Current perspectives on radiotherapy in hepatocellular carcinoma management: a comprehensive review.

This review examines the transformative role of external beam radiotherapy (EBRT) in managing hepatocellular carcinoma (HCC), spotlighting the progression from traditional EBRT techniques to advanced modalities like intensity-modulated radiotherapy (RT), stereotactic body RT (SBRT), and innovative particle therapy, including proton beam therapy and carbon ion RT. These advancements have significantly improved the precision and efficacy of RT, marking a paradigm shift in the multimodal management of HCC, particularly in addressing complex cases and enhancing local tumor control. The review underscores the synergistic potential of integrating RT with other treatments like transarterial chemoembolization, systemic therapies such as sorafenib, and emerging immunotherapies, illustrating enhanced survival and disease control outcomes. The efficacy of RT is addressed for challenging conditions, including advanced HCC with macrovascular invasion, and RT modalities, like SBRT, are compared against traditional treatments like radiofrequency ablation for early-stage HCC. Additionally, the review accentuates the encouraging outcomes of particle therapy in enhancing local control and survival rates, minimizing treatment-related toxicity, and advocating for continued research and clinical trials. In conclusion, the integration of RT into multimodal HCC treatment strategies, coupled with the emergence of particle therapy, is crucial for advancing oncologic management, emphasizing the need for relentless innovation and personalized treatment approaches.

Elevated CXCL12 in the plasma membrane of locally advanced rectal cancer after neoadjuvant chemoradiotherapy: a potential prognostic marker.

Background: Neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) has been shown to improve sphincter preservation and local pelvic control, but the efficacy of nCRT plateaus due to metastasis. CXC chemokine ligand 12 (CXCL12) has a critical impact on cancer development and metastasis. Methods: By investigating public databases containing LARC patient data, CXCL12, CXCR4 and FAPα expression was analyzed via the Tumor Immune Estimation Resource (TIMER) and GSEA. Immunohistochemistry was applied to a total of 121 surgically resected specimens consisting of 61 LARCs after nCRT and 60 LARCs with no nCRT and 16 cases with endoscopic resection of high-grade colorectal adenoma. Results: By investigating public databases containing LARC patient data, CXCL12 expression is correlated with poor prognosis, immune cell infiltration, epithelial- mesenchymal transition, and angiogenesis in LARC. Furthermore, radiation selectively induced CXCL12, CXCR4 and FAPα expression in tumor tissues. Immunohistochemistry results showed that the levels of CXCL12, CXCR4, and FAPα in LARC cells after nCRT were higher than in LARC cells untreated with nCRT (p < 0.001 for each). Elevated levels of CXCL12 in the plasma membrane of LARC cells after nCRT demonstrated an association with the period of freedom from recurrence (FFR) in univariate and multivariate survival analyses (p = 0.005 and p = 0.031, respectively). Conclusions: The expression of CXCL12 may influence the survival and invasive properties of LARC cells during nCRT and promote cancer recurrence. We suggest that CXCL12 expression in the plasma membrane of radioresistant LARC cells may be a predictive factor of recurrence and a viable therapeutic strategy to control radioresistant LARC recurrence.

Prognostic implication of PD-L1 polymorphisms in non-small cell lung cancer treated with radiotherapy.

