The efficacy and safety of adding PD-1 blockade to induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) for locoregionally advanced nasopharyngeal carcinoma: an observational, propensity score-matched analysis.

BACKGROUND: Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC  plus cisplatin CCRT ) for LANPC patients. METHODS: From January 2020 to November 2022, 347 patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0) were included. Of the 347 patients, 268 patients were treated with standard treatment (IC-CCRT), and 79 received PD-1 blockade plus IC-CCRT (PD-1 group). For the PD-1 group, PD-1 blockade was given intravenously once every 3 weeks for up to 9 cycles (3 induction and 6 adjuvant). The primary endpoint was disease-free survival (DFS) (i.e. freedom from local/regional/distant failure or death). The propensity score matching (PSM) with the ratio of 1:2 was performed to control confounding factors. RESULTS: After PSM analysis, 150 patients receiving standard treatment and 75 patients receiving additional PD-1 blockade remained in the current analysis. After three cycles of IC, the PD-1 group had significantly higher rates of complete response (defined as disappearance of all target lesions; 24% vs. 9%; P = 0.006) and complete biological response (defined as undetectable cell-free Epstein-Barr virus DNA, cfEBV DNA; 79% vs. 65%; P = 0.046) than that in the standard group. And the incidence of grade 3-4 toxicity during IC was 47% in the PD-1 group and 41% in the standard group, with no significant difference (P = 0.396). During follow-up period, additional PD-1 blockade to standard treatment improved 3-year DFS from 84 to 95%, with marginal statistical significance (HR, 0.28; 95%CI, 0.06-1.19; P = 0.064). CONCLUSION: Additiaonl PD-1 blockade to gemcitabine and cisplatin IC and adjuvant treatment results in significant improvement in tumor regression, cfEBV DNA clearance, superior DFS, and comparable toxicity profiles in high-risk LANPC patients.

The feasibility of reduced-dose radiotherapy in childhood nasopharyngeal carcinoma with favorable response to neoadjuvant chemotherapy.

BACKGROUND: To assess the feasibility of adjusting radiation dose (RD) in childhood NPC with favorable tumor response after neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Using an NPC-specific database, children and adolescents (≤18 years) with locoregionally advanced NPC (CA-LANPC) were retrospectively analyzed. Enrolled patients were those who received favorable tumor response after 2-4 cycles of NAC followed by concurrent chemoradiotherapy. Survival outcomes and treatment-related toxicities were compared for the standard RD on primary tumors (PT-RDstandard, 66-72 Gy) and the reduced RD on primary tumors (PT-RDreduced, 60-65.9 Gy). RESULTS: A total of 132 patients were included, and the median follow-up time was 75.2 months (IQR, 53.2-98.7 months) for the entire cohort. The PT-RDreduced group had a significantly decreased incidence of severe mucositis (51.3 % vs 32.1 %; P = 0.034) when compared to the PT-RDstandard group. The total incidence of severe sequela in the PT-RDstandard group were significantly higher than those in the PT-RDreduced group (31.8 % vs 13.7 %; P = 0.029). In the propensity-matched analysis, the PT-RDreduced group resulted in parallel 5-year survival with the PT-RDstandard group from the matched cohort (disease-free survival, 82.7 % vs 80.3 %, P = 0.841; overall survival, 91.7 % vs 91.3 %, P = 0.582; distant metastasis-free survival, 87.5 % vs 82.8 %, P = 0.573; and locoregional relapse-free survival, 95.6 % vs 97.3 %, P = 0.836). In multivariate analysis, the impact of PT-RDreduced on all survival end points remained insignificant. CONCLUSIONS: Chemoradiotherapy with RD at levels of 60-65.9 Gy may be a reasonable strategy for CA-LANPC with favorable tumor response after NAC.

Small nodules (≤ 6 mm in diameter) of multiple primary lung cancers: prevalence and management.

BACKGROUND: Synchronous multiple primary lung cancers associated with small non-dominant nodules are commonly encountered. However, the incidence, follow-up, and treatment of small non-dominant tumors have been but little studied. We explored the prevalence and management of small non-dominant tumors and factors associated with interval growth. METHODS: This observational, consecutive, retrospective single-center study enrolled patients diagnosed with synchronous multiple primary lung cancers and small non-dominant tumors (≤ 6 mm in diameter) who underwent resection of the dominant tumor. The incidence, follow-up, and management of small non-dominant tumors and predictors of nodule growth were analyzed. RESULTS: There were 88 patients (12% of all lung cancer patients) with pathological diagnoses of synchronous multiple primary lung cancers. A total of 131 (18%) patients were clinically diagnosed with at least one small (≤ 6 mm in diameter) multiple primary lung cancer non-dominant tumor. 94 patients with 125 small-nodule non-dominant tumors clinically diagnosed as multiple primary lung cancers were followed-up for at least 6 months. A total of 29 (29/125, 23.2%) evidenced small pulmonary nodules (≤ 6 mm in diameter) that exhibited interval growth on follow-up computed tomography (CT). On multivariate analysis, a part-solid nodule (compared to a pGGN) (OR 1.23; 95% CI 1.08-1.40) or a solid nodule (compared to a pGGN) (OR 3.50; 95% CI 1.94-6.30) predicted small nodule interval growth. CONCLUSION: We found a relatively high incidence of multiple primary lung cancers with small non-dominant tumors exhibiting interval growth on follow-up CT, suggesting that resection of non-dominant tumors at the time of dominant tumor resection, especially when the nodules are part-solid or solid, is the optimal treatment.

