Comparison of Emergence Agitation Scale Scores and Creatine Kinase Levels After General Anesthesia in Children: A Prospective Cohort Study.

Introduction A simple indicator of muscle damage is creatine kinase (CK). Although CK elevation is informative for malignant hyperthermia, no study has examined the relationship between the anesthetically awake state and CK in children. We aimed to prospectively examine the relationship between the awakening state and CK on the day after surgery in children who have undergone anesthesia with volatile inhalation anesthetics. Methods The study included 119 patients aged 0-15 years and scheduled to undergo general anesthesia for cleft lip and palate-related surgery. Emergence agitation (EA) was assessed after completion of general anesthesia using the five-point EA scale, and patients were divided into the following five groups according to the EA score: EA1, EA2, EA3, EA4, and EA5. The primary outcome was ΔCK (comparison of CK values one week prior to surgery to CK values on the day after surgery) in each EA group. The secondary outcome was ΔCK when the EA score was divided into the following two groups: EA ≤2 (EA score of 1 or 2) and EA ≥3 (EA score of 3, 4, or 5). Results The median ΔCK values in the EA1 to EA5 groups were 3 (quartile -19~9), 5 (-32~88), 99.5 (-18~190.5), 121 (29~219.5), and 144 (41~340.5), respectively, indicating a statistically significant difference overall. Statistically significant differences were also observed between the EA1 and EA4 groups and between the EA2 and EA4 groups. The median ΔCK values in the EA ≤2 and EA ≥3 groups were 3 (quartile -27~85) and 108 (23.5~206.7), respectively, indicating a statistically significant difference. Conclusion The results of this study revealed that a higher EA score at the time of anesthesia awakening is associated with a larger ΔCK, indicating that a high CK level on the day after surgery is highly related to the state of the patient upon awakening.

Hypofractionated intensity-modulated radiotherapy with concurrent chemotherapy for elderly patients with locally advanced pancreatic carcinoma.

BACKGROUND: It is important to understand how elderly patients with locally advanced pancreatic carcinoma (LAPC) should be treated, since the number of elderly cancer patients will increase. However, the optimal treatment for elderly patients with LAPC remains unclear. The purpose of this study was to evaluate the efficacy and safety of hypofractionated intensity-modulated radiotherapy (IMRT) with concurrent gemcitabine for elderly patients with LAPC. METHODS: We retrospectively analysed the data from LAPC patients aged ≥ 75 years treated with hypofractionated IMRT (48 Gy in 15 fractions) with concurrent weekly gemcitabine at our institution from February 2013 to December 2018. Overall survival (OS), progression-free survival (PFS), locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), and the pattern of recurrence and toxicity were analysed. RESULTS: Fifteen patients received treatment during the study period. The median age was 78 years (range 75-86 years), and the Eastern Cooperative Oncology Group (ECOG) performance status (PS) of all patients was 0-1. The median survival time (MST) and median PFS were 20.4 [95% confidence interval (CI) 10.3-36.8] and 13.5 (95% CI 6.4-20.3) months, respectively, and the 1-year OS and PFS rates were 80.0% (95% CI 50-93.1%) and 66.7% (95% CI 37.5-84.6%), respectively. The median LRPFS and median DMFS were 15.6 (95% CI 6.4-36.8) and 14.9 (95% CI 7.0-20.5) months, respectively, and the 1-year LRPFS and DMFS rates were 73.3% (95% CI 43.6-89.1%) and 66.7% (95% CI 37.5-84.6%), respectively. Non-haematologic grade 3 toxicity was observed in three cases, of which only one was induced by radiotherapy, whereas grade 4-5 non-haematologic acute or late toxicities were not observed. CONCLUSIONS: The OS and PFS of elderly patients with LAPC treated using hypofractionated IMRT with concurrent gemcitabine were favourable and without the occurrence of severe toxicity. This treatment strategy is feasible and promising for elderly LAPC patients with good PS.

Ubiquitin carboxyl-terminal hydrolase L1 promotes hypoxia-inducible factor 1-dependent tumor cell malignancy in spheroid models.

