New prognostic system specific for epidermal growth factor receptor-mutated lung cancer brain metastasis.

Introduction: Brain metastases (BM) from lung cancer are heterogeneous, and accurate prognosis is required for effective treatment strategies. This study aimed to identify prognostic factors and develop a prognostic system exclusively for epidermal growth factor receptor (EGFR)-mutated lung cancer BM. Methods: In total, 173 patients with EGFR-mutated lung cancer from two hospitals who developed BM and received tyrosine kinase inhibitor (TKI) and brain radiation therapy (RT) were included. Univariate and multivariate analyses were performed to identify significant EGFR-mutated BM prognostic factors to construct a new EGFR recursive partitioning analysis (RPA) prognostic index. The predictive discrimination of five prognostic scoring systems including RPA, diagnosis-specific prognostic factors indexes (DS-GPA), basic score for brain metastases (BS-BM), lung cancer using molecular markers (lung-mol GPA) and EGFR-RPA were analyzed using log-rank test, concordance index (C-index), and receiver operating characteristic curve (ROC). The potential predictive factors in the multivariable analysis to construct a prognostic index included Karnofsky performance status, BM at initial lung cancer diagnosis, BM progression after TKI, EGFR mutation type, uncontrolled primary tumors, and number of BM. Results and discussion: In the log-rank test, indices of RPA, DS-GPA, lung-mol GPA, BS-BM, and EGFR-RPA were all significant predictors of overall survival (OS) (p ≤ 0.05). The C-indices of each prognostic score were 0.603, 0.569, 0.613, 0.595, and 0.671, respectively; The area under the curve (AUC) values predicting 1-year OS were 0.565 (p=0.215), 0.572 (p=0.174), 0.641 (p=0.007), 0.585 (p=0.106), and 0.781 (p=0.000), respectively. Furthermore, EGFR-RPA performed better in terms of calibration than other prognostic indices.BM progression after TKI and EGFR mutation type were specific prognostic factors for EGFR-mutated lung cancer BM. EGFR-RPA was more precise than other models, and useful for personal treatment.

Risk of Recurrence and Metastasis for Patients with T1N0M0 Esophageal Carcinoma Who Achieve Completed Resection via Endoscopic Submucosal Resection: Evidence for the Appropriateness of the Watch and Wait Follow-Up Strategy.

PURPOSE: Endoscopic submucosal dissection (ESD) is a widely performed procedure for esophageal carcinoma when the depth of invasion reaches the epithelium and lamina propria. However, ESD for esophageal carcinoma with depth of invasion exceeding the muscularis mucosa is controversial. This study aimed to evaluate the long-term outcomes of ESD for T1N0M0 (tumor invading the mucosa and submucosa [T1], no regional lymph node metastasis [N0], no distant metastasis [M0]) esophageal cancer. PATIENTS AND METHODS: Esophageal cancer was evaluated via pathology and computed tomography (CT) in consecutive patients with negative margin and without additional therapy. A total of 84 patients were included. The mean follow-up time was 42 (range, 9-99) months. RESULTS: No recurrence and metastasis were detected in the M1 and M2 group. The 5-year locoregional recurrence rate and distant metastasis rate were 4.2% and 5.6% for the M3 group and were 0% and 1.4% for the SM group, respectively. The 3- and 5-year overall survival were 94.4% (M1+M2 group, 95.0%; M3 group, 95.0%; SM group, 92.9%) and 80.9% (M1+M2 group, 95.0%; M3 group, 95.0%; SM group, 92.9%). Meanwhile, the 3- and 5-year disease-specific survival rates were 100% (M1+M2 group, 100%; M3 group, 100%; SM group, 100%) and 90.8% (M1+M2 group, 100%; M3 group, 90.0%; SM group, 85.7%). The major complications were postoperative strictures, most of which were grade 1-2. In total, two (4.8%) and one (1.2%) patient developed grade 3 and 5 late esophageal strictures, respectively. CONCLUSION: ESD complete resection yields low recurrence and metastasis rates in early esophageal cancer (T1N0M0). Thus, additional treatment is not necessary, and a watch and wait strategy may be reasonable.