FGF2 is overexpressed in asthma and promotes airway inflammation through the FGFR/MAPK/NF-κB pathway in airway epithelial cells.

BACKGROUND: Airway inflammation is the core pathological process of asthma, with the key inflammatory regulators incompletely defined. Recently, fibroblast growth factor 2 (FGF2) has been reported to be an inflammatory regulator; however, its role in asthma remains elusive. This study aimed to investigate the immunomodulatory role of FGF2 in asthma. METHODS: First, FGF2 expression was characterised in clinical asthma samples and the house dust mite (HDM)-induced mouse chronic asthma model. Second, recombinant mouse FGF2 (rm-FGF2) protein was intranasally delivered to determine the effect of FGF2 on airway inflammatory cell infiltration. Third, human airway epithelium-derived A549 cells were stimulated with either HDM or recombinant human interleukin-1ß (IL-1ß) protein combined with or without recombinant human FGF2. IL-1ß-induced IL-6 or IL-8 release levels were determined using enzyme-linked immunosorbent assay, and the involved signalling transduction was explored via Western blotting. RESULTS: Compared with the control groups, the FGF2 protein levels were significantly upregulated in the bronchial epithelium and alveolar areas of clinical asthma samples (6.70 ± 1.79 vs. 16.32 ± 2.40, P = 0.0184; 11.20 ± 2.11 vs. 21.00 ± 3.00, P = 0.033, respectively) and HDM-induced asthmatic mouse lung lysates (1.00 ± 0.15 vs. 5.14 ± 0.42, P < 0.001). Moreover, FGF2 protein abundance was positively correlated with serum total and anti-HDM IgE levels in the HDM-induced chronic asthma model (R2 = 0.857 and 0.783, P = 0.0008 and 0.0043, respectively). Elevated FGF2 protein was mainly expressed in asthmatic bronchial epithelium and alveolar areas and partly co-localised with infiltrated inflammatory cell populations in HDM-induced asthmatic mice. More importantly, intranasal instillation of rm-FGF2 aggravated airway inflammatory cell infiltration (2.45 ± 0.09 vs. 2.88 ± 0.14, P = 0.0288) and recruited more subepithelial neutrophils after HDM challenge [(110.20 ± 29.43) cells/mm2 vs. (238.10 ± 42.77) cells/mm2, P = 0.0392] without affecting serum IgE levels and Th2 cytokine transcription. In A549 cells, FGF2 was upregulated through HDM stimulation and promoted IL-1ß-induced IL-6 or IL-8 release levels (up to 1.41 ± 0.12- or 1.44 ± 0.14-fold change vs. IL-1ß alone groups, P = 0.001 or 0.0344, respectively). The pro-inflammatory effect of FGF2 is likely mediated through the fibroblast growth factor receptor (FGFR)/mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) pathway. CONCLUSION: Our findings suggest that FGF2 is a potential inflammatory modulator in asthma, which can be induced by HDM and acts through the FGFR/MAPK/NF-κB pathway in the airway epithelial cells.

Pathological and genomic phenotype of second neuroendocrine carcinoma during long-term follow-up after radical radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: Second head and neck neuroendocrine carcinoma (NEC) after radical radiotherapy for nasopharyngeal carcinoma (NPC) treatment is rarely reported. The prognosis of second cancer is poor, and our research focuses on finding a breakthrough in the treatment. In this study, we aimed to investigate clinicopathological characteristics and to identify the genomic landscape of second head and neck NECs. METHODS: We collected five second head and neck NEC cases in the recent three years from our patient database. Clinicopathological data and images were obtained. Genomic analysis was performed using high-throughput second generation sequencing. KEGG pathway enrichment analyses between high-frequency mutations were performed using the STRING database. RESULTS: All patients had been diagnosed with second NEC, according to the pathological observations. The interval between diagnosis of NPC and NEC ranged from 10 to 18 years. Two patients had brain or liver metastasis at three and nine months, respectively, after the diagnosis of NEC. Three patients died of the disease with the overall survival time ranging from three to nine months. Commonly altered genes (50%) in second head and neck NECs included TP53, RB1, NOTCH2, PTEN, POLG, KMT2C, U2AF1, EPPK1, ELAC2, DAXX, COL22A1, and ABL1. Those genetic lesions might affect p53 signaling, MAPK signaling, PI3K-Akt signaling, sphingolipid signaling, and neurotrophin signaling pathways. CONCLUSIONS: Second head and neck NECs had poor prognosis. We revealed, for the first time, the mutational landscape, high-frequency somatic mutations, and potential signaling pathways of second head and neck NECs. Its optimal treatment model needs to be further studied in future clinical trials.

