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CDK4/6 inhibitors combined with endocrine therapy prolonged survival in hormone receptor (HR)-positive and HER2-negative advanced breast cancer. We investigated whether CDK4/6 inhibitors enhance radiosensitivity and their underlying mechanisms of this subtype of breast cancer. In vitro and in vivo experiments were conducted using two HR-positive and HER2-negative breast cancer cell lines (MCF-7 and T-47D), CDK4/6 inhibitors (ribociclib and palbociclib) and radiotherapy (RT) to assess the biological functions and mechanisms. The radiation-enhancing effect was assessed using clonogenic assays; γH2AX and 53BP1 levels were assessed by immunofluorescence to evaluate DNA damage. The levels of phospho (p)-ERK, c-Myc, and DNA-double strand break (DSB)-related molecules, p-DNA-PKcs, Rad51, and p-ATM, were assessed by western blotting. We used an NF-κB p65 transcription factor assay kit to evaluate NF-κB activity. We evaluated the antitumor effect of the combination of RT and ribociclib through the MCF-7 orthotopic xenograft model. The synergistic effects of combining RT with ribociclib and palbociclib pretreatment were demonstrated by clonogenic assay. CDK4/6 inhibitors synergistically increased the numbers of RT-induced γH2AX and 53BP1, downregulated the expression of p-DNA-PKcs, Rad51 and p-ATM activated by RT, and reduced RT-triggering p-ERK expression, NF-κB activation, and its down-streaming gene, c-Myc. Combined ribociclib and RT reduced the growth of MCF-7 cell xenograft tumors, and downregulated the immunohistochemical expression of p-ERK, p-NF-κB p65, and c-Myc compared to that in the control group. Combining CDK4/6 inhibitors enhanced radiosensitivity of HR-positive and HER2-negative breast cancer cells at least by reducing DNA-DSB repair and weakening the activation of ERK and NF-κB signaling by RT.

Abstract Background Few dosimetric comparisons have been published between linear accelerator (LA)-based systems and CyberKnife (CK)-based robotic radiosurgery systems for cardiac radio-ablation in ventricular tachycardia. This study aimed to compare the dosimetry of noninvasive cardiac radio-ablation deliverable on LA with that on CK. Methods Thirteen patients who underwent noninvasive cardiac radio-ablation by LA were included. The prescribed dose was 25 Gy in 1 fraction, and the average planning target volume was 49.8 ± 31.0 cm3 (range, 14.4–93.7 cm3). CK plans were generated for comparison. Results Both the CK and LA plans accomplished appropriate dose coverage and normal tissue sparing. Compared with the LA plans, the CK plans achieved significantly lower gradient indices (3.12 ± 0.71 vs. 3.48 ± 0.55, p = 0.031) and gradient measures (1.00 ± 0.29 cm vs. 1.17 ± 0.29 cm, p 50 cm3 or a non-spherical PTV, the LA and CK plans were similar regarding dosimetric parameters. CK plans involved more beams (232.2 ± 110.8 beams vs. 10.0 ± 1.7 arcs) and longer treatment times (119.2 ± 43.3 min vs. 22.4 ± 1.6 min, p = 0.007). Conclusions Both CK and LA are ideal modalities for noninvasive cardiac radio-ablation. Upfront treatment should be considered based on clinical intent.

Abstract Background Radiotherapy (RT) following breast-conserving surgery (BCS) is mainly used to decrease the rate of ipsilateral breast tumor recurrence (IBTR) in women with breast ductal carcinoma in situ (DCIS). Recent studies have demonstrated that low-dose tamoxifen significantly reduces IBTR in breast DCIS. Here, we aim to determine whether the administration of low-dose tamoxifen is non-inferior to RT in preventing IBTR in patients with low-risk characteristics of breast DCIS. Methods/design This is a prospective, international, open-label, randomized, non-inferiority trial. Patients with low-risk clinicopathologic features (> 40 years old, low risk of breast cancer susceptibility gene (BRCA) 1 and BRCA2 mutations, mammographically detected unicentric and non-mass lesions, low- or intermediate-grade without comedo or necrosis, measuring