Sequential boost of intensity-modulated radiotherapy with chemotherapy for inoperable esophageal squamous cell carcinoma: A prospective phase II study.

PURPOSE: This prospective phase II study aimed to determine the efficacy and tolerability of sequential boost of intensity-modulated radiation therapy (IMRT) with chemotherapy for patients with inoperable esophageal squamous cell carcinoma (ESCC). METHODS: Patients with histologically or cytologically proven inoperable ESCC were enrolled in this study (ChiCTR-OIC-17010485). A larger target volume for subclinical lesion was irradiated with 50 Gy, and then, a smaller target volume only including gross tumor was boosted to 66 Gy. The fraction dose was 2 Gy, and no elective node was irradiated. Concurrent and consolidation chemotherapy of fluorouracil (600 mg/m2 , days 1-3) plus cisplatin (25 mg/m2 , days 1-3) was administered every 4 weeks, for 4 cycles in total. The primary endpoint was 2-year progression-free survival (PFS). RESULTS: Eighty-eight patients were enrolled in this study. The median age was 65 years (range: 45-75 years), and 69 patients (78.4%) were men. With the median follow-up of 26 (range: 3-95) months, the 2- and 5-year PFS were 39.3% and 36.9%, respectively, and overall survival (OS) were 57.1% and 39.2%, respectively. Tumor stage and concurrent chemotherapy were independent OS predictors. Major acute adverse events were myelosuppression and esophagitis, most of which were grades 1-2. Nine percent and 2.3% of patients had grade 3 acute esophagitis and late esophageal strictures, respectively. CONCLUSIONS: Sequential boost to 66 Gy by IMRT with chemotherapy was safe and effective for inoperable ESCC. A randomized phase III study to compare with standard dose of 50 Gy is warranted.

Intensity Modulated Radiation Therapy Plus Etoposide/Cisplatin for Patients With Limited Advanced Unresectable Thymic Epithelial Tumors: A Prospective Phase 2 Study.

PURPOSE: This prospective phase 2 study evaluated the efficacy and safety of intensity modulated radiation therapy plus etoposide/cisplatin (EP) for patients with unresectable thymic epithelial tumors (TETs). METHODS AND MATERIALS: Patients with limited advanced unresectable TETs whose lesions could be encompassed within radiation fields were enrolled in this study. Two cycles of EP (75 mg/m2 etoposide and 25 mg/m2 cisplatin on days 1-3 and days 29-31) were administered concurrently with radiation therapy, followed by 2 cycles after radiation therapy. The primary endpoint was the objective response rate. The secondary endpoints were the progression-free survival rate, overall survival rate, and incidence of adverse events. RESULTS: Fifty-six patients were enrolled between June 2011 and May 2018. Twenty-two and 34 patients had thymomas and thymic carcinomas, respectively. The median age was 52 (range, 21-76) years, and 30 patients (53.6%) were men. Eight patients (14.3%) had stage III tumors, 6 (10.7%) had stage IVA tumors, and 42 (75.0%) had stage IVB tumors. The objective response rate was 85.7% (95% confidence interval, 76.3%-95.2%). With a median follow-up of 46 (range, 7-101) months, the 1-, 2-, and 5-year progression-free survival rates were 66.1%, 48.0%, and 29.5%, and the 1-, 2-, and 5-year overall survival rates were 91.0%, 76.2%, and 56.2%, respectively. The most common grade 3 to 4 adverse event was leukopenia (42.9%). Pulmonary fibrosis was also observed (5.3%). CONCLUSIONS: Because intensity modulated radiation therapy with EP is effective and safe for limited advanced unresectable TETs, it could be a suitable treatment option for such patients.

Dosimetry of the brain and hypothalamus predicting acute lymphopenia and the survival of glioma patients with postoperative radiotherapy.