Hypoxia-inducible factor 1 (HIF-1) is a critical heterodimeric transcription factor for tumor malignancy. Recently, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) has been reported to function as a deubiquitinating enzyme for the stabilization of its α subunit (HIF-1α). In the present study, we showed that UCHL1 inhibition can be an effective therapeutic strategy against HIF-1-dependent tumor malignancy. In 2D monolayer culture, a UCHL1 inhibitor suppressed HIF activity and decreased the transcription of HIF downstream genes by inhibiting the UCHL1-mediated accumulation of HIF-1α. Phenotypically, UCHL1 inhibition remarkably blocked cell migration. In 3D spheroid culture models, ectopic expression of UCHL1 significantly upregulated malignancy-related factors such as solidity, volume, as well as viable cell number in an HIF-1α-dependent manner. Conversely, inhibition of the UCHL1-HIF-1 pathway downregulated these malignancy-related factors and also abolished UCHL1-mediated cell proliferation and invasiveness. Finally, inhibition of UCHL1 promoted HIF-1α degradation and lowered the expression of HIF-1 target genes in the 3D model, as also observed in 2D monolayer culture. Our research indicates that the UCHL1-HIF-1 pathway plays a crucial role in tumor malignancy, making it a promising therapeutic target for cancer chemotherapy.

Variation in accumulated dose of volumetric-modulated arc therapy for pancreatic cancer due to different beam starting phases.

PURPOSE: To assess the effects of different beam starting phases on dosimetric variations in the clinical target volume (CTV) and organs at risk (OARs), and to identify the relationship between plan complexity and the dosimetric impact of interplay effects in volumetric-modulated arc therapy (VMAT) plans for pancreatic cancer. METHODS: Single and double full-arc VMAT plans were generated for 11 patients. A dose of 50.4 Gy in 28 fractions was prescribed to cover 50% of the planning target volume. Patient-specific Digital Imaging and Communications in Medicine-Radiation Therapy plan files were divided into 10 files based on the respiratory phases in four-dimensional computed tomography (4DCT) simulations. The phase-divided VMAT plans were calculated in consideration of the beam starting phase for each arc and were then combined in the mid-ventilation phase of 4DCT (4D plans). The dose-volumetric parameters were compared with the calculated dose distributions without consideration of the interplay effects (3D plans). Additionally, relationships among plan parameters such as modulation complexity scores, monitor units (MUs), and dose-volumetric parameters were evaluated. RESULTS: Dosimetric differences in the median values associated with different beam starting phases were within ± 1.0% and ± 0.2% for the CTV and ± 0.5% and ± 0.9% for the OARs during single and double full-arc VMAT, respectively. Significant differences caused by variations in the beam starting phases were observed only for the dose-volumetric parameters of the CTV during single full-arc VMAT (P < 0.05), associated with moderate or strong correlations between the MUs and the dosimetric differences between the 4D and 3D plans. CONCLUSIONS: The beam starting phase affected CTV dosimetric variations of single full-arc VMAT. The use of double full-arc VMAT mitigated this problem. However, variation in the dose delivered to OARs was not dependent on the beam starting phase, even for single full-arc VMAT.

Evaluation of Dynamic Tumor-tracking Intensity-modulated Radiotherapy for Locally Advanced Pancreatic Cancer.

Intensity-modulated radiotherapy (IMRT) is now regarded as an important treatment option for patients with locally advanced pancreatic cancer (LAPC). To reduce the underlying tumor motions and dosimetric errors during IMRT as well as the burden of respiratory management for patients, we started to apply a new treatment platform of the dynamic tumor dynamic tumor-tracking intensity-modulated radiotherapy (DTT-IMRT) using the gimbaled linac, which can swing IMRT toward the real-time tumor position under patients' voluntary breathing. Between June 2013 and March 2015, ten patients were treated, and the tumor-tracking accuracy and the practical benefits were evaluated. The mean PTV size in DTT-IMRT was 18% smaller than a conventional ITV-based PTV. The root-mean-squared errors between the predicted and the detected tumor positions were 1.3, 1.2, and 1.5 mm in left-right, anterior-posterior, and cranio-caudal directions, respectively. The mean in-room time was 24.5 min. This high-accuracy of tumor-tracking with reasonable treatment time are promising and beneficial to patients with LAPC.

Clinical evaluation of intensity-modulated radiotherapy for locally advanced pancreatic cancer.