Abstract Background Diffuse large B‐cell lymphoma (DLBCL) of the head‐and‐neck area primarily involves the Waldeyer ring (WR) and sinonasal area (SN). However, the differential clinical outcomes between patients with WR‐DLBCL and those with SN‐DLBCL in the rituximab era remain unclear. Methods To avoid confounding factors contributed by advanced DLBCL with WR and SN involvement, we assessed the clinical outcomes of patients with stage I/II WR‐DLBCL and SN‐DLBCL and compared them with those having corresponding stages of DLBCL in the lymph nodes but without other extranodal involvement (LN‐DLBCL) in the same period. We compared the patients' clinical characteristics, treatment modalities, event‐free survival (EFS), and overall survival (OS) among the three subgroups. Results We analyzed 67, 15, and 106 patients with WR‐DLBCL, SN‐DLBCL, and LN‐DLBCL, respectively, between January 2000 and December 2019. All patients received front‐line rituximab‐based regimens, and > 80% received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone‐based regimens. More patients with SN‐DLBCL had revised International Prognostic Index (R‐IPI) score 3 (27%) when compared with those with WR‐DLBCL (7%) and those with LN‐DLBCL (10%, p = 0.181). Patients with WR‐DLBCL, LN‐DLBCL, and SN‐DLBCL had 5‐year EFS and OS rates of 80.7%, 59.5%, and 41.9% (p = 0.021) and 83.7%, 70.8%, and 55.8% (p = 0.032), respectively. Compared to patients with LN‐DLBCL, those with WR‐DLBCL also had a significantly favorable 5‐year EFS rate (p = 0.021) and 5‐year OS rate (p = 0.023). Three of the 15 patients with SN‐DLBCL experienced lymphoma recurrence in the brain after front‐line treatment. In multivariate analyses, R‐IPI scores of 1–2 and 3 served as significantly poor prognostic factors for patients with poor EFS and OS. Conclusions Compared to patients with LN‐DLBCL, patients with WR‐DLBCL receiving front‐line rituximab‐based treatments had favorable clinical outcomes; however, patients with SN‐DLBCL had worse clinical outcomes. Further studies on molecular prognostic factors and treatment strategies for SN‐DLBCL are warranted.

Abstract Between January 2010 and December 2015, we enrolled 28 patients with stage IEI/IIE1 extragastric mucosa‐associated lymphoid tissue (MALT) lymphoma who received first‐line antibiotic treatment, after informing them about the pros and cons of alternative therapies. In addition, during the same period, 64 patients with stage IE/IIE1 disease who received conventional treatment were selected as the control group. The most common primary sites were the ocular adnexal area (17 cases), followed by the salivary glands (four cases), pulmonary (three cases), and thyroid, trachea, larynx, and colon region (one case each). First‐line antibiotic treatment resulted in an overall response rate of 57.1%: 12 patients achieved complete remission (CR), while four achieved partial remission (antibiotic‐responsive tumors). Monoclonal gammopathy was significantly prevalent in antibiotic‐unresponsive tumors than in antibiotic‐responsive tumors (50.0% [6/12] vs. 12.5% [2/16], p = 0.044). After a median follow‐up of 7 years, all patients with CR remained lymphoma‐free, with 7‐year event‐free survival (EFS) and overall survival (OS) rates of 62.7% and 96.4%, respectively. The 7‐year EFS and OS rates of patients who received conventional treatments were 73.1% and 91.1%, respectively. Compared with that noted in patients who received conventional treatment, antibiotic treatment was effective in some patients with localized extragastric MALT lymphoma.

Background: The prognosis of triple-negative breast cancer (TNBC) is worse and a major proportion of TNBC expresses epidermal growth factor receptor (EGFR). Afatinib can inhibit EGFR signal pathway; however, its treatment effect for TNBC is unknown. Thus, we aimed to assess the efficacy and biomarkers of afatinib in combination with paclitaxel in a neoadjuvant setting. Methods: Patients with stage II to III TNBC were enrolled. They received 40 mg of afatinib daily for 14 days, followed by daily afatinib and weekly paclitaxel (80 mg/m2) every 21 days for four to six cycles. To explore the mechanisms of responsiveness and non-responsiveness, 409 cancer-associated genes were sequenced. Results: Twenty-one patients were enrolled and one patient achieved a complete clinical response; however, a 2 mm residual tumor was noted in the surgical specimen. Overall, 33.0% patients were responders. Fifteen patients received molecular testing. No activated mutation of EGFR or Her2 were found. Activated PI3K or JAK2 pathway were trended to associate with non-responder (p = 0.057). Mutation of homologous recombination (HR) genes were correlated with non-responsiveness (p = 0.005). Seven patients did not have altered PI3K, JAK2 or HR pathway; six (85.7%) of them were responder. Patients with the amplified DAXX gene was associated with a favorable trend of response (p = 0.109). Conclusion: Adding afatinib to neoadjuvant paclitaxel generated a modest effect in TNBC. Exploratory molecular analysis suggested that activated PI3K, JAK2 pathways and mutation of HR genes were associated with therapeutic non-responsiveness, and amplification of DAXX genes was associated with responsiveness to afatinib in combination with paclitaxel.

Abstract Background Gastric diffuse large B‐cell lymphoma (DLBCL) is often associated with Helicobacter pylori (H. pylori) infection. Those in the early stage could be treated with H. pylori eradication therapy, and are classified into a sensitive group and a resistant group. Methods Genome‐wide miRNA and miRNA expression profiles were obtained from biopsy specimens of gastric DLBCL. MiRNAs and their targets as predictors of responses to H. pylori eradication therapy were identified through differential expression and pathway enrichment analysis, and further confirmed with transfection experiments in lymphoma cell lines of B‐cell origin. Results Genome‐wide miRNA and mRNA profiles showed miR‐200 was associated with the sensitive group, and that the resistant group had higher levels of miR‐155 and lower levels of DEPTOR (an inhibitor of mTOR) than the sensitive group. BJAB cells transfected with miR‐155 also had lower DEPTOR and higher mTOR levels. Therefore, miR‐155‐mediated inhibition of DEPTOR with secondary activation of mTOR was a potential marker for resistance to H. pylori eradication therapy. In contrast, pathway enrichment analysis showed that Toll‐like receptor 5 (TLR5), the receptor for bacterial flagellin, was a potential marker for sensitivity to H. pylori eradication therapy. In an independent series, stronger expression of pS6K1 (a direct target of mTOR) was associated with the resistant group and morphologic evidence of active gastritis was associated with the sensitive group. Conclusions These findings showed that activation of the miR‐155‐DEPTOR pathway is a marker for resistance to H. pylori eradication therapy, and that histological evaluation of active gastritis might be used as a surrogate marker to predict responses to H. pylori eradication therapy in gastric DLBCL.