BACKGROUND: To investigate the impact of programmed death-ligand 1 (PD-L1) polymorphisms on the prognosis of non-small cell lung cancer (NSCLC) patients treated with curative radiotherapy. METHODS: Four single nucleotide polymorphisms (SNPs) (rs822336G>C, rs822337T>A, rs822338C>T, and rs2297136A>G) in the PD-L1 gene were evaluated in 124 NSCLC patients. Clinical stage was I in 28, II in 17, and III in 79 patients. Fifty-seven patients received radiotherapy alone, including 28 patients who received stereotactic body radiotherapy. Sixty-seven patients received sequential or concurrent chemoradiotherapy. Risk factors for survival outcomes were analyzed with the log-rank test and multivariate Cox proportional hazards models. RESULTS: The rs822336GC+CC genotype was associated with better overall survival (OS) (hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.37-0.97, p = 0.036) and regional failure-free survival (RFFS) (HR = 0.32, 95% CI = 0.14-0.76, p = 0.009), compared with rs822336GG genotype. The rs822337TA+AA genotype was associated with better OS (HR =0.54, 95% CI = 0.34-0.88, p = 0.014), progression-free survival (PFS) (HR = 0.64, 95% CI = 0.41-0.99, p = 0.046), and RFFS (HR = 0.38, 95% CI = 0.17-0.81, p = 0.013), compared with rs822337TT genotype. Three SNPs (rs822336, rs822337, and rs822338) were in linkage disequilibrium. Combined GTC and GTT (GT*) haplotype was associated with significantly worse OS (p = 0.018), PFS (p = 0.044), and RFFS (p = 0.038), compared with those with other combined haplotypes. Patients with diplotypes of two GT* haplotypes showed significantly worse OS (p = 0.023) and RFFS (p = 0.014) than those with other diplotypes. CONCLUSIONS: These findings suggest that PD-L1 polymorphisms could be predictive markers for NSCLC patients receiving radiotherapy.

Small heterodimer partner as a predictor of neoadjuvant radiochemotherapy response and survival in patients with rectal cancer: A preliminary study.

Small heterodimer partner (SHP) plays an essential role in the regulation of innate immune and inflammatory responses. The aim of the present study was to identify whether SHP levels are associated with cancer immunology and treatment outcomes in rectal cancer. SHP expression was analyzed via gene set enrichment analysis and the OncoLnc database. In addition, immunohistochemistry and reverse transcription-quantitative PCR analyses were performed on the tissues of patients with locally advanced rectal cancer, and the associations of SHP expression with the clinicopathological and hematological features or treatment response to preoperative radiochemotherapy (pRCT) were analyzed retrospectively. Furthermore, the present study investigated whether SHP expression correlated with immune infiltration levels and immune checkpoint molecules in rectal cancer. The results revealed that low SHP mRNA expression was significantly associated with an inflammatory response and poor prognosis. The nuclear expression of SHP was associated with clinical N stage, neutrophil count, lymphocyte count, neutrophil-lymphocyte ratio and complete pathologic response following pRCT. The low nuclear expression of SHP was associated with poor overall and distant metastasis-free survival (DMFS). In multivariate analysis, the low nuclear expression of SHP was identified as a significant independent prognostic factor for DMFS and a marginally significant prognostic factor for overall survival in rectal cancer. Furthermore, patients with low SHP expression exhibited higher neutrophil and CD8+ T cell infiltration levels and higher PD-L1 expression in rectal adenocarcinoma. These results indicate that SHP may act as an anti-inflammatory mediator via the regulation of systemic and local immune responses in rectal cancer. Moreover, SHP might be useful a potential marker or therapeutic target in rectal cancer.

Is There a Role for Perioperative Pelvic Radiotherapy in Surgically Resected Stage IV Rectal Cancer?: A Propensity Score-matched Analysis.

OBJECTIVES: This study aimed to determine whether perioperative pelvic radiotherapy (RT) improves outcomes in stage IV rectal cancer patients treated with primary surgical resection and systemic chemotherapy and to identify predictive factors for selection of patients for these approaches. MATERIALS AND METHODS: We searched the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed between 2010 and 2015 with stage IV rectal cancer, but without brain or bone metastases. After applying the exclusion criteria, a total of 26,132 patients were included in the analysis; propensity score matching was used to balance their individual characteristics. RESULTS: Overall, 3283 (12.6%) patients received perioperative RT; the 3-year overall survival (OS) rates were 43.6% in the surgery group and 50.5% in the surgery with RT group (P<0.001). The survival benefit of RT was maintained after propensity score matching and multivariate adjustment (hazard ratio: 0.70; 95% confidence interval: 0.66-0.81; P<0.001). Interaction testing of the prognostic variables showed a significant interaction between RT and the presence of lung metastasis (P<0.001): the benefit of RT was observed only in patients without lung metastases (3 y OS 52.1% vs. 44.1%, P<0.001), but it was observed regardless of liver metastases. In addition, we developed a web-based calculator (http://bit.do/mRC_surv) to provide individualized estimates of OS benefit based on the receipt of perioperative pelvic RT. CONCLUSIONS: Perioperative pelvic RT significantly improved OS rates, especially in patients without lung metastases. We successfully developed a nomogram and web-based calculator that could predict survival benefit with the addition of RT for these patients.