BACKGROUND: The purpose was to retrospectively evaluate the effect of intensity-modulated radiotherapy (IMRT) on gastrointestinal (GI) toxicities and outcomes compared to three-dimensional conformal radiotherapy (3DCRT) for locally advanced pancreatic cancer (LAPC). METHODS: We included 107 consecutive patients who underwent CRT for LAPC from September 2001 to March 2015; 80 patients underwent 3DCRT and 27 patients underwent IMRT. They were compared for GI toxicities, locoregional progression free survival (LRPFS), distant metastasis free survival (DMS), and overall survival (OS). RESULTS: Median radiation dose and fractions for 3DCRT and IMRT were 54 Gy/30 fr. and 48 Gy/15 fr. The regimens of CRT consisted of weekly gemcitabine 250 mg/m2 (for 3DCRT) or 1000 mg/m2 (for IMRT). Acute GI toxicity ≥grade 2 occurred in 32 patients (40%) treated with 3DCRT compared with five patients (19%) treated with IMRT. Late GI toxicity of grade 3 occurred in 10 patients (12%) treated with 3DCRT and one patient (4%) treated with IMRT. Patients who underwent IMRT had superior 1-year LRPFS (73.1% vs. 63.2%, p = 0.035) and 1-year OS (92.3% vs. 68.2%, p = 0.037) as compared with those treated with 3DCRT. Multivariate analysis showed that in IMRT patients, higher dose (≥45 Gy) was an independent factor for better LRPFS and OS. CONCLUSIONS: LAPC patients treated with hypofractionated full-dose gemcitabine IMRT had improved OS and LRPFS without increased GI toxicities when compared to those of patients treated with conventionally fractionated low dose gemcitabine 3DCRT. In IMRT patients, higher dose was an independent favorable prognostic factor for better LRPFS and OS, which suggests that dose escalation with IMRT for LAPC is a promising strategy.

Clinical results of dynamic tumor tracking intensity-modulated radiotherapy with real-time monitoring for pancreatic cancers using a gimbal mounted linac.

OBJECTIVES: We performed dynamic tumor-tracking IMRT (DTT-IMRT) in locally advanced pancreatic cancer (LAPC) patients using a gimbaled linac of Vero4DRT. The purpose of this study is to report the first clinical results. METHODS: From June 2013 to June 2015, eleven LAPC patients enrolled in this study and DTT-IMRT was successfully performed. The locoregional progression free survival (LRPFS), distant metastasis free survival (DMFS), overall survival (OS), hematologic and gastrointestinal (GI) toxicities were evaluated. Oncologic outcomes were estimated using Kaplan-Meier analysis, and toxicities using CTCAE v4.0. RESULTS: The median radiation dose was 48 Gy (range, 45-51) in 15 fractions. Concurrent chemoradiotherapy (CCRT) was performed using gemcitabine in 9 patients and S-1 in one, while one patient refused. With a median follow-up of 22.9 months, 1-year LRPFS, DMFS, and OS rates were 90.9%, 70.7%, and 100%, respectively. Median survival time was 23.6 months. Grade-3 leucopenia and neutropenia were observed in two (18%) and one patient (9%), respectively. Grade-2 acute GI toxicity occurred in 2 patients (18%) and late grade-3 in 1 patient (9%). CONCLUSIONS: Preliminarily application of DTT-IMRT using a gimbaled linac on CCRT in LAPC patients resulted in excellent locoregional control and OS without severe toxicity.

Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge.

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF-1 activity have been implicated in the pathogenesis of various diseases including malignant tumors and, thus, elucidating the molecular mechanisms underlying the activation of HIF-1 is eagerly desired for the development of novel anti-cancer strategies. The importance of oxygen-dependent and ubiquitin-mediated proteolysis of the regulatory subunit of HIF-1 (HIF-1α) was first reported in 1997. Since then, accumulating evidence has shown that HIF-1α may become stable and active even under normoxic conditions; for example, when disease-associated genetic and functional alterations in some genes trigger the aberrant activation of HIF-1 regardless of oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF-1 activity from conventional oxygen- and proteolysis-dependent mechanisms to up-to-the-minute information on cancer-associated genetic and functional alteration-mediated mechanisms.