Abstract Background We previously demonstrated that nuclear BCL10 translocation participates in the instigation of NF-κB in breast cancer and lymphoma cell lines. In this study, we assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC). Method and materials We analyzed the expression of BCL10-, cell cycle-, and NF-κB- related signaling molecules, and the DNA-binding activity of NF-κB in three PDAC cell lines (mutant KRAS lines: PANC-1 and AsPC-1; wild-type KRAS line: BxPC-3) using BCL10 short hairpin RNA (shBCL10). To assess the anti-tumor effect of BCL10 knockdown in PDAC xenograft model, PANC-1 cells treated with or without shBCL10 transfection were inoculated into the flanks of mice. We assessed the expression patterns of BCL10 and NF-κB in tumor cells in 136 patients with recurrent, advanced, and metastatic PDAC using immunohistochemical staining. Results We revealed that shBCL10 transfection caused cytoplasmic translocation of BCL10 from the nuclei, inhibited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines. Inhibition of BCL10 differentially blocked cell cycle progression in PDAC cell lines. Arrest at G1 phase was noted in wild-type KRAS cell lines; and arrest at G2/M phase was noted in mutant KRAS cell lines. Furthermore, shBCL10 transfection downregulated the expression of phospho-CDC2, phospho-CDC25C, Cyclin B1 (PANC-1), Cyclins A, D1, and E, CDK2, and CDK4 (BxPC-3), p-IκBα, nuclear expression of BCL10, BCL3, and NF-κB (p65), and attenuated the NF-κB pathway activation and its downstream molecule, c-Myc, while inhibition of BCL10 upregulated expression of p21, and p27 in both PANC-1 and BxPC-3 cells. In a PANC-1-xenograft mouse model, inhibition of BCL10 expression also attenuated the tumor growth of PDAC. In clinical samples, nuclear BCL10 expression was closely associated with nuclear NF-κB expression (p

Abstract We report the first Asian series on stereotactic body radiation (SBRT) for refractory ventricular arrhythmia (VA) in Taiwanese patients. Three-dimensional electroanatomic maps, delayed-enhancement magnetic resonance imaging (DE-MRI), and dual-energy computed tomography (CT) were used to identify scar substrates. The main target volume was treated with a single radiation dose of 25 Gy and the margin volume received 20 Gy using simultaneous integrated boost delivered by the Varian TrueBeam system. Efficacy was assessed according to VA events recorded by an implantable cardioverter-defibrillator (ICD) or a 24-h Holter recorder. Pre- and post-radiation therapy imaging studies were performed. From February 2019 to December 2019, seven patients (six men, one woman; mean age, 55 years) were enrolled and treated. One patient died of hepatic failure. In the remaining six patients, at a median follow-up of 14.5 months, the VA burden and ICD shocks significantly decreased (only one patient with one ICD shock after treatment). Increased intensity on DE-MRI might be associated with a lower risk for VA recurrence, whereas dual-energy CT had lower detection sensitivity. No acute or minimal late adverse events occurred. In patients with refractory VA, SBRT is associated with a marked reduction in VA burden and ICD shocks, and DE-MRI might be useful for monitoring treatment effects.

Background: Primary intestinal lymphomas (PILs) are rare, and this study compared the clinical outcomes of aggressive primary intestinal B-cell lymphomas (aB-PILs) and T/natural killer-cell lymphomas (T/NK-PILs). Methods: The clinical information of patients diagnosed with aggressive PILs at our institution between 1995 and 2015 were retrospectively investigated. Pathological subtypes were confirmed according to the 2016 revision of the World Health Organization classification. The correlation between clinicopathological features and overall survival (OS) was determined using univariate and multivariate analyses. Results: Cases of T/NK-PILs had higher initial bowel perforation incidence (67% vs. 7%, P

Maintenance therapy is rarely considered in pancreatic ductal adenocarcinoma (PDAC). We describe the case of a 57-year-old man with metastatic PDAC treated with an initially full but subsequently de-escalated dose of combination chemotherapy due to intolerance to neurotoxicity. After a complete response to combined radiofrequency ablation for the liver metastasis and radiotherapy for the pancreatic tumor was achieved, chemotherapy was terminated and maintenance therapy was applied: nivolumab plus cytokine-induced killer cell therapy initially and then a de-escalated dosing interval of nivolumab monotherapy subsequently. No adverse events occurred during nivolumab therapy for more than 2 years, and the patient remains disease-free. To date, this is the first report of maintenance nivolumab after successful multimodality therapy in metastatic PDAC.