Differential Expression and Clinicopathological Significance of HER2, Indoleamine 2,3-Dioxygenase and PD-L1 in Urothelial Carcinoma of the Bladder.

PURPOSE: Evasion of the immune system by cancer cells allows for the progression of tumors. Antitumor immunotherapy has shown remarkable effects in a diverse range of cancers. The aim of this study was to determine the clinicopathological significance of human epidermal growth factor receptor 2 (HER2), indoleamine 2,3-dioxygenase (IDO), and programmed death ligand-1 (PD-L1) expression in urothelial carcinoma of the bladder (UCB). MATERIALS AND METHODS: We retrospectively studied 97 patients with UCB. We performed an immunohistochemical study to measure the expression levels of HER2, IDO, and PD-L1 in UCB tissue from these 97 patients. RESULTS: In all 97 cases, the PD-L1 expression of tumor-infiltrating immune cells (ICs) was significantly correlated with higher pathologic tumor stage (pT). In pT2-pT4 cases (n = 69), higher levels of HER2 and IDO expression in invasive tumor cells (TCs) were associated with shorter periods of disease-free survival (DFS). CONCLUSION: These results imply that the expression of PD-L1 in ICs of the UCB microenvironment is associated with cancer invasion and the expression of HER2 or IDO in the invasive cancer cell and suggestive of the potential for cancer recurrence. We suggest that the expression levels of IDO, HER2, and PD-L1 could be useful as targets in the development of combined cancer immunotherapeutic strategies.

Clinical Outcomes of Postoperative Radiotherapy Following Radical Prostatectomy in Patients with Localized Prostate Cancer: A Multicenter Retrospective Study (KROG 18-01) of a Korean Population.

PURPOSE: The purpose of this study was to investigate the clinical outcomes of postoperative radiotherapy (PORT) patients who underwent radical prostatectomy for localized prostate cancer. MATERIALS AND METHODS: Localized prostate cancer patients who received PORT after radical prostatectomy between 2001 and 2012 were identified retrospectively in a multi-institutional database. In total, 1,117 patients in 19 institutions were included. Biochemical failure after PORT was defined as prostate-specific antigen (PSA) ≥ nadir+2 after PORT or initiation of androgen deprivation therapy (ADT) for increasing PSA regardless of its value. RESULTS: Ten-year biochemical failure-free survival, clinical failure-free survival, distant metastasisfree survival, overall survival (OS), and cause-specific survival were 60.5%, 76.2%, 84.4%, 91.1%, and 96.6%, respectively, at a median of 84 months after PORT. Pre-PORT PSA ≤ 0.5 ng/ml and Gleason's score ≤ 7 predicted favorable clinical outcomes, with 10-year OS rates of 92.5% and 94.1%, respectively. The 10-year OS rate was 82.7% for patients with a PSA > 1.0 ng/mL and 86.0% for patients with a Gleason score of 8-10. The addition of longterm ADT (≥ 12 months) to PORT improved OS, particularly in those with a Gleason score of 8-10 or ≥ T3b. CONCLUSION: Clinical outcomes of PORT in a Korean prostate cancer population were very similar to those in Western countries. Lower Gleason score and serum PSA level at the time of PORT were significantly associated with favorable outcomes. Addition of long-term ADT (≥ 12 months) to PORT should be considered, particularly in unfavorable risk patients with Gleason scores of 8-10 or ≥ T3b.

Clinicopathological Profiling of LC3B, an Autophagy Marker, and ESRRA (Estrogen-related Receptor-alpha) in Muscle-invasive Bladder Cancer.

