The role of serum sodium in poor prognosis evaluation of pulmonary hypertension associated with left heart disease.

BACKGROUND: Previous studies have shown that hyponatremia was strongly associated with a poor prognosis of type 1 pulmonary hypertension, and our team's antecedent studies found that low serum sodium was associated with the severity and the length of hospitalization of pulmonary hypertension associated with left ventricular disease (PH-LHD). However, the relationship between serum sodium and the prognosis of PH-LHD remains unclear. This study aims to determine the clinical value of serum sodium in evaluating poor prognosis in patients with PH-LHD. METHODS: We successfully followed 716 patients with PH-LHD. Kaplan-Meier was used to plot survival in PH-LHD patients with different serum sodium levels. The effect of serum sodium on poor prognosis was analyzed using a Cox proportional risk model. The trends between patients serum sodium and survival were visualized by restricted cubic spline (RCS). RESULTS: The survival rates at 1, 2, 3 and 4 years were 52%, 41%, 31% and 31% for the patients with hyponatremia associated with PH-LHD and 71%, 71%, 71% and 54% for the patients with hypernatremia, respectively. The observed mortality rate in the hyponatremia and hypernatremia groups surpassed that of the normonatremic group. The adjusted risks of death (risk ratio) for patients with hyponatremia and hypernatremia were found to be 2.044 and 1.877. Furthermore, the restricted cubic spline demonstrated an L-shaped correlation between serum sodium and all-cause mortality in patients with PH-LHD. CONCLUSIONS: Abnormal serum sodium level is strongly associated with poor prognosis in PH-LHD. Serum sodium may play an important pathogenic role in PH-LHD occurrence and could be used as a marker to assess the survival in patients.

Evaluation of total tumor volume reduction ratio in initially unresectable colorectal liver metastases after first-line systemic treatment.

PURPOSE: Total tumor volume (TTV) may play an essential role in the estimation of tumor burden. This study is aimed to investigate the clinical value of the reduction ratio of TTV as a valuable indicator of clinical outcomes in patients with colorectal liver metastases (CRLM). METHODS: A total of 240 initially unresectable CRLM patients who underwent first-line systemic treatment were enrolled in this study. TTV at baseline and at the end of first-line treatment were assessed using a three-dimensional reconstruction system according to CT or MRI images. Survival was evaluated using Kaplan-Meier analysis and compared using Cox proportional hazard ratios (HR). RESULTS: A total of 212 (88.3%) patients achieved tumor regression with a median reduction ratio of TTV of 86.0%. An increasing reduction ratio of TTV was associated with a gradually ascending successful conversion outcome. Patients with a reduction ratio >86.0% had better survival than those with a reduction ratio 0-86.0% or <0 (5-year overall survival (OS) rates, 64.4% vs. 44.9% vs. 23.5%, P < 0.001; 5-year progression-free survival (PFS) rates, 36.3% vs. 28.2% vs. 6.5%, P < 0.001). Multivariate analysis indicated that the reduction ratio of TTV ≤ 86.0% (OR [95%CI]: 4.956 [2.654-9.253], P < 0.001) was an independent factor for conversion failure outcome. Cox analyses revealed that the reduction ratio of TTV ≤ 86.0% was an independent factor for both unfavorable OS (HR [95%CI]: 2.216 [1.332-3.688], P = 0.002) and PFS (HR [95%CI]: 2.023 [1.376-2.974], P < 0.001). CONCLUSIONS: The reduction ratio of TTV was an effective indicator for conversion outcome and long-term prognosis in patients with initially unresectable CRLM after first-line systemic treatment.

Neoadjuvant PD-1 blockade with sintilimab in mismatch-repair deficient, locally advanced rectal cancer: an open-label, single-centre phase 2 study.