Background and purpose: To develop and validate a magnetic resonance imaging (MRI)-derived radiomic signature (RS) for the prediction of 1-year locoregional failure (LRF) in patients with hypopharyngeal squamous cell carcinoma (HPSCC) who received organ preservation therapy (OPT) Material and methods: A total of 800 MRI-based features of pretreatment tumors were obtained from 116 patients with HPSCC who received OPT from two independent cohorts. The least absolute shrinkage and selection operator regression model were used to select the features used to develop the RS. Harrell’s C-index and corrected C-index were used to evaluate the discriminative ability of RS. The Youden index was used to select the optimal cut-point for risk category. Results: The RS yielded 1000 times bootstrapping corrected C-index of 0.8036 and 0.78235 in the experimental (n = 82) and validation cohorts (n = 34), respectively. With respect to the subgroup of patients with stage III/IV and cT4 disease, the RS also showed good predictive performance with corrected C-indices of 0.760 and 0.754, respectively. The dichotomized risk category using an RS of 0.0326 as the cut-off value yielded a 1-year LRF predictive accuracy of 79.27%, 79.41%, 76.74%, and 71.15% in the experimental, validation, stage III/IV, and cT4a cohorts, respectively. The low-risk group was associated with a significantly better progression-free laryngectomy-free and overall survival outcome in two independent institutions, stage III/IV, and cT4a cohorts. Conclusion: The RS-based model provides a novel and convenient approach for the prediction of the 1-year LRF and survival outcome in patients with HPSCC who received OPT.

Background and purpose: Thoracic re-irradiation may be an alternative treatment for lung cancer patients who develop intrathoracic locoregional recurrence without systemic progression. This study aimed to retrospectively assess locoregional control, clinical outcomes, and toxicities in lung cancer patients who received thoracic re-irradiation. Materials and methods: We retrospectively reviewed 50 lung cancer patients who received thoracic re-irradiation using conventional photon radiotherapy (RT) and stereotactic body radiotherapy (SBRT) between 2009 and 2017. The correlations of clinicopathologic factors, treatment factors, and dosimetric factors of RT with time to local progression (TTLP), progression-free survival (PFS), and overall survival (OS) after starting thoracic re-irradiation were calculated using log-rank tests and Cox regression models. Results: The median re-irradiation dose in equivalent dose in 2-Gy fractions was 51.1 Gy, and the mean re-irradiation planning target volume was 201.58 ml. The median mean lung dose (MLD) was 4.18 Gy, and the total lung volumes receiving a dose of 5 Gy (lung V5) and of 20 Gy (V20) were 19.8% and 5.85%, respectively. The TTLP, PFS, and OS were 18.0, 5.9, and 25.1 months, respectively. Lung V5 (p

Abstract Background The optimal adjuvant treatment for stage III endometrial cancer in the era of modern radiotherapy remains undefined. We investigated the benefit of adjuvant radiotherapy for women who underwent optimal resection for stage III endometrial cancer in the era of modern radiotherapy. Methods We retrospectively reviewed patients with endometrial cancer who were treated between 2010 and 2018. Adjuvant treatment included radiotherapy by modern radiotherapy techniques (intensity-modulated or volumetric modulated arc radiotherapy), chemotherapy, or both. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed via multivariate Cox proportional hazards models. Results One hundred sixty-one patients were initially included (52, 9, and 100 with stages IIIA, IIIB, and IIIC cancer, respectively); 154 patients (96%) received adjuvant therapy. Such adjuvant treatment was associated with improved RFS (p = 0.014) and OS (p = 0.044) over surgery alone. Adjuvant radiotherapy by modern radiotherapy techniques led to low incidence of acute (25%) and chronic (7%) grade ≥ 2 gastrointestinal toxicity. On univariate analysis, non-endometrioid histology and grade 3 status were associated with higher risks of tumor recurrence and death, whereas adjuvant radiotherapy alone or in combination chemotherapy reduced their risks. On multivariate analysis, non-endometrioid histology was associated with increased recurrence (hazard ratio [HR], 2.95; p = 0.009), whereas adjuvant radiotherapy alone or with chemotherapy was associated with lower recurrence (HR, 0.62; p = 0.042). Patients > 60 years of age (p = 0.038) as well as those with endometrioid histology (p = 0.045), lymphovascular space invasion (p = 0.031), and ≥ 2 positive lymph nodes (p = 0.044) benefited most from adjuvant radiotherapy. Conclusions Modern adjuvant radiotherapy (intensity-modulated or volumetric modulated arc radiotherapy) alone or with chemotherapy should be considered for women with optimally resected stage III endometrial cancer. Trial registration ClinicalTrials.gov, NCT04251676 . Registered 24 January 2020. Retrospectively registered.

