including personal history of alcohol and smoking, age, height, weight, the follow-up duration, haemoglobin A1c (HbA1c), fasting blood sugar (FBS), ferritin levels, and lead and cadmium levels within 1 year after exposure were collected. PRIMARY OUTCOME MEASURE: In subjects without diabetes, changes in FBS and HbA1c were analysed through repeated tests at intervals of 1 year or longer after the occupational exposure to heavy metals. RESULTS: In Cohort A, DM was diagnosed in 33 subjects. There was a significant difference in lead concentrations between the subjects diagnosed with DM and those without DM during the follow-up period (3.94±2.92 mg/dL vs 2.81±2.03 mg/dL, p=0.002). Simple exposure to heavy metals (lead and cadmium) was not associated with DM in Cox regression models (lead exposure (HR) 1.01, 95% CI: 0.58 to 1.77, p 0.971; cadmium exposure HR 1.48, 95% CI: 0.61 to 3.55, p=0.385). Annual changes in FBS according to lead concentration at the beginning of exposure showed a positive correlation (r=0.072, p=0.032). CONCLUSION: Our findings demonstrated that simple occupational exposure to heavy metals lead and cadmium was not associated with the incidence of DM. However, lead concentrations at the beginning of the exposure might be an indicator of DM and glucose elevations.

Clinicopathological significance of nuclear factor-kappa B, HIF-1 alpha, and vascular endothelial growth factor expression in stage III colorectal cancer.

Nuclear factor-kappaB (NF-kappaB), hypoxia-inducible factor 1alpha (HIF-1alpha), and vascular endothelial growth factor (VEGF) are involved in cell proliferation, invasion, angiogenesis, and metastases. The principal objective of this study was to assess the prognostic significance of NF-kappaB, HIF-1alpha, and VEGF expression in stage III colorectal cancer. Tumor tissues from 148 patients with stage III colorectal carcinoma, all of whom underwent potentially curative resection, were immunohistochemically evaluated using monoclonal antibodies against NF-kappaB, HIF-1alpha, and VEGF. Positivity rates of NF-kappaB, HIF-1alpha, and VEGF were 47.3%, 42.6%, and 61.5%, respectively. NF-kappaB expression in tumor tissues was correlated significantly with HIF-1alpha expression (P < 0.001), VEGF expression (P = 0.044), and the presence of vascular invasion (P = 0.013). Univariate analysis demonstrated that NF-kappaB expression was associated with poor 5-year overall survival (55.8 months vs 76.9 months, P = 0.012). Multivariate analysis verified that NF-kappaB was independently associated with adverse outcomes (relative risk: 1.92, P = 0.049). However, HIF-1alpha and VEGF did not appear to be related to clinical outcomes. NF-kappaB expression in tumor tissue is associated with angiogenesis and poor 5-year overall survival in stage III colorectal cancer patients.

Stage IV marginal zone B-cell lymphoma--prognostic factors and the role of rituximab: Consortium for Improving Survival of Lymphoma (CISL) study.

Stage IV marginal zone B-cell lymphomas (MZL) are detected in more than 25% of lymphoma patients. In this study, we conducted retrospective analyses of specific cases of stage IV MZL in order to assess their clinical features, as well as the treatments and prognoses of these cases. A total of 94 patients with histological diagnosis of stage IV-MZL from 17 different institutions in Korea were included. Multiple-mucosa-associated lymphoid tissue (MALT)-organs-involved MZL (M-MZL) was detected in 34 patients (36.2%). Bone-marrow-involved stage IV MZL (BM-MZL) was detected in 33 patients (35.1%). Median time to progression (TTP) was 2.4years (95% CI, 1.9-2.9). Five- and 10-year overall survival rates were 84.5% and 79.8%, respectively. Patients with lymph node involvement in stage IV MZL appeared to have worse prognoses in TTP (P=0.015). Thirty-one patients were treated with a regimen including rituximab (CTx-R[+]), and 31 with a regimen that did not include rituximab (CTx-R[-]). The CTx-R(+) group showed better responses than the CTx-R(-) group (83.9%versus 54.8%, P=0.026). However, no differences in TTP duration were detected (P=0.113). Stage IV MZL tend to follow an indolent disease course. Therefore, lymph node involvement is a more valuable prognostic factor for TTP. Rituximab appears to contribute to better responses, but not in cases of TTP.