BACKGROUND/AIM: Microtubule-associated protein 1 light chain 3B (LC3B), an autophagy marker, has been used as a promising marker in various cancer types. However, the expression of LC3B in muscle-invasive bladder cancer (MIBC) and its prognostic significance have not been investigated. Recent studies pointed to the involvement of ESRRA in regulating autophagy via both transcriptional and post-translational control. In the current study, prognostic importance of LC3B and ESRRA in MIBC was investigated. PATIENTS AND METHODS: We immunohistochemically studied the expression of LC3B and ESRRA in 56 MIBC samples. RESULTS: LC3B was stained high in 16 patients (28.6%) and low or negative in 40 patients (71.4%). ESRRA expression was high for 20 patients (35.7%) and low for 36 patients (64.3%). Both LC3B (p=0.003) and ESRRA (p=0.026) expression correlated significantly with disease-free survival rates. Double-positive LC3B and ESRRA correlated with poor overall survival (p=0.007) and disease-free survival (p=0.001) in MIBC patients. CONCLUSION: LC3B and ESRRA might be a useful prognostic factor in patients with MIBC. The co-expression of LC3B and ESRRA might be a prognostic and therapeutic target for patients with bladder cancer.

Ionizing Radiation Induces Innate Immune Responses in Macrophages by Generation of Mitochondrial Reactive Oxygen Species.

During radiotherapy for tumors, the innate immune system also responds to ionizing radiation and induces immune modulation. However, little is known about the molecular mechanisms by which radiation modulates innate immune responses. In this study, we observed that radiation triggered the generation of mitochondrial reactive oxygen species (mROS), leading to innate immune responses in murine bone marrow-derived macrophages (BMDM). Radiation-induced mROS was essential for robust induction of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-12p40 mRNA and protein in BMDM. Exposure to radiation also led to rapid activation of the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB pathways in BMDM. Notably, radiation-induced MAPK activation and NF-κB signaling were regulated by mROS in macrophages. Additionally, radiation-induced expression of TNF-α, IL-6 and IL-12p40 was dependent on JNK, p38 and NF-κB activation in BMDM. These data suggest a key role for radiation-induced pro-inflammatory responses and activation of the MAPK and NF-κB pathways through a triggering mechanism involving mROS generation.

Hydroxymethylglutaryl-coenzyme a synthase 2 expression is associated with chemoradiotherapy responses in colorectal cancer.

BACKGROUND: Preoperative chemoradiotherapy has become a standard treatment modality for locally advanced rectal cancer. Favorable long-term outcomes have been reported for patients with good responses to chemoradiotherapy. Therefore, predictive factors for chemoradiotherapy responses can be useful for their applicability to risk-adaptive therapy in patients with colorectal cancer. OBJECTIVE: The aim of this study was to investigate whether hydroxymethylglutaryl-coenzyme A synthase 2, a key enzyme in ketogenesis, is associated with the responses of colorectal cancer cells to chemoradiotherapy. DESIGN: Hydroxymethylglutaryl-coenzyme A synthase 2 was identified by a 2-dimensional gel electrophoresis -based proteome analysis. It was analyzed in 12 colorectal cancer cells for associations with radiation or 5-fluorouracil susceptibility by Western blotting, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium Bromide assay, and small interfering RNA transfection. Then, tumor tissues obtained from 45 patients with rectal cancer before chemoradiotherapy were analyzed by Western blotting for associations with chemoradiotherapy responses. RESULTS: Expression of hydroxymethylglutaryl-coenzyme A synthase 2 was significantly correlated with intrinsic radiation resistance of 12 cancer cells. Hydroxymethylglutaryl-coenzyme A synthase 2 expression was significantly affected by treatment with either 5-fluorouracil or radiation depending on cell types. The artificial suppression of hydroxymethylglutaryl-coenzyme A synthase 2 did not result in the change of chemoradiation susceptibility in colorectal cancer cells. Nevertheless, in multivariate analyses, hydroxymethylglutaryl-coenzyme A synthase 2 expression in rectal cancer tissues was shown to be a significant predictive factor for chemoradiotherapy responses, as evaluated in terms of tumor regression grade and downstaging. LIMITATIONS: Overall findings in vitro showed that the expression level of hydroxymethylglutaryl-coenzyme A synthase 2 was highly variable depending on colon cancer cell types, and it cannot directly affect on chemoradiotherapy responses. The molecular mechanism underpinning the association between hydroxymethylglutaryl-coenzyme A synthase expression and chemoradiotherapy responses needs to be elucidated through future research. CONCLUSIONS: Hydroxymethylglutaryl-coenzyme A synthase 2 was associated with the effects of chemoradiotherapy on human colorectal cancer cells. Pretreatment levels of hydroxymethylglutaryl-coenzyme A synthase 2 in rectal cancer may be useful in predicting the responses to chemoradiotherapy.