BACKGROUND: The aim of this study was to investigate dosimetric factors for predicting acute lymphopenia and the survival of glioma patients with postoperative intensity-modulated radiotherapy (IMRT). METHODS: A total of 148 glioma patients were reviewed. Acute lymphopenia was defined as a peripheral lymphocyte count (PLC) lower than 1.0 × 109 /L during radiotherapy with a normal level at pretreatment. PLCs with the corresponding dates and dose volume histogram parameters were collected. Univariate and multivariate Cox regression analyses were constructed to assess the significance of risk factors associated with lymphopenia and overall survival (OS). RESULTS: Sixty-nine (46.6%) patients developed lymphopenia during radiotherapy. Multivariate analyses revealed that the risk increased with the maximal dose of the hypothalamus (HT Dmax) ≥56 Gy (58.9% vs 28.5%, P = 0.002), minimal dose of the whole brain (WB Dmin) ≥2 Gy (54.3% vs 33.9%, P = 0.006), or mean dose of the WB (WB Dmean) ≥34 Gy (56.0% vs 37.0%, P = 0.022). Patients with older age, high-grade glioma, development of lymphopenia, high HT Dmax, WB Dmin, and WB Dmean had significantly inferior OS in the multivariate analyses. CONCLUSIONS: HT Dmax, WB Dmin, and WB Dmean are promising indicators of lymphopenia and the survival of glioma patients undergoing postoperative IMRT. The necessity and feasibility of dosimetric constraints for HT and WB is warranted with further investigation.

The prognostic value of tumor depth for cervical lymph node metastasis in hypopharyngeal and supraglottic carcinomas.

BACKGROUND: To analyze the prognostic value of the clinicopathological parameters of primary lesions for predicting cervical lymph node metastasis in patients with hypopharyngeal and/or supraglottic carcinoma. METHODS: We enrolled 127 patients with squamous cell carcinomas originating in the hypopharyngeal and/or supraglottic regions. RESULTS: Multivariate analysis identified the tumor depth as an independent predictive factor for lymph node metastasis (odds ratio, 4.959; 95% confidence interval, 2.290-10.739; P < 0.0001) with a predictive value of 0.966. A cutoff value of 4.5 mm was determined. CONCLUSION: The tumor depth of the primary lesion is a potent predictor of cervical lymph node metastasis in hypopharyngeal and supraglottic carcinomas. In cases with clinically negative nodal status, elective neck dissection should be adopted for patients with a tumor depth reaching 4.5 mm. Regular outpatient follow-up is recommended for patients with a tumor depth less than 1.0 mm. Close follow-up or preventative therapy should be considered between 1.0 and 4.5 mm.

Three-dimensional conformal radiation therapy alone for esophageal squamous cell carcinoma: 10-year survival outcomes.

BACKGROUND: Concurrent chemoradiation is the standard treatment for locally advanced esophageal squamous cell carcinoma (SCC). We conducted a phase II study to explore the effect of three-dimensional conformal radiotherapy (3-DCRT) alone for patients with locally advanced esophageal SCC. This study aimed to analyze the long-term survival outcomes. METHODS: Between November 2004 and April 2007, 30 patients with thoracic esophageal SCC underwent late-course sequential boost 3-DCRT at Fudan University Shanghai Cancer Center. The planning target volume (PTV1) comprised a 1.2-1.5 cm lateral margin around the gross tumor volume and a 3.0 cm margin, superior and inferior to the gross tumor volume. PTV2 encompassed the gross tumor volume with a margin of 0.5-0.7 cm. The PTV1 dose delivered was 50 Gy, and the PTV2 dose was a boost dose of 16 Gy, resulting in a total dose of 66 Gy. No chemotherapy was administered. RESULTS: The median follow-up time was 30 months for all patients, and 132 months for patients who were alive. The median overall survival was 27 months (95% confidence interval [CI] 18.9-35.0). The 2-, 5-, and 10-year overall survival rates were 56.6%, 33.3%, and 26.6%, respectively. The median progression-free survival was 14 months (95% CI 7.7-20.2 months), and the 2-, 5-, and 10-year progression-free survival rates were 33.3%, 30.0%, and 26.6%, respectively. No severe late toxicity was observed in long-term survivors. CONCLUSION: Late-course sequential boost 3-DCRT is safe and feasible with promising long-term outcomes for esophageal SCC.