BACKGROUND: The current standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by radical surgery, but this approach can lead to multiple complications. We aimed to investigate the clinical activity and safety of neoadjuvant therapy with sintilimab, a single-agent PD-1 antibody, in patients with mismatch-repair deficient locally advanced rectal cancer. METHODS: This open-label, single-arm, phase 2 study was done at the Sun Yat-sen University Cancer Center, Guangzhou, China. Patients aged 18-75 years with mismatch-repair deficient or microsatellite instability-high locally advanced rectal cancer were enrolled and received neoadjuvant sintilimab monotherapy (200 mg by intravenous infusion) every 21 days. After an initial four cycles of treatment, patients and clinicians could choose one of the following options: total mesorectal excision surgery, followed by four cycles of adjuvant sintilimab with or without CapeOX chemotherapy (capecitabine 1000 mg/m2, orally administered twice daily on days 1-14; oxaliplatin 130 mg/m2, intravenously administered on day 1 every 3 weeks), determined by clinicians; or another four cycles of sintilimab followed by radical surgery or observation (only for patients with a clinical complete response; also known as the watch and wait strategy). The primary endpoint was the complete response rate, which included both a pathological complete response after surgery and a clinical complete response after completion of sintilimab treatment. Clinical response was evaluated by digital rectal examination, MRI, and endoscopy. Response was assessed in all patients who received treatment at least until the first tumour response assessment, after the first two cycles of sintilimab. Safety was analysed in all patients who received at least one dose of treatment. This trial is closed to enrolment and is registered with ClinicalTrials.gov (NCT04304209). FINDINGS: Between Oct 19, 2019, and June 18, 2022, 17 patients were enrolled and received at least one dose of sintilimab. The median age was 50 years (IQR 35-59) and 11 (65%) of 17 patients were male. One patient was excluded from efficacy analyses because they were lost to follow-up after the first sintilimab cycle. Of the remaining 16 patients, six underwent surgery, of whom three had a pathological complete response. Nine other patients had a clinical complete response and chose the watch and wait strategy. One patient had a serious adverse event and discontinued treatment; this patient did not have a complete clinical response and refused to undergo surgery. A complete response was thus noted for 12 (75%; 95% CI 47-92) of 16 patients. One of the three patients who underwent surgery but did not have a pathological complete response showed an increase in tumour volume after the initial four cycles of sintilimab (at which point they underwent surgery); this patient was deemed to have primary resistance to immune checkpoint inhibitors. After a median follow-up of 17·2 (IQR 8·2-28·5) months, all patients were alive and none had disease recurrence. Only one (6%) patient had a grade 3-4 adverse event, which was deemed a serious adverse event (grade 3 encephalitis). INTERPRETATION: The preliminary results of this study suggest that anti-PD-1 monotherapy is effective and tolerable for patients with mismatch-repair deficient locally advanced rectal cancer and could potentially spare some patients from radical surgery. Longer treatment courses might be needed to achieve maximum effects in some patients. Longer follow-up is also needed to observe the duration of response. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, Science and Technology Program of Guangzhou, and Innovent Biologics.

Integrating Postradiotherapy MRI-Detected Lymph Node Necrosis and Pre- and Posttreatment Epstein-Barr Virus-DNA for Risk Stratification in Nasopharyngeal Carcinoma.

BACKGROUND: Residual lymphadenopathy and detectable Epstein-Barr virus (EBV) DNA after radiotherapy (RT) are known negative prognostic factors for nasopharyngeal carcinoma (NPC). However, there is a need to distinguish between patients with residual disease that will metastasize and those who will not. PURPOSE: To develop a prognostic model to improve the risk stratification of NPC patients after RT. STUDY TYPE: Retrospective. POPULATION: Three hundred eighty-seven NPC patients treated with RT between January 2010 and January 2013. FIELD STRENGTH/SEQUENCE: T1-, T2-weighted and enhanced T1-weighted imaging at 1.5 or 3.0 T pretreatment and 3-4 months post-RT. ASSESSMENT: Post-RT central nodal necrosis (CNN) and other nodal characteristics on MRI were assessed by three radiologists independently. EBV DNA was measured by quantitative polymerase chain reaction. The association between these variables and the primary endpoint (5-year distant metastasis-free survival [DMFS], time from the day of diagnosis to any distant metastasis) was analyzed. Nomograms A (pre-/posttreatment EBV-DNA + N stage + post-RT retropharyngeal lymph node [RLN] CNN), B (tumor-node-metastasis [TNM] stage + pretreatment EBV-DNA), and C (TNM stage + post-RT EBV-DNA) were developed. STATISTICAL TESTS: Univariate and multivariate analyses were performed with the Cox regression model. Nomograms were developed based on the Cox regression model and two prognostic models. The concordance index (C-index) and calibration curve were used to evaluate the discriminative ability of the nomograms and TNM stage. P-values < 0.05 were considered statistically significant. RESULTS: Post-RT RLN CNN was an independent prognostic factor for 5-year DMFS (hazard ratio, 2.88 [1.48-5.62]). Nomogram A (C-index 0.728 [0.660-0.797]) demonstrated better risk discrimination than nomogram B (0.638 [0.571-0.705]), nomogram C (0.707 [0.636-0.778]), and the TNM stage (0.587 [0.515-0.659]) for 5-year DMFS in NPC. DATA CONCLUSION: Nomogram A combining pretreatment EBV-DNA and N stage with post-RT EBV-DNA and RLN CNN improved the prognostic risk stratification for DMFS in NPC. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Carotid space involvement is a prognostic factor and marker for induction chemotherapy in patients with nasopharyngeal carcinoma.