A Prospective Study of Intensity-modified Radiation Therapy in Comparison with Conventional 3D-RT for BR Pancreatic Cancer Patients with Arterial Involvement.

BACKGROUND/AIM: Intensity-modulated radiation therapy (IMRT) is a form of radiation therapy that allows accurate irradiation with reduced damage to surrounding tissues. Here, we analyzed borderline-resectable pancreatic cancer (BRPC) with arterial abutment (BR-A) patients with IMRT as neoadjuvant therapy and performed comparisons with patients with conventional RT to clarify the advantages of IMRT as a neoadjuvant therapy. PATIENTS AND METHODS: Thirty BR-A patients treated at our hospital between January 2012 and December 2015 were divided into two groups: 12 patients underwent conventional 3D-RT before resection (RT group); and 18 patients underwent IMRT before resection (IMRT group). We analyzed safety, tumor resection rate, histological classification of the tumor and overall survival. RESULTS: The R0 rate was 84% for the IMRT group and 83% for the RT group. Local therapeutic effects as assessed by Evans classification showed a higher local control rate in the IMRT group (Grade: 1, 0%; 2a, 25%; 2b, 41.6%; 3, 17%; 4, 8%) than in the RT group (Grade: 1, 17%; 2a, 50%; 2b, 17%; 3, 17%; 4, 0%). The cumulative dose of S1 treatment as adjuvant therapy was much smaller in the RT group (18.3%) compared to that in the IMRT group (57.1%, p=0.047), and with better subsequent overall survival rate (MST 32 months vs. 13.8 months, p=0.0273). CONCLUSION: The IMRT group showed a better control rate than the RT group. The neoadjuvant IMRT has advantages of higher completion rate of adjuvant chemotherapy with better nutritional status and better subsequent overall survival rate (OS).

A circadian clock gene, PER2, activates HIF-1 as an effector molecule for recruitment of HIF-1α to promoter regions of its downstream genes.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor functioning in cellular adaptive responses to hypoxia. Recent studies have suggested that HIF-1 activity is upregulated by one of the important circadian clock genes, period circadian clock 2 (PER2); however, its underlying mechanism remains unclear. Here, we show that PER2 functions as an effector protein for the recruitment of HIF-1α to its cognate enhancer sequence, the hypoxia-response element (HRE). We found that the forced expression of PER2 enhanced HIF-1 activity without influencing expression levels of the regulatory subunit of HIF-1, HIF-1α, at either mRNA or protein levels. A series of coimmunoprecipitation-based experiments revealed that PER2 interacted with HIF-1α and facilitated the recruitment of HIF-1α to HRE derived from vascular endothelial growth factor (VEGF) promoter. The PER2-mediated activation of HIF-1 was observed only when the asparagine residue at position 803 of HIF-1α (HIF-1α N803) was kept unhydroxylated by hypoxic stimulation, by introducing an N803A point mutation, or by an inhibitor of N803-dioxygenase, deferoxamine. However, the extent of PER-2-HIF-1α interaction was equivalent regardless of the N803 hydroxylation status. Taken together, these results suggest that, with the help of an unknown sensor molecule for the N803 hydroxylation status, PER2 functions as an effector molecule for the recruitment of HIF-1 to promoter regions of its downstream genes. Our findings reveal a novel regulatory step in the activation of HIF-1, which can be targeted to develop therapeutic strategies against HIF-1-related diseases, such as cancers.

Extralobar pulmonary sequestration in two pinniped species.

Two cases of extralobar pulmonary sequestrations from a walrus (Odobenus rosmarus) and a Steller sea lion (Eumetopias jubatus) are described in the present study. Grossly, an independent, soft unilocular cystic mass was found within the abdominal cavities of both animals, adherent to the diaphragm in O. rosmarus and attached to the cardia of the stomach in E. jubatus. Histopathologically, the cysts were lined by pseudostratified ciliated columnar epithelium with abundant goblet cells, while the wall comprised of glands, hyaline cartilage, bronchiole- and alveolus-like structures, smooth muscles, and large, well-developed elastic and muscular arteries. The pinniped cases presented are exceptionally rare and to the best of the authors' knowledge, marks the first descriptions of this congenital anomaly in wildlife.