Dopamine-Modified Zero-Valent Iron Nanoparticles for Dual-Modality Photothermal and Photodynamic Breast Cancer Therapy.

Phototherapy has the advantages of minimal invasion, few side effects, and improved accuracy for cancer therapy. The application of a polydopamine (PDA)-modified nano zero-valent iron (nZVI@PDA) as a new synergistic agent in combination with photodynamic/photothermal (PD/PT) therapy to kill cancer cells is discussed here. The nZVI@PDA offered high light-to-heat conversion and ROS generation efficiency under near-infrared (NIR) irradiation (808 nm), thus leading to irreversible damage to nZVI@PDA-treated MCF-7 cells at low concentration, without inducing apoptosis in normal cells. Irradiation of nZVI@PDA using an NIR laser converted the energy of the photons to heat and ROS. Our results showed that modification of the PDA on the surface of nZVI can improve the biocompatibility of the nZVI@PDA. This work integrated the PD and PT effects into a single nanodevice to afford a highly efficient cancer treatment. Meanwhile, nZVI@PDA, which combines the advantages of PDA and nZVI, displayed excellent biocompatibility and tumoricidal ability, thus suggesting its huge potential for future clinical research in cancer therapy.

Histologic lung cancer subtype differentiates synchronous multiple primary lung adenocarcinomas from intrapulmonary metastases.

BACKGROUND: Distinguishing synchronous multiple primary lung cancers (SMPLCs) from intrapulmonary metastases is important. The objective of this study was to determine long-term survival in patients who underwent surgical resection for synchronous multiple lung cancers and identify additional criteria that may be useful to distinguish patients with SMPLCs from those with more advanced disease. METHODS: The medical records of patients with lung cancer who underwent planned resection for synchronous multiple lung cancers from 2007 to 2012 at our institutions were reviewed retrospectively. A comprehensive histologic assessment was used to determine whether the tumors were metastases or separate synchronous primary tumors. RESULTS: A total of 51 patients with synchronous multiple lung cancers underwent surgical resection. Twenty-nine patients had ipsilateral synchronous multiple lung cancers, and 22 had bilateral synchronous multiple lung cancers. No perioperative death occurred. The survival analysis of all 51 patients with synchronous multiple lung cancers who underwent planned resection of all lesions showed 3- and 5-year overall survival rates of 86% and 67%, respectively, The median overall survival was not reached. The comprehensive histologic assessment identified six patients with intrapulmonary metastasis and 45 patients with SMPLCs. Intrapulmonary metastases were associated with decreased survival. Among patients with SMPLCs, the epidermal growth factor receptor mutation distribution shown high concordant frequency rate of 35% (5/14). CONCLUSIONS: Survival after surgical resection of synchronous multiple lung cancers in different lobes was promising. A comprehensive histologic assessment was useful for differentiating SMPLCs from intrapulmonary metastases.

Unusual primary intracranial dural-based poorly differentiated synovial sarcoma with t(X; 18)(p11; q11).

Synovial sarcoma is a rare aggressive neoplasm occurring at any site of the body, mainly in young adults. It may also arise in the CNS but has seldom been reported. We report a case of unusual intracranial synovial sarcoma in a young male patient. Neuroimaging revealed a large gadolinium-enhancing mass was located at the right anterior cranial fossa and was associated with multiple cyst formation. The mass was dural-based and was observed to invade the right orbital apex and ethmoidal bulla. Histologically, the tumor was composed of uniform oval and round cells with scant cytoplasm and indistinct borders. The tumor cells were observed to form densely cellular sheets, but in some areas, the tumor showed hemangiopericytomatous vascular pattern consisting of tumor cells arranged around dilated, thin-walled blood vessels. By immunohistochemistry, vimentin, CD99 and Bcl-2 were diffusely positive in most cells, and a focally weak reactivity for S-100 protein was also observed. However, the tumor cells were negative for cytokeratin (AE1/AE3), CK7, CK8/18, CK19, epithelial membrane antigen, CD34, synaptophysin, GFAP, desmin, myogenin, and smooth muscle actin. Cytogenetic analysis using fluorescence in situ hybridization (FISH) demonstrated a translocation t(X;18)(p11;q11), an aberration specific for synovial sarcoma. A diagnosis of primary dural-based poorly differentiated synovial sarcoma was made. To our knowledge, this is the first report of a poorly differentiated variant of synovial sarcoma occurring in dura mater and confirmed by cytogenetic analysis. The present case indicates that appropriate immunohistochemical analysis, and in particular molecular analysis, are essential for accurately diagnosing small, round-cell neoplasms in unusual locations.