OBJECTIVES: The carotid space is an integral part of the parapharyngeal space, with ambiguous prognostic value for patients with nasopharyngeal carcinoma (NPC). This study aimed to investigate the prognostic significance of carotid space involvement (CSI) and propose a treatment strategy. MATERIALS AND METHODS: This retrospective study enrolled 792 patients with biopsy-confirmed, non-distant metastatic NPC staged by magnetic resonance imaging before treatment. We used multivariable Cox regression models and Kaplan-Meier methods to assess the association between the variables and survival outcomes. A matched-pair method (1:1) was used to compare the survival differences between the patients with CSI treated with induction chemotherapy (ICT)and that of those who were not. RESULTS: The incidence rate of CSI was 21.7 % (172/792). Multivariate analysis revealed that CSI was not an independent prognostic factor for survival outcomes in the 792 patients with NPC; however, the Chi-square test showed a different distribution of treatment strategies with ICT for patients with and without CSI. After stratification by ICT, CSI was an independent prognostic factor for overall survival (OS) (p = 0.049) in patients without ICT, but not for distant metastasis-free, local recurrence-free, or progression-free survival (p˃0.05). Additionally, ICT improved OS in patients with CSI (hazard ratio, 0.42; p = 0.019). Matched pair analysis showed that patients with CSI gained prolonged OS from ICT compared with the non-ICT group (88.4 % vs 69.4 %, p = 0.028). CONCLUSION: CSI was an independent negative prognostic factor for OS in patients with NPC without ICT and might be an imaging marker for identifying eligible candidates for ICT.

Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer.

BACKGROUND: Both Response Evaluation Criteria in Solid Tumors (RECIST) and tumor regression grade (TRG) play key roles in evaluating tumor response. We analyzed the consistency of TRG and RECIST 1.1 for gastric cancer (GC) patients and compared their prognostic values. METHODS: Patients with GC who received preoperative chemotherapy or chemoimmunotherapy and had records of TRG from December 2013 to October 2021 were enrolled retrospectively. TRG 0-1 and 2-3 are considered as corresponding to complete response (CR)/partial response (PR) and stable disease (SD)/progress disease (PD) in RECIST 1.1, respectively. The primary endpoints were disease-free survival (DFS) and overall survival (OS). The consistency of RECIST and TRG was examined by kappa statistics. Survival analysis was performed using the Kaplan Meier method. RESULT: One hundred fifty seven GC patients were enrolled, including 125 with preoperative chemotherapy and 32 with chemoimmunotherapy. Among them, 56 patients had measurable lesions. Only 19.6% (11/56) of the patients had consistent results between RECIST 1.1 and TRG. TRG was correlated with both OS and DFS (P = 0.02 and 0.03, respectively) while response according to RECIST1.1 was not (P = 0.86 and 0.23, respectively). The median DFS had not reached in the TRG 0-1 group and was 16.13 months in TRG 2-3 group. TRG 2-3 was associated with young age and peritoneal or liver metastasis. Besides, preoperative chemoimmunotherapy had a significantly higher pCR rate than chemotherapy alone (34.4% vs 8.0%, P < 0.001). CONCLUSION: TRG was in poor agreement with RECIST 1.1. TRG was better than RECIST 1.1 in predicting DFS and OS for GC patients who received preoperative therapy.

MRI of nasopharyngeal carcinoma: parapharyngeal subspace involvement has prognostic value and influences T-staging in the IMRT era.