The emerging roles of the ubiquitination/deubiquitination system in tumor radioresistance regarding DNA damage responses, cell cycle regulation, hypoxic responses, and antioxidant properties: Insight into the development of novel radiosensitizing strategies.

Radiation therapy is one of the first-line treatments for many cancers, with no less than half of cancer patients receiving it in the US. Despite the development of innovative and high-precision radiation therapy strategies, many patients still experience local tumor recurrence after the treatment, at least in part, due to the existence of radioresistant cells in malignant tumor tissues. Among the various biological processes known to induce radioresistance, a post-translational protein modification, ubiquitination, has received marked attention in recent years. Ubiquitination, in which highly conserved ubiquitin polypeptides are covalently attached to their target proteins, has long been recognized as a system to tag unnecessary proteins for 26S proteasome-dependent proteolysis. However, accumulating lines of evidence recently revealed that it acts as a signal molecule in diverse biological processes as well, and its functional disorder was found to cause not only tumor development and various diseases but also tumor radioresistance. The present review summarizes the latest knowledge about how the cancer-related disorder of the ubiquitination systems induces the radioresistance of cancer cells by influencing intrinsic pathways, each of which potentially affects the radioresistance/radiosensitivity of cells, such as DNA damage responses, cell cycle regulation, hypoxic responses, and antioxidant properties. In addition, this review aims to provide insights into how we can exploit the disorders in order to develop novel radiosensitizing strategies.

UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization.

Hypoxia-inducible factor 1 (HIF-1) has been recognized as an important mediator of the reprogramming of carbohydrate metabolic pathways from oxidative phosphorylation to accelerated glycolysis. Although this reprogramming has been associated with the antioxidant and radioresistant properties of cancer cells, gene networks triggering the HIF-1-mediated reprogramming and molecular mechanisms linking the reprogramming with radioresistance remain to be determined. Here, we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1), which we previously identified as a novel HIF-1 activator, increased the radioresistance of cancer cells by producing an antioxidant, reduced glutathione (GSH), through HIF-1-mediated metabolic reprogramming. A luciferase assay to monitor HIF-1 activity demonstrated that the overexpression of UCHL1, but not its deubiquitination activity-deficient mutant (UCHL1 C90S), upregulated HIF-1 activity by stabilizing the regulatory subunit of HIF-1 (HIF-1α) in a murine breast cancer cell line, EMT6. UCHL1 overexpression induced the reprogramming of carbohydrate metabolism and increased NADPH levels in a pentose phosphate pathway (PPP)-dependent manner. The UCHL1-mediated reprogramming elevated intracellular GSH levels, and consequently induced a radioresistant phenotype in a HIF-1-dependent manner. The pharmacological inhibition of PPP canceled the UCHL1-mediated radioresistance. These results collectively suggest that cancer cells acquire antioxidant and radioresistant phenotypes through UCHL1-HIF-1-mediated metabolic reprogramming including the activation of PPP and provide a rational basis for targeting this gene network for radiosensitization.

Inter- and Intrafractional Variation in the 3-Dimensional Positions of Pancreatic Tumors Due to Respiration Under Real-Time Monitoring.

PURPOSE: To quantify the 3-dimensional pancreatic tumor motion during the overall treatment course using real-time orthogonal kilovoltage X-ray imaging. METHODS AND MATERIALS: This study included 10 patients with pancreatic cancer who underwent 6-port static intensity modulated radiation therapy with real-time tumor tracking in 15 fractions, except for 1 patient (5 fractions). The tumor and abdominal wall positions were acquired simultaneously during the overall treatment course. Then the tumor motion amplitude and reference positions were determined. RESULTS: The mean tumor amplitudes were 4.9, 6.5, and 13.4 mm in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. The intrafractional variations of the reference tumor position were up to 5.4, 10.2, and 10.7 mm in the LR, AP, and SI directions, and those of the reference abdominal position were up to 10.5 mm. The reference tumor position drifted significantly in the AP and SI directions after 10 minutes, and that of abdominal wall motion drifted during the first 15 minutes (P<.05). The interfractional variation of the reference tumor position after setup correction, based on bony structures, was up to 8.9, 9.8, and 11.0 mm in the LR, AP, and SI directions, respectively. CONCLUSIONS: Appropriate respiratory motion management techniques should be applied for the accurate localization of pancreatic tumors.