[Expression and significance of neutrophil gelatinase-associated lipocalin in renal interstitial fibrosis in rats].

OBJECTIVE: To explore the expression and significance of neutrophil gelatinase-associated lipocalin(NGAL)in renal interstitial fibrosis (RIF) in rats. METHODS: A total of 60 male Sprague-Dawley rats were randomly divided into 3 groups of sham operation (SOR), unilateral ureteral obstruction (UUO) and angiotensin-converting enzyme inhibitor (ACEI). The serum concentrations of NGAL and tumor necrosis factor-alpha (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). And the expressions of NGAL, matrix metalloproteinase-9 (MMP-9) and transforming growth factor-ß1 (TGF-ß1) were observed by immunohistochemistry. RESULTS: (1) The levels of serum NGAL and TNF-α in UUO group obviously increased as compared to those in ACEI and SOR groups (NGAL: (69.2 ± 5.6) vs (41.0 ± 10.4), (10.8 ± 3.8) pg/ml; TNF-α: (116.2 ± 9.2) vs (99.8 ± 14.0), (29.2 ± 5.7) ng/ml; all P < 0.05). (2) The expressions of NGAL, TGF-ß1 and MMP-9 in renal tubular epithelial cells of UUO group increased as compared to those in SOR group. The expression of TGF-ß1 in ACEI group was apparently less than that in UUO group. The protein levels of NGAL and MMP-9 in ACEI group were obviously lower than those in UUO group within Day 14 post-operation and significantly higher than those in UUO group at Days 21 and 28. (3) In UUO group, the level of NGAL was positively correlated with the serum levels of TNF-α and serum creatinine (r = 0.910, 0.673, P < 0.01). The expression of NGAL had a highly positive correlation with MMP-9 (r = 0.913, P < 0.01) and the index of interstitial damage and the degrees of TGF-ß1 at Days 3-7 post-operation(r = 0.937, 0.847, P < 0.01). And the expression of NGAL was negatively correlated with the index of interstitial damage and the degrees of TGF-ß1 at Days 14-28 post-operation (r = -0.945, -0.944, P < 0.01). CONCLUSION: The expression of NGAL significantly increases in UUO modal of rats. And it is closely correlated with MMP-9, TNF-α and TGF-ß1. ACEI may influence the biological effects of NGAL by suppressing inflammatory responses, down-regulating the expression of TGF-ß1 and regulating the expression and the activity of MMP-9.

[Correlation of early phase contrast enhancement of multi-detector row computed tomography to tumor stroma of nodular solid lung adenocarcinoma].

BACKGROUND & OBJECTIVE: Dynamic enhanced multi-detector row CT (MDCT) has been used in differential diagnosis of pulmonary nodules, but its mechanism was unclear yet. This study was to evaluate the correlations of early phase enhancement of MDCT to proportion and distribution of stroma in solid lung adenocarcinoma. METHODS: A total of 31 patients with lung adenocarcinoma underwent routine contrast-enhanced MDCT. All lesions were solid solitary pulmonary nodules confirmed by pathology. CT observation items included net enhancement and distribution of enhancement. Tumor morphology was observed with HE staining. About 25 fields of view of each specimen at low magnification were scanned to obtain digital data. Semi-auto segmentation software was used to calculate mean stroma proportion. RESULTS: The proportion of invasive stroma in tumors was correlated positively to CT enhancement value (r=0.483, P=0.006). Of the 31 nodules, 18 (58.1%) showed homogenous enhancement, 10 (32.3%) showed peripheral inhomogenous enhancement, 1 (3.2%) showed central inhomogenous enhancement, 1 (3.2%) showed asymmetrical inhomogenous enhancement, 1 (3.2%) showed no enhancement; 18 (58.1%) nodules showed mixed distribution of stroma, 11 (35.5%) showed peripheral distribution, 1 (3.2%) showed central distribution, 1 (3.2%) showed asymmetrical distribution. Most acinar adenocarcinomas had net enhancement of > 20 Hu, which was significantly higher than that of solid adenocarcinomas with mucin subtype (P=0.005). CONCLUSIONS: Extent and pattern of CT enhancement of solid lung adenocarcinoma nodules reflect the proliferation and distribution of stroma, respectively. It is helpful to comprehend some false negative on CT enhancement by adequately understanding of the pathologic features of different subtypes of lung adenocarcinoma.