Background: Heavily pretreated pancreatic cancer patients have a grave prognosis. In this case series study, we evaluated the safety and efficacy of nab-paclitaxel-based chemotherapy for such patients. Methods: The data of pancreatic adenocarcinoma patients (n = 40) treated with nab-paclitaxel after the failure of gemcitabine or fluoropyrimidines at our institution in 2013–2015 were reviewed. Results: The median number of prior chemotherapy regimens was two (range, 1–6). Eighteen patients had an Eastern Cooperative Oncology Group performance status of ≥2. The regimens comprised nab-paclitaxel combined with the following drugs: gemcitabine (n = 28), gemcitabine and fluoropyrimidine (n = 3), platinum and fluoropyrimidine (n = 4), fluoropyrimidine (n = 4), and irinotecan and fluoropyrimidine (n = 1). The median dose of nab-paclitaxel was 63 (range, 51–72) mg/m2/dose, with the schedule of D1/15, D1/8, and D1/8/15 followed in 23, 14, and 3 patients, respectively. The median overall survival was 5.1 (95% CI, 4.6–5.7) months. Among 32 evaluable patients, two partial responses and six stable diseases were observed. The median progression-free survival was 2.6 (95% CI, 1.9–3.2) months. Grade 3/4 leucopenia or neutropenia was observed in three and two patients, respectively. Grade 3/4 anemia was observed in four patients. Other significant (grade 3 or more) nonhematological toxicities were not frequent, except for sepsis/infection (n = 7). However, more severe anemia or sepsis/infection was significantly associated with disease control. Conclusion: In heavily pretreated pancreatic adenocarcinoma patients, low-dose nab-paclitaxel-based chemotherapy was fairly tolerable with modest efficacy. Keywords: Chemotherapy, Nab-paclitaxel, Pancreatic cancer, Pretreated, Prognosis

PurposeWe investigated potential factors, including clinicopathological features, treatment modalities, neutrophil-to-lymphocyte ratio (NLR), carbohydrate antigen (CA) 19-9 level, tumor responses correlating with overall survival (OS), local progression (LP), and distant metastases (DMs), in patients with locally advanced pancreatic cancer (LAPC) who received definitive radiotherapy (RT).MethodsWe retrospectively analyzed demographic characteristics; biologically effective doses (BED10, calculated with an α/β of 10) of RT; and clinical outcomes of 57 unresectable LAPC (all pancreatic adenocarcinoma) patients receiving definitive RT using modern techniques with and without systemic therapy between January 2009 and March 2019 at our institution. We used Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 to evaluate the radiographic tumor response after RT. The association between prognostic factors and OS was assessed using the Kaplan–Meier analysis and a Cox regression model, whereas baseline characteristics and treatment details were collected for competing-risk regression of the association with LP and DM using the Fine–Gray model.ResultsA median BED10 of 67.1 Gy resulted in a disease control rate of 87.7%, and the median OS was 11.8 months after a median follow-up of 32.1 months. The 1-year OS rate, cumulative incidences of LP, and DM were 49.2%, 38.5%, and 62.9%, respectively. Multivariate analyses showed that pre-RT NLR ≥3.5 (adjusted hazard ratio [HR] = 8.245, p < 0.001), CA19-9 reduction rate ≥50% (adjusted HR = 0.261, p = 0.005), RT without concurrent chemoradiotherapy (adjusted HR = 5.903, p = 0.004), and administration of chemotherapy after RT (adjusted HR = 0.207, p = 0.03) were independent prognostic factors for OS. Positive lymph nodal metastases (adjusted subdistribution HR [sHR] = 3.712, p = 0.003) and higher tumor reduction after RT (adjusted sHR = 0.922, p < 0.001) were significant prognostic factors for LP, whereas BED10 ≥ 67.1 Gy (adjusted sHR = 0.297, p = 0.002), CA19-9 reduction rate ≥50% (adjusted sHR = 0.334, p = 0.023), and RT alone (adjusted sHR = 2.633, p = 0.047) were significant prognostic factors for DM.ConclusionOur results indicate that pre-RT NLR and post-RT monitoring of CA19-9 and tumor size reduction can help identify whether patients belong to the good or poor prognostic group of LAPC. The incorporation of new systemic treatments during and after a higher BED10 RT dose for LAPC patients is warranted.

BackgroundPatients with stage II to III breast cancer have a high recurrence rate. The early detection of recurrent breast cancer remains a major unmet need. Circulating tumor DNA (ctDNA) has been proven to be a marker of disease progression in metastatic breast cancer. We aimed to evaluate the prognostic value of ctDNA in the setting of neoadjuvant therapy (NAT).MethodsPlasma was sampled at the initial diagnosis (defined as before NAT) and after breast surgery and neoadjuvant therapy(defined as after NAT). We extracted ctDNA from the plasma and performed deep sequencing of a target gene panel. ctDNA positivity was marked by the detection of alterations, such as mutations and copy number variations.ResultsA total of 95 patients were enrolled in this study; 60 patients exhibited ctDNA positivity before NAT, and 31 patients exhibited ctDNA positivity after NAT. A pathologic complete response (pCR) was observed in 13 patients, including one ER(+)Her2(-) patient, six Her2(+) patients and six triple-negative breast cancer (TNBC) patients. Among the entire cohort, multivariate analysis showed that N3 classification and ctDNA positivity after NAT were independent risk factors that predicted recurrence (N3, hazard ratio (HR) 3.34, 95% confidence interval (CI) 1.26 – 8.87, p = 0.016; ctDNA, HR 4.29, 95% CI 2.06 – 8.92, p < 0.0001). The presence of ctDNA before NAT did not affect the rate of recurrence-free survival. For patients with Her2(+) or TNBC, patients who did not achieve pCR were associated with a trend of higher recurrence (p = 0.105). Advanced nodal status and ctDNA positivity after NAT were significant risk factors for recurrence (N2 – 3, HR 3.753, 95% CI 1.146 – 12.297, p = 0.029; ctDNA, HR 3.123, 95% CI 1.139 – 8.564, p = 0.027). Two patients who achieved pCR had ctDNA positivity after NAT; one TNBC patient had hepatic metastases six months after surgery, and one Her2(+) breast cancer patient had brain metastasis 13 months after surgery.ConclusionsThis study suggested that the presence of ctDNA after NAT is a robust marker for predicting relapse in stage II to III breast cancer patients.