Prognostic significance of human apurinic/apyrimidinic endonuclease (APE/Ref-1) expression in rectal cancer treated with preoperative radiochemotherapy.

PURPOSE: Human apurinic endonuclease/redox factor 1 (APE/Ref-1) mediates repair of radiation-induced DNA lesions and regulates transcription via redox-based activation. We investigated the predictive and prognostic significance of APE/Ref-1 expression in pretreatment biopsy specimens in locally advanced rectal cancer (LARC) (cT3-T4 or N+). METHODS AND MATERIALS: APE/Ref-1 expression was analyzed by immunohistochemistry in pretreatment biopsy specimens obtained from 83 patients with LARC. Patients received preoperative radiotherapy of 50.4 Gy in 28 fractions, combined with oral capecitabine and leucovorin chemotherapy, followed by curative surgery. The prognostic significance of various clinicopathologic characteristics, including APE/Ref-1 protein expression, was evaluated. RESULTS: APE/Ref-1 was expressed in 97% of patient samples. Exclusive APE/Ref-1 nuclear staining was observed in 49 of 83 samples (59%), and mixed nuclear and cytoplasmic staining was observed in 31 samples (37%). APE/Ref-1 nuclear expression levels were low in 49 patients (59%) and high in 34 patients (41%). The level of APE/Ref-1 nuclear expression was not a prognostic factor for overall and disease-free survival. Cytoplasmic expression of APE/Ref-1 was a borderline-significant predictive factor for pathologic tumor response (p = 0.08) and a significant prognostic factor for disease-free survival, as shown by univariate analysis (p = 0.037). Multivariate analysis confirmed that cytoplasmic localization of APE/Ref-1 is a significant predictor of disease-free survival (hazard ratio, 0.45; p = 0.046). CONCLUSIONS: APE/Ref-1 was expressed in a majority of pretreatment biopsy specimens from patients with LARC. The level of APE/Ref-1 nuclear expression was not a significant predictive and prognostic factor; however, cytoplasmic localization of the protein was negatively associated with disease-free survival. These results indicate that cytoplasmic expression of APE/Ref-1 represents an adverse prognostic factor for LARC patients who receive preoperative radiochemotherapy.

Retrospective analysis of treatment outcomes after postoperative chemoradiotherapy in advanced gastric cancer.