OBJECTIVES: To identify the prognosis of parapharyngeal space involvement (PPSI) based on the number of subspaces involved (pre-styloid space, carotid space (CS), areas outside the CS) and explore its significance for current T-staging in patients with nasopharyngeal carcinoma (NPC). METHODS: PPSI was retrospectively identified in 1224 patients with non-disseminated NPC at two centers on MRI and separated into four invasion patterns: pattern A (only post-styloid space), pattern B (post-styloid space, CS extension), pattern C (post-styloid space, pre-styloid space extension), and pattern D (all spaces). The Kaplan-Meier analysis and multivariate Cox regression models were used. RESULTS: PPSI was diagnosed in 63.4% of cases, with patterns A, B, C, and D in 14.3%, 3.8%, 25.3%, and 18.6% of cases, respectively. No prognostic heterogeneity was observed between pattern B and pattern C (p > 0.05). Thus, the degree of PPSI was based on the number of subspaces involved: grade 0 (none), grade 1 (one), grade 2 (two), and grade 3 (three), which could independently predict overall survival (OS) (p < 0.001). T3 patients with grade 0/1 PPSI (slight-T3) had a better prognosis than those with grade 2/3 PPSI (severe-T3) in terms of OS, locoregional-free survival (LRFS), and progression-free survival (PFS) (all p < 0.001), whose hazard ratios were higher and lower than those with T1 and T2, respectively. Combining the T2 and slight-T3 groups as the proposed T2 provided significant differences in OS, LRFS, and PFS between T2 and T3 (all p < 0.05). CONCLUSIONS: The risk of death increased with the number of parapharyngeal subspaces involved. The degree of PPSI is recommended to optimize T3 heterogeneity. KEY POINTS: • Parapharyngeal space involvement was proposed to differentiate patient risk groups based on the number of involved subspaces: grade 0 (none), grade 1 (one), grade 2 (two), or grade 3 (three). • The degree of parapharyngeal space involvement was an independent negative prognosticator for OS. • The degree of parapharyngeal space involvement may influence T-staging in patients with nasopharyngeal carcinoma.

An ESIPT-Dependent AIE Fluorophore Based on HBT Derivative: Substituent Positional Impact on Aggregated Luminescence and its Application for Hydrogen Peroxide Detection.

Aiming to develop the facile organic fluorophore possessing excited state intramolecular proton transfer (ESIPT) and aggregation-induced emission (AIE), we designed and synthesized two isomers with different linkage site between hydroxyl of 2-(2-hydroxyphenyl) benzothiazole (HBT) and a benzothiazole substituent (para position refers to p-BHBT and ortho position refers to o-BHBT). Fluorescence emission properties of p-BHBT and o-BHBT in THF/water mixtures with different water volume fractions indicated an opposite luminescence in aggregates, in which p-BHBT showed an ESIPT-dependent AIE properties while o-BHBT displayed ESIPT effect and aggregation-caused quenching (ACQ) qualities. A possible mechanism for molecular actions to illustrate the aggregating luminescence alteration of these two isomers had been proposed and verified by theoretical and experimental studies. More importantly, Probe-1, generated from dual ESIPT-AIE fluorophore p-BHBT, was successfully used as a ratiometric fluorescent chemosensor for highly selective (above 15-fold over other ROS) and sensitive (69-fold fluorescence enhancement with 0.22 µM of detection limit) detection of hydrogen peroxide in aqueous solution and living cells, respectively.

A ratiometric ESIPT probe based on 2-aza-Cope rearrangement for rapid and selective detection of formaldehyde in living cells.

Formaldehyde (FA) is a crucial reactive signaling molecule participating in epigenetic and metabolic pathways. However, abnormally elevated levels of FA are implicated in various diseases spanning from tumors to neurodegenerative disorders. Despite being highly selective for FA, current 2-aza-Cope-based fluorescent probes leave room for improvement because their relatively slow reaction kinetics (1-9 hours response time) hinder their capability to track transient biological FA. Herein, we present a ratiometric fluorescent probe, FormAFP, based on excited state intramolecular photon transfer (ESIPT) for rapid (within 10 min), selective (above 70-fold over other RCS) and sensitive (240-times fluorescence enhancement with 66 nM detection limit) detection of FA via 2-aza-Cope rearrangement. The probe also displayed a fast response (<20 min) to both exogenous and endogenous FA in living cells. Besides, FormAFP was capable of monitoring FA released by folate degradation in living MCF7 cells. More importantly, FormAFP successfully detected fluctuations of endogenous FA levels in oxidative stress stimulation, demonstrating its potential as an ideal tool to explore FA biology.

Bone turnover markers are associated with the PTH levels in different subtypes of pseudohypoparathyroidism type 1 patients.