Immune checkpoint inhibitors have limited efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). We investigated prognostic markers for nivolumab-based therapy in advanced or recurrent PDAC. Consecutive patients receiving nivolumab-based therapy at our institution between 2015 and 2020 were evaluated. Overall survival (OS) was analyzed through univariate and multivariate analyses. Spleen volume was estimated from the width, thickness, and length of the spleen. A total of 45 patients were identified. Biweekly nivolumab was administered as monotherapy (n = 5) or in combination with chemotherapy or targeted therapy (n = 40). Among 31 evaluable patients, the response and disease control rates were 7% and 36%, respectively. The baseline median spleen volume was 267 (110–674) mL. Patients with spleens ≥267 mL had significantly shorter median OS (1.9 months, 95% confidence interval [CI], 1.0–2.7) than did those with smaller spleens (8.2 months, 95% CI, 5.6–10.8; P = .003). In the multivariate analysis, spleen volume of

Abstract Background Our aim was to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in operable tongue cancer patients. Methods The presence of CD3+, CD4+, CD8+, and forkhead box protein P3-positive (FOXP3+) TILs in tumor tissues obtained from 93 patients during surgery was examined using immunohistochemistry. Results The 3-year overall survival (OS) of patients with a low CD8/FOXP3 ratio was significantly lower than that of patients with a high CD8/FOXP3 ratio (63.8% vs. 87.3%, p = 0.001). Patients with high FOXP3 had a significantly lower 3-year regional recurrence-free survival (RRFS) than did patients with low FOXP3 (49.3% vs. 87.3%, univariate log rank p = 0.000). A low CD4/FOXP3 ratio (68.4% vs. 93.7%, univariate log rank p = 0.002) was significantly unfavorable prognostic factors for 3-year distant metastasis-free survival (DMFS). Conclusions In addition to clinicopathological characteristics, TIL markers represent prognosticators for clinical outcomes.

We evaluated the prognostic significance of immunologic inhibitory biomarkers in head and neck squamous cell carcinoma (HNSCC) patients undergoing definitive chemoradiotherapy (CRT). Thirty patients were prospectively enrolled. Plasma levels of soluble MHC class I polypeptide-related sequence A (sMICA) and transforming growth factor-β1 (TGF-β1) were measured before and 2 weeks after CRT. The median follow-up was 32.9 months (range: 12.4-40.6 months). The pre-treatment sMICA (p < 0.001) and TGF-β1 (p < 0.001) levels were significantly increased in HNSCC patients, compared to healthy controls. In HNSCC patients, the median pre-CRT and post-CRT sMICA levels were 43.1 pg/mL and 65.3 pg/mL, respectively, while the median pre-CRT and post-CRT TGF-β1 levels were 57.7 ng/mL and 36.0 ng/mL, respectively. After CRT, 19 patients (63.3%) exhibited persistently elevated sMICA, six patients (20.0%) exhibited persistently elevated TGF-β1, and five patients (16.7%) exhibited persistently elevated sMICA and TGF-β1. Patients with persistently elevated sMICA and TGF-β1 after CRT experienced an earlier tumor progression (p = 0.030), and poor overall survival (p = 0.010). Our results suggest that HNSCC patients who exhibit persistently elevated sMICA and TGF-β1 levels after CRT are at higher risk of tumor progression or death.

BACKGROUND:Whether the characteristics and prognosis of gastric cancer (GC) are different in patients with and without Helicobacter pylori (HP) remains controversial. The definitions of HP status in patients with atrophic gastritis but negative tests for HP are heterogeneous. We aimed to assess the impact of HP on the prognosis of GC using different definitions. METHODS:From 1998 Nov to 2011 Jul, five hundred and sixty-seven consecutive patients with GC were included. HP status was determined by serology and histology. Patients with any positive test were defined as HP infection. Patients without HP infection whose serum pepsinogen (PG) I