PURPOSE: To evaluate retrospectively the survival outcome, patterns of failure, and complications in patients treated with postoperative chemoradiotherapy (CRT) in advanced gastric cancer. MATERIALS AND METHODS: Between January 2000 and December 2006, 80 patients with advanced gastric cancer who received postoperative concurrent CRT were included. Pathological staging was IB-II in 9%, IIIA in 38%, IIIB in 33%, and IV in 21%. Radiotherapy consisted of 45 Gy of radiation. Concurrent chemotherapy consisted of a continuous intravenous infusion of 5-fluorouracil and leucovorin on the first 4 days and last 3 days of radiotherapy. RESULTS: The median follow-up period was 48 months (range, 3 to 83 months). The 5-year overall survival, disease-free survival, and locoregional recurrence-free survivals were 62%, 59%, and 80%, respectively. In the multivariate analysis, significant factors for disease-free survival were T stage (hazard ratio [HR], 0.278; p = 0.038), lymph node dissection extent (HR, 0.201; p = 0.002), and maintenance oral chemotherapy (HR, 2.964; p = 0.004). Locoregional recurrence and distant metastasis occurred in 5 (6%) and 18 (23%) patients, respectively. Mixed failure occurred in 10 (16%) patients. Grade 3 leukopenia and thrombocytopenia were observed in 4 (5%) and one (1%) patient, respectively. Grade 3 nausea and vomiting developed in 8 (10%) patients. Intestinal obstruction developed in one (1%). CONCLUSION: The survival outcome of the postoperative CRT in advanced gastric cancer was similar to those reported previously. Our postoperative CRT regimen seems to be a safe and effective method, reducing locoregional failure without severe treatment toxicity in advanced gastric cancer patients.

Pathologic complete response of primary tumor following preoperative chemoradiotherapy for locally advanced rectal cancer: long-term outcomes and prognostic significance of pathologic nodal status (KROG 09-01).

OBJECTIVE: To investigate long-term outcomes of locally advanced rectal cancer (LARC) patients with postchemoradiotherapy (post-CRT) pathologic complete response of primary tumor (ypT0) and determine prognostic significance of post-CRT pathologic nodal (ypN) status. BACKGROUND: LARC patients with post-CRT pathologic complete response were suggested to have favorable long-term outcomes, but prognostic significance of ypN status has never been specifically defined in ypT0 patients. METHODS: The Korean Radiation Oncology Group collected clinical data for 333 LARC patients with ypT0 following preoperative CRT and curative radical resections between 1993 and 2007. Sphincter preservation surgery and abdominoperineal resection were performed in 283 (85.0%) and 50 (15.0%) patients, respectively. Postoperative chemotherapy was given to 285 (85.6%) patients. Survival was estimated by the Kaplan-Meier method, and the Cox proportional hazard model was used in multivariate analyses. RESULTS: After median follow-up of 43 (range = 14-172) months, 5-year disease-free survival (DFS) was 84.6% and overall survival (OS) was 92.8%. The ypN status was ypT0N0 in 304 (91.3%), ypT0N1 in 22 (6.6%), and ypT0N2 in 7 (2.1%) patients. The ypN status was the most relevant independent prognostic factor for both DFS and OS in ypT0 patients. The 5-year DFS and OS was 88.5% and 94.8% in ypT0N0 patients, and 45.2% and 72.8% in ypT0N+ patients (both, P < 0.001). CONCLUSIONS: LARC patients achieving ypT0N0 after preoperative CRT had favorable long-term outcomes, whereas positive ypN status had a poor prognosis even after total regression of primary tumor.

Bacillus calmette-guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy.

The cell wall skeleton of Mycobacterium bovis Bacillus Calmette-Guerin (BCG/CWS) is an effective antitumor immunotherapy agent. Here, we demonstrate that BCG/CWS has a radiosensitizing effect on colon cancer cells through the induction of autophagic cell death. Exposure of HCT116 colon cancer cells to BCG/CWS before ionizing radiation (IR) resulted in increased cell death in a caspase-independent manner. Treatment with BCG/CWS plus IR resulted in the induction of autophagy in colon cancer cells. Either the autophagy inhibitor 3-methyladenine or knockdown of beclin 1 or Atg7 significantly reduced tumor cell death induced by BCG/CWS plus IR, whereas the caspase inhibitor z-VAD-fmk failed to do so. BCG/CWS plus IR-mediated autophagy and cell death was mediated predominantly by the generation of reactive oxygen species (ROS). The c-Jun NH(2)-terminal kinase pathway functioned upstream of ROS generation in the induction of autophagy and cell death in HCT116 cells after co-treatment with BCG/CWS and IR. Furthermore, toll-like receptor (TLR) 2, and in part, TLR4, were responsible for BCG/CWS-induced radiosensitization. In vivo studies revealed that BCG/CWS-mediated radiosensitization of HCT116 xenograft growth is accompanied predominantly by autophagy. Our data suggest that BCG/CWS in combination with IR is a promising therapeutic strategy for enhancing radiation therapy in colon cancer cells through the induction of autophagy.