Simultaneously avoiding the hippocampus and hypothalamic-pituitary axis during whole brain radiotherapy: A planning study.

Whole brain radiotherapy (WBRT) is the preferred treatment for multiple brain metastases, and patients with limited-stage small cell lung cancer undergo prophylactic cranial irradiation after complete remission. However, neurotoxicity remains a complication. In addition to protecting the hippocampus from irradiation to preserve cognitive function, it is also critical to avoid irradiating the hypothalamic-pituitary axis to preserve endocrine and immune function. This study aimed to evaluate the feasibility of delivering WBRT while protecting the hippocampus and hypothalamic-pituitary axis. Thirteen patients with limited-stage small cell lung cancer were enrolled in this study. The hippocampus, hypothalamus, and pituitary gland were contoured based on T1-weighted magnetic resonance imaging. The prescribed dose to the whole brain planning target volume was 25 Gy in 10 fractions. Two treatment plans using equispaced coplanar intensity-modulated radiotherapy (IMRT) were generated: WBRT with hippocampus avoidance (H-A) and WBRT with hippocampus, hypothalamus, and pituitary gland avoidance (H-HP-A). Both "H-A" and "H-HP-A" plans successfully protected the hippocampus, which received mean doses of 9.1 and 9.6 Gy, respectively (p = 0.0002), whereas the "H-HP-A" plan decreased the doses to both the hypothalamus (mean dose 11.06 Gy) and the pituitary gland (mean dose 10.66 Gy). Both "H-A" and "H-HP-A" plans showed similar target coverage of 95.1%. The homogeneity index of the "H-A" plan was slightly better than that of the "H-HP-A" plan (0.20 vs 0.23, p= 0.0012). In conclusion, the use of equispaced coplanar IMRT was found to simultaneously protect the hippocampus and hypothalamic-pituitary axis while delivering WBRT with acceptable target coverage and homogeneity.

Impact of tumor dimensions and lymph node density on the survival of patients with hypopharyngeal squamous cell carcinoma.

PURPOSE: To analyze the potential variables affecting the survival of patients undergoing primary surgery for hypopharyngeal squamous cell carcinoma. PATIENTS AND METHODS: Between August 2007 and December 2016, 93 patients with primary hypopharyngeal squamous cell carcinomas undergoing radical surgery at Fudan University Shanghai Cancer Center were reviewed. The clinicopathological features were analyzed retrospectively. The optimal cutoff values were determined based on the receiver operating characteristic curve analysis. Pearson correlation coefficients were used to assess the correlations between variables. The Kaplan-Meier and Cox proportional hazard methods were used to evaluate the impact of variables on overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). RESULTS: Cox multivariate analysis revealed that a depth of invasion (DOI) ≥ 4.3 mm was correlated with inferior OS (P=0.045), DSS (P=0.046), and DFS (P=0.046). A primary tumor volume (PTV) ≥0.36 mL was related to poor OS (P=0.018), DSS (P=0.026), and DFS (P=0.036). A lymph node density (LND) ≥0.07 was also associated with worse OS (P=0.014) and DSS (P=0.045). Moreover, additional prognostic value was observed in the combined use of PTV and LND. CONCLUSION: The DOI, PTV, and LND obtained from the surgical specimens could provide additional valuable information for prognostic stratification and allowed the more appropriate selection of suitable candidates for more aggressive adjuvant therapy.

Electroacupuncture Improves Cognitive Function and Hippocampal Neurogenesis after Brain Irradiation.