OBJECTIVE: Bone responsiveness to parathyroid hormone (PTH) in different subtypes of pseudohypoparathyroidism type 1 (PHP1) remains controversial. We aimed to investigate this phenomenon using bone turnover markers (BTMs) in a large cohort of PHP1 patients. DESIGN: Retrospective study. PATIENTS: Sixty-three PHP1 patients diagnosed by molecular analysis were used as subjects, and 48 sex- and age-matched patients with nonsurgical hypoparathyroidism (NS-HP) were used for comparison. MEASUREMENTS: Bone turnover markers, alkaline phosphatase (ALP), C-terminal telopeptide of type I collagen (ß-CTX) and related parameters in PHP1 were compared among different subtypes and with NS-HP. RESULTS: Among all the PHP1 patients (15 PHP1A, 14 familial 1B and 34 sporadic 1B), 23.8% had elevated baseline BTM levels. No significant difference was found in the ß-CTX levels among different subtypes. The ß-CTX level was positively correlated with the PTH level for all PHP1, PHP1B and PHP1A patients (B = 0.001, 0.001 and 0.004, respectively; all p < .05). The BTM levels of PHP1 patients were significantly higher than those of NS-HP patients (ß-CTX: 0.56 ng/ml vs. 0.20 ng/ml, p = .001; ALP: 105 U/L vs. 72 U/L, p = .001). The serum ß-CTX levels in different PHP1 subtypes were all significantly higher than those in NS-HP patients in adults. Among the 22 followed up patients, changes in BTMs were associated with changes in PTH (ß-CTX: r = .507, p = .023; ALP: r = .475, p = .034). CONCLUSIONS: Bone tissues respond to PTH in different PHP1 subtypes, and it is reasonable to monitor and normalize PTH and BTMs in addition to the serum and urinary calcium levels in the follow-up of PHP1 patients.

Characteristic of Tumor Regrowth After Gamma Knife Radiosurgery and Outcomes of Repeat Gamma Knife Radiosurgery in Nonfunctioning Pituitary Adenomas.

OBJECTIVE: This study aimed to report the characteristic of tumor regrowth after gamma knife radiosurgery (GKRS) and outcomes of repeat GKRS in nonfunctioning pituitary adenomas (NFPAs). DESIGN AND METHODS: This retrospective study consisted of 369 NFPA patients treated with GKRS. The median age was 45.2 (range, 7.2-84.0) years. The median tumor volume was 3.5 (range, 0.1-44.3) cm3. RESULTS: Twenty-four patients (6.5%) were confirmed as regrowth after GKRS. The regrowth-free survivals were 100%, 98%, 97%, 86% and 77% at 1, 3, 5, 10 and 15 year, respectively. In multivariate analysis, parasellar invasion and margin dose (<12 Gy) were associated with tumor regrowth (hazard ratio [HR] = 3.125, 95% confidence interval [CI] = 1.318-7.410, p = 0.010 and HR = 3.359, 95% CI = 1.347-8.379, p = 0.009, respectively). The median time of regrowth was 86.1 (range, 23.2-236.0) months. Previous surgery was associated with tumor regrowth out of field (p = 0.033). Twelve patients underwent repeat GKRS, including regrowth in (n = 8) and out of field (n = 4). Tumor shrunk in seven patients (58.3%), remained stable in one (8.3%) and regrowth in four (33.3%) with a median repeat GKRS margin dose of 12 (range, 10.0-14.0) Gy. The actuarial tumor control rates were 100%, 90%, 90%, 68%, and 68% at 1, 3, 5, 10, and 15 years after repeat GKRS, respectively. CONCLUSIONS: Parasellar invasion and tumor margin dose (<12 Gy) were independent risk factors for tumor regrowth after GKRS. Repeat GKRS might be effective on tumor control for selected patients. For regrowth in field due to relatively insufficient radiation dose, repeat GKRS might offer satisfactory tumor control. For regrowth out of field, preventing regrowth out of field was the key management. Sufficient target coverage and close follow-up might be helpful.

Pituitary hemorrhage in pituitary adenomas treated with gamma knife radiosurgery: incidence, risk factors and prognosis.