LY6E: a conductor of malignant tumor growth through modulation of the PTEN/PI3K/Akt/HIF-1 axis.

Lymphocyte antigen 6 complex, locus E (LY6E) has been implicated in the malignant progression of various types of cancers; however, the underlying mechanism remains unclear. Here, we identified LY6E as an activator of HIF-1 and revealed their mechanistic and functional links in malignant tumor growth. The aberrant overexpression of LY6E increased HIF-1α gene expression principally at the transcription level. This, in turn, led to the expression of the pro-angiogenic factors, VEGFA and PDGFB, through decreases in the expression levels of PTEN mRNA and subsequent activation of the PI3K/Akt pathway. The LY6E-HIF-1 axis functioned to increase tumor blood vessel density and promoted tumor growth in immunodeficient mice. LY6E expression levels were significantly higher in human breast cancers than in normal breast tissues, and were strongly associated with the poor prognoses of various cancer patients. Our results characterized LY6E as a novel conductor of tumor growth through its modulation of the PTEN/PI3K/Akt/HIF-1 axis and demonstrated the validity of targeting this pathway for cancer therapy.

UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α.

Hypoxia-inducible factor 1 (HIF-1) plays a role in tumour metastases; however, the genes that activate HIF-1 and subsequently promote metastases have yet to be identified. Here we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1) abrogates the von Hippel-Lindau-mediated ubiquitination of HIF-1α, the regulatory subunit of HIF-1, and consequently promotes metastasis. The aberrant overexpression of UCHL1 facilitates distant tumour metastases in a HIF-1-dependent manner in murine models of pulmonary metastasis. Meanwhile, blockade of the UCHL1-HIF-1 axis suppresses the formation of metastatic tumours. The expression levels of UCHL1 correlate with those of HIF-1α and are strongly associated with the poor prognosis of breast and lung cancer patients. These results indicate that UCHL1 promotes metastases as a deubiquitinating enzyme for HIF-1α, which justifies exploiting it as a prognostic marker and therapeutic target of cancers.

Body mass index and waist circumference are independent risk factors for low vital capacity among Japanese participants of a health checkup: a single-institution cross-sectional study.

OBJECTIVE: This study aimed to examine the associations between obesity and percentage vital capacity (%VC), as well as lifestyle-related disorders, among Japanese participants of a voluntary health checkup. METHODS: Subjects were 7,892 individuals who participated in a medical health checkup from January to December 2007. Multivariate logistic regression analysis was performed to assess associations between low %VC (<80) and body mass index (BMI) and waist circumference (WC), as well as lifestyle-related disorders. RESULTS: Medical histories of hypertension and dyslipidemia were more frequent in the low %VC group than in the normal %VC group in both sexes. In men, BMI was significantly associated with low %VC (25.0 ≤ C2 < 27.5, odds ratio (OR) = 2.10; 27.5 ≤ C3 < 30.0, OR = 2.23; C4 ≥ 30.0, OR = 3.46) relative to the first category (C1 < 25.0). A significant association was also observed between WC and low %VC (85 ≤ C2 < 90, OR = 1.40; 90 ≤ C3 < 95, OR = 1.55; 95 ≤ C4, OR = 2.51; relative to C1 < 85.0 cm). In women, BMI was significantly associated with low %VC in C3 and C4 (C3, OR = 2.05; C4, OR = 2.84), and WC was significantly associated with low %VC in C4 (C4, OR = 2.32). CONCLUSION: Our results suggest that obesity may be associated with restrictive pulmonary function and underscore the importance of maintaining ideal body weight for the prevention of restrictive pulmonary dysfunction.

Clinical outcome and patterns of recurrence of head and neck squamous cell carcinoma with a limited field of postoperative radiotherapy.