This study evaluated the prognostic roles of murine double minute 2 (MDM2) and p53 in pancreatic cancer patients treated with gemcitabine-based chemotherapy. A total of 137 advanced or recurrent adenocarcinoma patients who were treated with gemcitabine-based palliative chemotherapy were reviewed, selected from 957 patients with pancreatic malignancy between 2008 and 2013 at our hospital. Immunohistochemical staining for MDM2 and p53 with formalin-fixed, paraffin-embedded tumor tissues was independently reviewed. Nuclear or cytoplasmic expression of MDM2 and p53 was found in tumor cells of 30 (21.9%) and 71 (51.8%) patients, respectively. Patients with MDM2 expression had shorter median overall survival (OS) (3.7 vs 5.8 mo; P = .048) and median progression-free survival (PFS) (1.5 vs 2.5 mo; P < .001); by contrast, p53 expression was not correlated with OS or PFS. In the multivariate analysis, MDM2 expression (hazard ratio = 1.731; P = .025) was an independent and unfavorable prognostic factor of OS. Additionally, MDM2 expression was significantly associated with progressive disease (PD) and death (P = .015) following first-line gemcitabine-based therapy. In advanced pancreatic cancer patients, MDM2 expression is associated with shorter OS and PFS after gemcitabine-based chemotherapy.

Gastric mucosa-associated lymphoid tissue lymphoma (MALToma) usually presents at an early stage involving only the stomach and/or regional lymph nodes. Although a sequential transformation from low-grade gastric MALToma (GM) to high-grade GM to secondary diffuse large B-cell lymphoma (DLBCL) is commonly assumed, documented cases of transformation are rare. We aim to determine the frequency of transformation. Methods: We identified 55 early low-grade GMs, 18 early high-grade GMs, and 13 advanced GMs at the National Taiwan University Hospital from 1995 to 2005. The median follow-up time was 59 months. Results: We found that only one early low-grade GM and two early high-grade GMs transformed into secondary DLBCLs and progressed outside the stomach and regional lymph nodes. Significantly, we identified 13 low-grade GMs that were refractory to Helicobacter eradication therapy or relapsed after initial response. All 13 cases had been followed-up for at least 3 years without development of secondary DLBCLs. The frequency of transformation for early low-grade GM was less than 2% (1/55). Although two lymphoma-unrelated mortalities were identified, none of the 55 patients with early-low grade GMs died of the disease. Conclusion: Compared with chronic lymphocytic leukemia, which has a 16% transformation rate and a median transformation time of 24 months, we conclude that early low-grade GM rarely transforms into secondary DLBCL or progresses beyond the stomach. Without transformation or progression, patients with early low-grade GM rarely die of the disease and should be treated conservatively.

The accuracy of radiation delivery is increasingly important as radiotherapy technology continues to develop. The goal of this study was to evaluate intrafractional motion during intracranial radiosurgery and the relationship between motion change and treatment time.A total of 50 treatment records with 5988 images, all acquired during treatments with the CyberKnife Radiosurgery System, were retrospectively analyzed in this study. We measured translation and rotation motion including superior-inferior (SI), right-left (RL), anterior-posterior (AP), roll, tilt and yaw. All of the data was obtained during the first 45 minutes of treatment. The records were divided into 3 groups based on 15-min time intervals following the beginning of treatment: group A (0-15 min), group B (16-30 min) and group C (31-45 min). The mean deviations, systematic errors, random errors and margin for planning target volume (PTV) were calculated for each group.The mean deviations were less than 0.1 mm in all three translation directions in the first 15 minutes. Greater motion occurred with longer treatment times, especially in the SI direction. For the 3D vector, a time-dependent change was observed, from 0.34 mm to 0.77 mm (p=0.01). There was no significant correlation between the treatment time and deviations in the AP, LR and rotation axes. Longer treatment times were associated with increases in systematic error, but not in random error. The estimated PTV margin for groups A, B and C were 0.86 / 1.14 / 1.31 mm, 0.75 / 1.12 / 1.20 mm, and 0.43 / 0.54 / 0.81 mm in the SI, RL, and AP directions, respectively.During intracranial radiosurgery, a consistent increase in the positioning deviation over time was observed, especially in the SI direction. If treatment time is greater than 15 minutes, we recommend increasing the PTV margins to ensure treatment precision.

A rapid surge of female breast cancer has been observed in young women in several East Asian countries. The BIM deletion polymorphism, which confers cell resistance to apoptosis, was recently found exclusively in East Asian people with prevalence rate of 12%. We aimed to evaluate the possible role of this genetic alteration in carcinogenesis of breast cancer in East Asians.Female healthy volunteers (n = 307), patients in one consecutive stage I-III breast cancer cohort (n = 692) and one metastatic breast cancer cohort (n = 189) were evaluated. BIM wild-type and deletion alleles were separately genotyped in genomic DNAs.Both cancer cohorts consistently showed inverse associations between the BIM deletion polymorphism and patient age (≤35 y vs. 36-50 y vs. >50 y: 29% vs. 22% vs. 15%, P = 0.006 in the consecutive cohort, and 40% vs. 23% vs. 13%, P = 0.023 in the metastatic cohort). In healthy volunteers, the frequencies of the BIM deletion polymorphism were similar (13%-14%) in all age groups. Further analyses indicated that the BIM deletion polymorphism was not associated with specific clinicopathologic features, but it was associated with poor overall survival (adjusted hazard ratio 1.71) in the consecutive cohort.BIM deletion polymorphism may be involved in the tumorigenesis of the early-onset breast cancer among East Asians.