Objective: The aims of this study were to investigate the incidence, risk factors and prognosis of pituitary hemorrhage in pituitary adenomas treated with gamma knife radiosurgery (GKRS). Methods and materials: Between December 1993 and December 2016, 751 consecutive pituitary adenoma patients treated with GKRS were retrospectively reviewed in a single center. There were 271 male (36.1%) and 480 female (63.9%) patients with a median age of 38.5 (range, 7.2-84.0) years. The number of nonfunctioning pituitary adenomas (NFPAs) and functioning pituitary adenomas were 369 (49.1%) and 382 (50.9%) respectively. The median follow-up time was 61.1 (range, 12.1-304.4) months. Results: In this study, 88 patients (11.7%) were diagnosed with pituitary hemorrhage before GKRS, 55 patients (7.3%) developed new or worsened pituitary hemorrhage after GKRS (excluding 3 patients with new or worsened pituitary hemorrhage due to tumor regrowth). The median time to new or worsened pituitary hemorrhage after GKRS was 18.9 (range 3.1-70.7) months. Overall, 128 patients (17.0%) were diagnosed with pituitary hemorrhage in the entire series. After adjustment with logistic regression, nonfunctioning pituitary adenomas (NFPAs) (odds ratio [OR]=2.121, 95% confidence interval [CI]=1.195-3.763, p=0.010) and suprasellar extension (OR=2.470, 95% CI=1.361-4.482, p=0.003) were associated with pituitary hemorrhage before GKRS. NFPA (OR=3.271, 95% CI=1.278-8.373, p=0.013) was associated with new or worsened pituitary hemorrhage after GKRS. Five patients received surgical resection for new or worsened pituitary hemorrhage were considered as GKRS treatment failure. Two patients with new hypopituitarism were considered to be owed to new or worsened pituitary hemorrhage after GKRS. Conclusions: New or worsened pituitary hemorrhage after GKRS was not an uncommon phenomenon. NFPA was an independent risk factor of new or worsened pituitary hemorrhage after GKRS. New or worsened pituitary hemorrhage after GKRS could lead to GKRS treatment failure. GKRS might be a precipitating factor of pituitary hemorrhage.

Long-term results of Gamma Knife Radiosurgery for Postsurgical residual or recurrent nonfunctioning Pituitary Adenomas.

Introduction: The aim of this retrospective study was to analyze the long-term outcomes and factors associated with treatment failure of Gamma Knife radiosurgery (GKRS) for postsurgical residual or recurrent nonfunctioning pituitary adenomas (NFPAs). Design and Methods: A total of 148 cases of postsurgical residual or recurrent NFPA patients were enrolled in the study. There were 111 cases with residual tumor and 37 cases with recurrent tumor. The median age was 46.0 years (Range: 10.9-75.8 years). The median tumor volume at GKRS was 3.6 cm3 (Range: 0.3-74.5 cm3), and the median tumor margin dose was 14.0 Gy (Range: 9 - 20 Gy). Results: Tumor shrunk in 111 patients (75%), remained stable in 17 patients (11.5%), and progressed in 20 patients (13.5%) during a median of 64.5 months (Range: 14.5 - 236.0 months) of imaging follow-up. The progression-free survival rates were 99%, 91%, 88% and 74% at 1, 3, 5 and 10 years after GKRS, respectively. In a multivariate analysis, tumor margin dose (<13 Gy) was significantly associated with tumor progression (hazard ratio=3.526, 95% confidence interval=1.400-8.877, p=0.007). New hypopituitarism occurred in 22 out of 80 patients (27.5%), including hypogonadism (n=7), hypothyroidism (n=9), hypocortisolism (n=15) and growth hormone deficiency (n=1). In univariate and multivariate analysis, there were no factors significantly associated with new hypopituitarism. Six patients (4.1%) developed new or worsening visual dysfunction. Four patients (2.7%) developed new cranial neuropathy. Conclusion: In this study, GKRS can offer a high tumor control rate as well as a low rate of complications in postsurgical residual or recurrent NFPA patients.

Initial Gamma Knife radiosurgery for nonfunctioning pituitary adenomas: results from a 26-year experience.