BACKGROUND: Postoperative radiotherapy is the standard treatment for head and neck squamous cell carcinoma having high-risk features in surgical specimens. However, its severe toxicity can be a significant problem. This study was undertaken to evaluate the efficacy of our limited-field postoperative radiotherapy with the aim of reducing morbidity by minimizing the radiation field. METHODS: Between 2000 and 2009, 154 patients with head and neck squamous cell carcinoma received limited-field postoperative radiotherapy. The reason for postoperative radiotherapy was close/positive margins in 33 patients and extracapsular extension in 91. The median radiation dose was 50 Gy (30-66.4). The radiation field covered the tumor bed without lymph node regions for close/positive margins and only involved sites of the neck region were irradiated for multiple nodes or extracapsular extension. RESULTS: With a median follow-up of 43 months for surviving patients, the 3-year overall survival and progression-free survival rates were 53.7 and 42.1%, respectively. The 3-year rates of progression-free survival of the group having major risks (i.e. close/positive margins and/or extracapsular extension) and the group with other risks were 34.7 and 62.8%, respectively (P < 0.01). Thirty-one local recurrences (20%), of which 22 were located out-of-field, and 44 regional recurrences (29%), of which 16 were located out-of-field, developed. Late toxicity of grade 3 or greater developed in only six patients (3.8%). CONCLUSIONS: Although the toxicities associated with limited-field postoperative radiotherapy could be kept to lower levels, the locoregional control rate did not seem to be sufficient. We should arrange the radiation field depending on risk factors.

Alternating chemoradiotherapy in patients with nasopharyngeal cancer: prognostic factors and proposal for individualization of therapy.

The purpose of this study is to assess the efficacy of alternating chemoradiation in patients with nasopharyngeal cancer. From 1990-2006, 100 patients with nasopharyngeal cancer were treated with alternating chemoradiation at the Aichi Cancer Center. Of these, 4, 2, 23, 34, 13 and 23 patients were staged as I, IIA, IIB, III, IVA and IVB, respectively. The median radiation doses for primary tumors and metastatic lymph nodes were 66.6 Gy (range, 50.4-80.2 Gy) and 66 Gy (range, 40.4-82.2 Gy), respectively. A total of 82 patients received chemotherapy with both cisplatin and 5-fluorouracil (5-FU), while 14 patients received nedaplatin (CDGP) and 5-FU. With a median follow-up of 65.9 months, the 5-year rates of overall survival (OAS) and progression-free survival (PFS) were 78.1% and 68.3%, respectively. On multivariate analysis (MVA), elderly age, N3, and WHO type I histology proved to be significantly unfavorable prognostic factors of OAS. As for PFS, there were T4, N3, and WHO type I histology in MVA. Acute toxicities of hematologic and mucositis/dermatitis ≥ Grade 3 were relatively high (32%); however, they were well-managed. Late toxicities of ≥ Grade 3 were three (3%) mandibular osteomyelitis and one (1%) lethal mucosal bleeding. Results for alternating chemoradiation for nasopharyngeal carcinoma are promising. In order to improve outcomes, usage of intensity-modulated radiation therapy and application of active anticancer agents are hopeful treatments, especially for groups with poor prognosis factors with WHO type I histopathology, T4 and/or N3 disease.

Microenvironments and cellular characteristics in the micro tumor cords of malignant solid tumors.

Because of the accelerated proliferation of cancer cells and the limited distance that molecular oxygen can diffuse from functional tumor blood vessels, there appears to be a unique histology in malignant solid tumors, conglomerates of micro tumor cords. A functional blood vessel exists at the center of each tumor cord and is sequentially surrounded by well-oxygenated, oxygen-insufficient, and oxygen-depleted cancer cells in the shape of baumkuchen (layered). Cancer cells, by inducing the expression of various genes, adapt to the highly heterogeneous microenvironments in each layer. Accumulated evidence has suggested that not only tumor microenvironments but also cellular adaptive responses to them, influence the radioresistance of cancer cells. However, precisely how these factors affect one another and eventually influence the therapeutic effect of radiation therapy remains to be elucidated. Here, based on recent basic and clinical cancer research, we deduced extrinsic (oxygen concentration, glucose concentration, pH etc.) and intrinsic (transcriptional activity of hypoxia-inducible factor 1, metabolic pathways, cell cycle status, proliferative activity etc.) parameters in each layer of a tumor cord. In addition, we reviewed the latest information about the molecular mechanism linking these factors with both tumor radioresistance and tumor recurrence after radiation therapy.