Interstitial fluid pressure as a prognostic factor in cervical cancer following radiation therapy.

PURPOSE: To investigate tumor interstitial fluid pressure as a prognostic factor for recurrence-free survival in patients with cervical cancer following radiation therapy. EXPERIMENTAL DESIGN: Tumor interstitial fluid pressure was measured in 55 cervical cancer patients who received radiation therapy between August 1998 and September 2002. Interstitial fluid pressure measurements were made before radiation therapy (pre-radiation therapy interstitial fluid pressure) and after a median of 28.8 Gy in 16 fractions (range, 25.2-30.6 Gy in 14-17 fractions) of radiation therapy (mid-radiation therapy interstitial fluid pressure), using a modified wick-in-needle technique. Median follow-up was 74 months (range, 2-118 months). The Kaplan-Meier method with the log-rank test and Cox's proportional hazard model were used in univariate and multivariate analyses, respectively, of prognostic factors for recurrence-free survival. RESULTS: Median pre-radiation therapy and mid-radiation therapy interstitial fluid pressure were 29.0 mm Hg (range, 4.0-93.9 mm Hg) and 20.0 mm Hg (range, -1.2 to 29.6 mm Hg), respectively (P = 0.001). Pre-radiation therapy interstitial fluid pressure was significantly higher in adenocarcinomas than squamous cell carcinomas (P = 0.028). Significant reduction of interstitial fluid pressure was noted only in patients with complete responses (P = 0.002), and mid-radiation therapy interstitial fluid pressure was significantly lower in patients with complete responses (P = 0.036). In the multivariate analysis including interstitial fluid pressures and clinical variables, pre-radiation therapy interstitial fluid pressure was an independent prognostic factor for local and distant recurrence-free survival (P = 0.001 and 0.027, respectively). CONCLUSIONS: Mid-radiation therapy interstitial fluid pressure measurement may be useful in predicting radiation therapy responses, and pre-radiation therapy interstitial fluid pressure was a significant prognostic factor for local and distant relapse-free survival in patients with cervical cancer after radiation therapy.

Radiation-induced thymidine phosphorylase upregulation in rectal cancer is mediated by tumor-associated macrophages by monocyte chemoattractant protein-1 from cancer cells.

PURPOSE: The mechanisms of thymidine phosphorylase (TP) regulation induced by radiation therapy (XRT) in various tumors are poorly understood. We investigated the effect and mechanisms of preoperative XRT on TP expression in rectal cancer tissues. METHODS AND MATERIALS: TP expression and CD68 and monocyte chemoattractant protein-1 (MCP-1) levels in rectal cancer tissues and cancer cell lines were evaluated before and after XRT in Western blotting, immunohistochemistry, enzyme-linked immunoassay, and reverse transcription-polymerase chain reaction studies. Isolated peripheral blood monocytes were used in the study of chemotaxis under the influence of MCP-1 released by irradiated colon cancer cells. RESULTS: Expression of TP was significantly elevated by 9 Gy of XRT in most rectal cancer tissues but not by higher doses of XRT. In keeping with the close correlation of the increase in both TP expression and the number of tumor-associated macrophages (TAMs), anti-TP immunoreactivity was found in the CD68-positive TAMs and not the neoplastic cells. Expression of MCP-1 was increased in most cases after XRT, and this increase was strongly correlated with TP expression. However, this increase in MCP-1 expression occurred in tumor cells and not stromal cells. The XRT upregulated MCP-1 mRNA and also triggered the release of MCP-1 protein from cultured colon cancer cells. The supernatant of irradiated colon cancer cells showed strong chemotactic activity for monocyte migration, but this activity was completely abolished by neutralizing antibody. CONCLUSIONS: Use of XRT induces MCP-1 expression in cancer cells, which causes circulating monocytes to be recruited into TAMs, which then upregulate TP expression in rectal cancer tissues.