OBJECTIVE: The aim of this study was to evaluate the long-term outcomes of initial Gamma Knife radiosurgery (GKRS) for patients with nonfunctioning pituitary adenomas (NFPAs). DESIGN AND METHODS: This was a single-center retrospective study. Eighty-one patients with NFPAs undergoing initial GKRS were enrolled. The median age was 44.9 years (range, 7.2-75.5 years). The median tumor volume was 2.3 cm3 (range, 0.1-31.3 cm3), and the median tumor margin dose was 13.0 Gy (range, 8-22 Gy). RESULTS: Tumor shrunk in 63 patients (77.8%), remained stable in 9 (11.1%), treatment failure in 9 (11.1%) during a median follow-up of 67.1 months (range, 11.5-263.9 months). The tumor control rates were 100%, 99%, 95%, and 84%, at 1, 3, 5, and 10 years, respectively. In multivariate analysis, tumor volume (≥4 cm3) and margin dose (<12 Gy) were associated with treatment failure (hazard ratio (HR) = 7.093, 95% confidence interval (CI) = 1.098-45.083, p = 0.040, and HR = 9.643, 95% CI = 1.108-83.927, p = 0.040, respectively). New apoplexy occurred in seven patients (8.6%) after GKRS with a median time of 39.9 months (range, 11.9-166.8 months). In multivariate analysis, tumor volume (≥10 cm3) was a significant risk factor (HR = 10.642, 95% CI = 2.121-53.398, p = 0.004). New hypopituitarism occurred in 14 patients (17.3%). No factors were associated with new hypopituitarism. Four patients (4.9%) developed new or worsening visual dysfunction. No new cranial neuropathy was noted. CONCLUSIONS: In this study, initial GKRS can provide a high tumor control rate, as well as a low incidence rate of complications in NFPAs. GKRS may be an alternative initial treatment for selected NFPAs.

Nodal grouping in nasopharyngeal carcinoma: prognostic significance, N classification, and a marker for the identification of candidates for induction chemotherapy.

OBJECTIVES: This study aimed to evaluate the value of nodal grouping (NG), defined as the presence of at least three contiguous lymph nodes (LNs) within one LN region, in staging and management of patients with non-metastatic nasopharyngeal carcinoma (NPC). METHODS: MR images were reviewed to evaluate LN variables, including NG. The Kaplan-Meier method and multivariate Cox regression models evaluated the association between the variables and survival. Harrell's concordance index (C-index) was used to measure the performance of prognostic models. The outcome of induction chemotherapy (IC) in patients with and without NG was compared using matched-pair analysis. RESULTS: In 1224 patients enrolled, NG was found to be an independent prognostic factor for overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and regional recurrence-free survival. The hazard ratio and 95% confidence interval (CI) of NG for OS (3.86, 2.09-7.12) were higher than those of stage N2 (3.54, 1.89-6.70). On upgrading patients with NG from stages N1 to N2, the revised N staging yielded a higher C-index compared to the American Joint Committee on Cancer system in predicting PFS (0.664 vs. 0.658, p = 0.022) and DMFS (0.699 vs. 0.690, p = 0.005). Results of the matched-pair analysis revealed that for patients with NG in stages N1 and N2, IC was correlated with improved OS (p = 0.022), PFS (p = 0.007), and DMFS (p = 0.021). CONCLUSIONS: NG is a significant prognostic factor for patients with NPC. Patients with NG may be upgraded from stages N1 to N2. NG was also a marker for identifying patients who would benefit from IC. KEY POINTS: • Nodal grouping, defined as the presence of at least three contiguous LNs within one LN region on MRI, was identified as a significant prognostic factor. • In patients with nasopharyngeal carcinoma, nodal grouping may influence lymph node staging. • Nodal grouping was a marker for identifying patients who may benefit from induction chemotherapy.

Bone Mineral Density and Its Serial Changes Are Associated With PTH Levels in Pseudohypoparathyroidism Type 1B Patients.