Cognitive impairments after brain irradiation seriously affect quality of life for patients, and there is currently no effective treatment. In this study using an irradiated rat model, the role of electroacupuncture was investigated for treatment of radiation-induced brain injury. Animals received 10 Gy exposure to the entire brain, and electroacupuncture was administered 3 days before irradiation as well as up to 2 weeks postirradiation. Behavioral tests were performed one month postirradiation, and rats were then sacrificed for histology or molecular studies. Electroacupuncture markedly improved animal performance in the novel place recognition test. In the emotion test, electroacupuncture reduced defecation during the open-field test, and latency to consumption of food in the novelty suppressed feeding test. Brain irradiation inhibited the generation of immature neurons, but did not cause neural stem cell loss. Electroacupuncture partially restored hippocampal neurogenesis. Electroacupuncture decreased the amount of activated microglia and increased resting microglia in the hippocampus after irradiation. In addition, electroacupuncture promoted mRNA and protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In conclusion, electroacupuncture could improve cognitive function and hippocampal neurogenesis after irradiation, and the protective effect of electroacupuncture was associated with the modulation of microglia and upregulation of BDNF in the hippocampus.

Stage IVb thymic carcinoma: patients with lymph node metastases have better prognoses than those with hematogenous metastases.

BACKGROUND: This study aimed to analyze the pattern of lymphogenous and hematogenous metastases in patients with stage IVb thymic carcinomas and identify prognostic factors for their survivals. METHODS: Between September 1978 and October 2014, 68 patients with pathologically confirmed stage IVb thymic carcinomas were treated at Fudan University Shanghai Cancer Center. Forty-three patients had lymph node involvement without distant metastases, and the remaining 25 patients had hematogenous metastases. Clinical-pathological characteristics, including age, sex, histologic subtype, tumor size, metastasis, treatment modalities, such as surgical resection, radiotherapy, and chemotherapy, and clinical outcomes, such as overall survival (OS) and progression free survival (PFS), were analyzed. RESULTS: The median follow-up time was 22 months (range, 1-126 months). The median OS of all patients with stage IVb thymic carcinomas was 30 months, and the 5-year overall survival rate was 25.1%. The median PFS was 11 months, and the 5-year PFS was 17.9%. Stage IVb patients with lymph node involvement had a better survival than those with distant metastasis (40 vs. 20 months, p = 0.002). Patients with myasthenia gravis had a worse prognosis (p = 0.033). Multivariate analysis identified metastatic status as an independent prognostic factor for OS in patients with stage IVb thymic carcinomas. CONCLUSIONS: Patients with lymph node involvement had a better survival than those with distant metastases. Much work remains to investigate the prognosis of patients with stage IVb thymic carcinomas and to explore different treatment strategies for patients with lymph node involvement and distant metastases.

Electroacupuncture prevents cognitive impairments by regulating the early changes after brain irradiation in rats.

Cognitive impairments severely affect the quality of life of patients who undergo brain irradiation, and there are no effective preventive strategies. In this study, we examined the therapeutic potential of electroacupuncture (EA) administered immediately after brain irradiation in rats. We detected changes in cognitive function, neurogenesis, and synaptic density at different time points after irradiation, but found that EA could protect the blood-brain barrier (BBB), inhibit neuroinflammatory cytokine expression, upregulate angiogenic cytokine expression, and modulate the levels of neurotransmitter receptors and neuropeptides in the early phase. Moreover, EA protected spatial memory and recognition in the delayed phase. At the cellular/molecular level, the preventative effect of EA on cognitive dysfunction was not dependent on hippocampal neurogenesis; rather, it was related to synaptophysin expression. Our results suggest that EA applied immediately after brain irradiation can prevent cognitive impairments by protecting against the early changes induced by irradiation and may be a novel approach for preventing or ameliorating cognitive impairments in patients with brain tumors who require radiotherapy.