BACKGROUND AND PURPOSE:For metastatic non-small cell lung cancer (NSCLC) patients with controlled extrathoracic disease after systemic treatment, stable or progressive primary lung lesions may cause respiratory symptoms and increase comorbidities. In the present study, we sought to investigate whether aggressive palliative thoracic radiotherapy (RT) can enhance local control and improve the survival for this subgroup of patients. MATERIALS AND METHODS:Between March 2006 and December 2014, 56 patients with metastatic NSCLC who had responsive or stable extrathoracic diseases after chemotherapy and/or molecular targets, and received thoracic RT for stable and progressive primary lung lesions were included. RT with a median dose of 55 Gy (range, 40-62 Gy) was administered in 1.8-2.5 Gy fractions to primary lung tumor and regional mediastinal lymph nodes using modern RT technique. Overall survival (OS) from diagnosis, and locoregional progression-free survival (LRPFS), and survival calculated from radiotherapy (OS-RT) were estimated using the Kaplan-Meier method. RESULTS:There were 37 men and 19 women with a median age of 60 years at diagnosis. The median interval from the diagnosis of metastatic disease to thoracic RT was 8 months. Following thoracic RT, 26 patients (46%) achieved complete or partial response (overall response rate, ORR). Patients with squamous cell carcinoma or poorly-differentiated carcinoma had a higher ORR than those with adenocarcinoma (63% vs. 34%, P = 0.034). EGFR mutations was closely associated with a better ORR (45% vs. 29%, P = 0.284). At a median follow-up time of 44 months, the median OS, LRPFS after RT, and OS-RT were 50 months, 15 months, and 18 months. CONCLUSION:Radical palliative throractic RT is safe and might be beneficial for primary lung lesions of metastatic NSCLC patients with controlled extrathoracic diseases.

Lysophosphatidic acid (LPA) is a multi-function glycerophospholipid. LPA affects the proliferation of hepatocytes and stellate cells in vitro, and in a partial hepatectomy induced liver regeneration model, the circulating LPA levels and LPA receptor (LPAR) expression levels in liver tissue are significantly changed. Liver sinusoidal endothelial cells (Lsecs) play an important role during liver regeneration. However, the effects of LPA on Lsecs are not well known. Thus, we investigated the effects of LPA on the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs.Mouse Lsecs were isolated using CD31-coated magnetic beads. The mRNA expression levels of LPAR's and other target genes were determined by quantitative RT-PCR. The protein levels of angiogenesis factors, cytokines, and chemokines were determined using protein arrays and enzyme immunoassay (EIA). Critical LPAR related signal transduction was verified by using an appropriate chemical inhibitor.LPAR1 and LPAR3 mRNA's were expressed in mouse LPA-treated Lsecs. Treating Lsecs with a physiological level of LPA significantly enhanced the protein levels of angiogenesis related proteins (cyr61 and TIMP-1), cytokines (C5/C5a, M-CSF, and SDF-1), and chemokines (MCP-5, gp130, CCL28, and CXCL16). The LPAR1 and LPAR3 antagonist ki16425 significantly inhibited the LPA-enhanced expression of cyr61, TIMP-1, SDF-1, MCP-5, gp130, CCL28, and CXCL16, but not that of C5/C5a or M-CSF. LPA-induced C5/C5a and M-CSF expression may have been through an indirect regulation mechanism.LPA regulated the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs that was mediated via LPAR1 and LPAR3 signaling. Most of the factors that were enhanced by LPA have been found to play critical roles during liver regeneration. Thus, these results may prove useful for manipulating LPA effects on liver regeneration.

Helicobacter pylori is a Gram-negative bacterium that infects the human gastric mucosa and causes various gastric diseases. H. pylori infection induces the production of inflammatory chemokine CCL20 in gastric mucosa and leads to gastric inflammation. Given that the IL-22/IL-22R axis plays a critical role in the regulation of homeostasis and inflammation of epithelial cells at barrier surfaces, we investigated the effect of IL-22 on CCL20 expression induced by H. pylori. We demonstrated that H. pylori infection of the gastric epithelia-derived AGS cells significantly induced CCL20 expression and the induction was inhibited by IL-22. Functional analysis of the CCL20 promoter revealed that the H. pylori-induced CCL20 expression required the activation of NF-κB, and that IL-22 inhibited the induction by attenuating NF-κB activation. Knockdown of endogenous STAT3 by either short interfering RNAs or a short hairpin RNA significantly reduced the inhibitory effect of IL-22. Furthermore, STAT3 phosphorylation elicited by IL-22 was crucial for the inhibition of H. pylori-induced CCL20 expression. Consistent with the in vitro data showing that IL-22 negatively regulated H. pylori-induced CCL20 expression in gastric epithelial cells, studies on the tissue sections from patients with H. pylori infection also revealed an inverse association of IL-22 expression and CCL20 expression in vivo. Together, our findings suggest that IL-22 plays a role in the control of overproduction of the inflammatory chemokine and thus may protect the gastric mucosa from inflammation-mediated damage.