Bone responsiveness to serum parathyroid hormone (PTH) in pseudohypoparathyroidism 1B (PHP1B) is controversial. Forty-eight PHP1B patients diagnosed by molecular analysis were recruited from 2000 to 2016 from the Peking Union Medical College Hospital. Fifty-five sex-matched nonsurgical hypoparathyroidism (NS-HP) patients were selected and included for comparison. Basic information, laboratory test, and dual-energy X-ray absorptiometry (DXA) results were collected. Linear regression was performed to identify independent predictors of lumbar spine (LS), femoral neck (FN), and total hip (TH) bone mineral density (BMD) Z-scores in PHP1B patients. BMD and related markers were compared between PHP and NS-HP patients. Longitudinal observation of 10 PHP1B patients was performed. The BMD Z-score for the LS (1.14 ± 1.41) was higher than that for the FN (-0.20 ± 1.00, p < 0.001) and the TH (0.03 ± 1.06, p < 0.001) in PHP1B patients. Despite lower serum calcium levels in untreated patients (1.72 mmol/L in untreated patients versus 2.14 mmol/L in treated patients, p = 0.024), the PTH levels as well as BMD Z-scores were comparable between treated and untreated patients at baseline. PTH was a negative predictor for LS-BMD Z-score (B = -0.004, p = 0.028) for sporadic PHP1B patients, and a similar result was obtained for all the PHP1B patients (B = -0.002, p = 0.053). Z-scores for FN- and LS-BMDs after treatment increased by 0.31 ± 0.10 and 0.58 ± 0.12, respectively, where the increase in LS-BMD correlated with a decrease in PTH (r = -0.72, p = 0.044). All BMD Z-scores were significantly lower in PHP1B patients than in IHP patients for the FN, LS, and TH (-0.20 ± 1.00 versus 1.57 ± 1.07, 1.14 ± 1.41 versus 1.96 ± 1.32, 0.03 ± 1.06 versus 1.67 ± 1.01, respectively, all p < 0.05). Skeletal tissue in PHP1B patients responds to PTH, where heterogenous sensitivities to PTH may exist in different regions of bone. Therefore, it is reasonable to normalize PTH levels when treating PHP1B to avoid negative effects of PTH on bone. © 2017 American Society for Bone and Mineral Research.

Clinical and genetic characteristics of Pseudohypoparathyroidism in the Chinese population.

BACKGROUND: Pseudohypoparathyroidism (PHP) is caused by mutations and epimutations in the GNAS locus, and characterized by the possibility of resistance to multiple hormones and Albright's hereditary osteodystrophy. PHP can be classified into the forms 1A/C, sporadic 1B and familial 1B. OBJECTIVES: To obtain an overall view of the clinical and genetic characteristics of the Chinese PHP patient population. METHODS: From 2000 to 2016, 120 patients were recruited and studied using Sanger sequencing, methylation-specific multiple ligation-dependent probe amplification (MS-MLPA) and combined bisulfite restriction analysis (COBRA). Of these patients, 104 had positive molecular alterations indicative of certain forms of PHP and were included in data analysis. Clinical and laboratory features were compared between PHP1A/C and PHP1B patients. RESULTS: Ten PHP1A/C, 21 familial PHP1B and 73 sporadic PHP1B patients were identified. Four novel GNAS mutations were discovered in these patients, including c.1038+1G>T, c.530+2T>C, c.880_883delCAAG and c.311_312delAAG, insT. The most common symptoms in this series were recurrent tetany (89.4%) and epilepsy (47.1%). The prevalence of weight excess increased with age for PHP1B (10%-35%) and PHP1A/C (50%-75%). Intracranial calcification had a prevalence of 94.6% and correlated with seizures (r = .227, P = .029). Cataracts occurred in 56.2% PHP patients, and there was a trend towards longer disease duration in patients with cataracts (P = .051). Statistically significant differences (P < .05) were observed when comparing certain clinical characteristics between PHP1B and PHP1A/C patients, including age of onset (10 vs 7 year), short stature (21.3% vs 70%), rounded face (60.6% vs 100%), brachydactyly (25.5% vs 100%), ectopic ossification (1.1% vs 40%) and TSH resistance (44.6% vs 90%), respectively. CONCLUSIONS: This study is the largest single-centre series of PHP patients and summarizes the clinical and genetic features of the Chinese PHP population. While there was substantial clinical overlap between PHP1A/C and PHP1B, differences in disease progression were observed.

The dynamic mutation characteristics of thermonuclear reaction in Tokamak.

The stability and bifurcations of multiple limit cycles for the physical model of thermonuclear reaction in Tokamak are investigated in this paper. The one-dimensional Ginzburg-Landau type perturbed diffusion equations for the density of the plasma and the radial electric field near the plasma edge in Tokamak are established. First, the equations are transformed to the average equations with the method of multiple scales and the average equations turn to be a Z 2-symmetric perturbed polynomial Hamiltonian system of degree 5. Then, with the bifurcations theory and method of detection function, the qualitative behavior of the unperturbed system and the number of the limit cycles of the perturbed system for certain groups of parameter are analyzed. At last, the stability of the limit cycles is studied and the physical meaning of Tokamak equations under these parameter groups is given.