Differential cytokine levels and immunoreactivities against Mycobacterium tuberculosis antigens between tuberculous and malignant effusions.

Much effort has been devoted to the identification of immunologically important factors in tuberculous pleurisy (TBP) and malignant pleurisy (MP) to improve the differential diagnosis of the two major causes of lymphocyte-dominant pleurisy. This study evaluated the immunoreactivity and potential diagnostic utility of both host (cytokines and chemokines) and pathogen (mycobacterial proteins) factors in pleural effusions. Effusion samples were collected from 41 patients with MP caused by lung cancer and from 81 patients with TBP. The concentrations of nine cytokines and chemokines (interleukin (IL)-12 p40, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-6, IL-10, CXCL8/IL-8, CXCL10/IP-10, CCL3/MIP-1alpha, and CCL4/MIP-1beta) and antibody responses (IgG, IgM, and IgA) against five Mycobacterium tuberculosis antigens (early secreted antigenic target (ESAT)-6, 30-kDa, MTB12, 38-kDa, and a heparin-binding hemagglutinin (HBHA)) were determined in pleural fluids using enzyme-linked immunosorbent assays (ELISA). In the logistic regression, IFN-gamma (odds ratio, 7.178; 95% confidence interval (CI), 2.258-22.817; p=0.001), IL-12 p40 (odds ratio, 11.037; 95% CI, 3.38-36.037; p<0.001), and IL-6 (odds ratio, 3.295; 95% CI, 1.147-9.463; p=0.027) were found to be statistically significant cytokines predicting tuberculous from malignant effusions. Although IgG responses to all of the M. tuberculosis antigens tested were significantly higher in effusions from TBP (p<0.001) compared with those from MP, the logistic regression showed IgG levels for ESAT-6 and MTB12 to be statistically significant for differentiation of TBP from MP. HBHA showed the highest sensitivity of IgM antibody responses in TBP in comparison with other antigens. These data indicate that selected mycobacterial antigens (ESAT-6 and MTB12) and cytokine markers (IFN-gamma, IL-12p40, and IL-6) provide useful information for differentiating tuberculous and malignant effusions in clinical practice.

Cyclooxygenase-2 expression as a predictor of para-aortic lymph node recurrence in uterine cervical cancer.

PURPOSE: The overexpression of cyclooxygenase-2 (COX-2) is associated with a worse prognosis and the development of distant metastases in cervical cancer. This matched-pair analysis examined whether COX-2 expression is associated with para-aortic lymph node (PALN) recurrence in uterine cervical cancer treated with radiotherapy (RT). METHODS AND MATERIALS: For this study, we matched 20 patients with PALN recurrence after definitive or postoperative RT by stage with 20 others who did not have PALN recurrence. Of the 20 patients with PALN recurrence, definitive or postoperative RT was performed in 11 and 9 patients, respectively. COX-2 expression was assessed immunohistochemically using a mouse monoclonal antibody on formalin-fixed paraffin-embedded tumor specimens taken before RT. A logistic regression model was used to predict for PALN recurrence. RESULTS: COX-2 was expressed in 28 (70%) of the 40 patients. The staining intensity was as follows: weak in 19 (47%), moderate in 6 (15%), and strong in 3 (8%) patients. The patients with PALN recurrence had much greater expression of COX-2 (17 patients, 85%) than did the control group (11 patients, 55%; p = 0.04). Strong staining intensity of COX-2 was seen only in the PALN recurrence group. The statistically significant factors associated with PALN recurrence were positive pelvic lymph nodes (odds ratio, 7.61; 95% confidence interval, 1.55-37.37; p = 0.01) and COX-2 expression (odds ratio, 1.47; 95% confidence interval, 1.04-2.09; p = 0.03). CONCLUSION: Our findings suggest that COX-2 overexpression in the initial tumor tissue might be associated with PALN recurrence after RT in cervical cancer patients.