N-Heterocyclic carbene-catalyzed cascade reaction of 2-aroylvinylcinnamaldehydes with 2-aroylvinylchalcones: rapid assembly of six contiguous stereogenic centers with high diastereoselectivity.

N-Heterocyclic carbene-catalyzed reaction of 2-aroylvinylcinnamaldehydes with 2-aroylvinylchalcones proceeded via a triple Michael addition and intramolecular lactonization cascade to produce novel 9-(2-aroyl-3-aroylmethyl-1-indanyl)-3-arylindeno[2,1-c]pyran-1-ones in good yields with high diastereoselectivity. This reaction constructed six contiguous stereogenic centers in a single reactive event. Among 32 possible diastereoisomers that contain six stereocenters, only two diastereoisomers were detected with diastereomeric ratios being 10 : 1-28 : 1. This work opens up a new avenue for the synthesis of complex indane derivatives, a type of compound that has been reported to possess various biological and pharmaceutical activities.

Variation in background intensity affects PET-based gross tumor volume delineation in non-small-cell lung cancer: the need for individualized information.

PURPOSE: Efficient tumor volume delineation by the combined use of PET/CT scanning is necessary for the proper treatment of non-small cell lung cancer (NSCLC). To understand the effect of variation in background intensity on PET-based gross tumor volume (GTV) delineation, we determined the background standard uptake values (SUVs) in normal lung, aorta (blood pool), and liver tissues and determined GTVs using different methods. METHODS: Thirty-seven previously untreated patients with pathologically confirmed NSCLC underwent PET/CT scanning with (18)F-fluorodeoxyglucose ((18)F-FDG). To obtain (18)F-FDG uptake values in normal tissues, regions of interest in the lung lobes (left upper, left lower, right upper, right middle, and right lower), aorta, and liver zones (left, intermediate, and right) were measured. The coefficient of variation (CV) of the SUV was measured for each normal structure. The CT-based GTV (GTV(CT)) was considered as the standard to which all PET-based GTVs were compared, and the correlation coefficient was analyzed to compare GTV obtained by the various delineation methods. Linear and logarithmic regression analyses were used to determine the relationship between GTV(CT) and GTV(PET). RESULTS: Normal lung tissue showed a significantly lower SUV and less stability than tissue of the aorta or liver. For the lung, aorta, and liver, the maximum SUV (SUV(max)) was 0.82 ± 0.32, 2.35 ± 0.37, and 3.24 ± 0.50 (CV: 38.79%, 15.82%, and 15.30%) and average SUV (SUV(ave)) was 0.49 ± 0.18, 1.68 ± 0.32, and 2.34 ± 0.36 (CV: 36.38%, 18.92%, and 15.44%), respectively. The SUVs of the lung varied from lobe to lobe. The GTV delineation method using the SUV(ave) of the lung lobe in which the tumor was found as background in the source-to-background ratio (SBR) method showed the best correlation with the volume of CT-based GTV (r=0.81). CONCLUSIONS: Our results show vast variation in the SUV among normal tissues, as well as in the different lung lobes. The tumor volume delineated using the SBR method correlated well with the CT-based tumor volume. We conclude that it is reasonable and precise to contour GTV in patients with NSCLC after taking into account the background intensity of the lung lobe in which the tumor is found.

NHC Brønsted base-catalyzed transformations of isochromene derivatives: regulation of products by the structures of carbene catalysts.

Two different transformations of α-(isochromen-1-yl)ketones catalyzed by NHC Brønsted bases are reported. In the presence of a triazole carbene, α-(isochromen-1-yl)ketones isomerized into ß-(2-(aroylmethylene)phenyl)-α,ß-unsaturated ketones in 38-88% yields, while the same reaction catalyzed by an imidazole carbene produced 1-aroylnaphthalene derivatives in 90-99% yields. This work not only provides a new method for the synthesis of a novel type of α,ß-unsaturated ketone and multi-substituted naphthalene derivatives, but also advances the application of NHC catalysts in the field of Brønsted base-catalysis.