The intrinsic radiosensitivity and sublethal damage repair capacity of five cervical carcinoma cell lines tested with the 96-well-plate assay

We have tested the intrinsic radiosensitivity and capacity for sublethal damage repair (SLDR) in split-dose experiments with the 96-well plate clonogenic assay. Four out of five cell lines were squamous-cell carcinoma (SCC) lines (CaSki, ME-180, HX151c, HX156c) and one cell line was established from glassy-cell carcinoma (UM-GCC-1). Comparison of radiosensitivities was by withD value, the mean inactivation dose.D for these cell lines varied from 1.7 Gy to 2.5 Gy. As a group, cervical carcinoma cell lines were more radioresistant than endometrial adenocarcinoma cell lines tested with the same assay, but more radiosenstive than vulvar SCC lines. Three cell lines showed clear SLDR, but two cell lines were unable to carry out this function. Furthermore, cell lines capable of SLDR also showed significant increase in survival whenD values were compared after the radiation dose was split into three instead of two fractions. These results indicate the importance of adding another radiobiological parameter to the intrinsic radiosensitivity when predictive tests are planned.Abbreviations SLDR sublethal damage repair - SCC squamous cell carcinoma - SF2 fraction surviving after 2 Gy of radiation - AUC area under the radiation survival curve This study was financially supported by the Southwestern Division of the Finnish Cancer Society and the Turku University Foundation.     

Radiosensitivity of dermal and tumor fibroblasts derived from the same patient

The in vitro radiosensitivity of dermal fibroblasts has been found to vary between individuals, and a number of studies have also shown that this parameter correlates with radiation-induced late injuries in clinical radiotherapy. In addition, certain genetic disorders are known to effect radiosensitivity, e.g. normal tissues of patients homozygous or heterozygous for the ataxia teleangiectasia gene show unusual sensitivity to radiation both in vivo and in vitro. Thus, it has been assumed that there is a genetically determined component resulting in a certain intrinsic cellular radiation response in an individual. To study this possible relationship between different cells of a specific patient, we established eight pairs of dermal and tumor fibroblast cultures. The donor patients had either adenocarcinoma of the uterus or squamous cell carcinoma (SCC) of the head and neck. The radiosensitivity of these strains was determined by a 96-well plate clonogenic assay, previously used by us for radiosensitivity testing of cancer cells. From a paired comparison, the values for the cell fraction surviving 2.0 Gy (SF₂), of both fibroblast strains, were found to be on the same level in five out of eight cases. In patient 6, the SF₂ of tumor fibroblasts was significantly higher than that of dermal fibroblasts (P = 0.0014). In two additional cases the tendency was the same, but not statistically significant. As groups, the two types of fibroblasts did not differ from each other, mean SF₂ values of 0.24 ± 0.07 and 0.21 ± 0.05, respectively. The SF₂ of tumor fibroblasts from SCC patients proved to be significantly higher than that of the adenocarcinoma patients (P = 0.030). These preliminary results indicate that the in vitro radiosensitivity of tumor fibroblasts correlates with normal cell sensitivity in many cases, but not in all. The radiosensitivity of tumor fibroblasts also seems to follow the level of in vitro radiosensitivity determined for the corresponding histological type of tumor cells. Further studies are needed to determine more closely the relationship between the radiosensitivities of tumor cells and tumor fibroblasts, thus evaluating the possibility of testing radiosensitivity from tumor fibroblasts in order to estimate tumor response. Received: 18 November 1997 / Accepted: 15 April 1998     

Kinematic Effects of Hyolaryngeal Electrical Stimulation Therapy on Hyoid Excursion and Laryngeal Elevation

The purpose of this study was to assess the effect of repeated sessions of electrical stimulation therapy (EST) on the neck muscles with respect to the stimulation site by using quantitative kinematic analysis of videofluoroscopic swallowing studies (VFSS) in dysphagia patients with acquired brain injury. We analyzed 50 patients in a tertiary hospital who were randomly assigned into two different treatment groups. One group received EST on the suprahyoid muscle only (SM), and the other group received stimulation with one pair of electrodes on the suprahyoid muscle and the other pair on the infrahyoid muscle (SI). All patients received 10–15 sessions of EST over 2–3 weeks. The VFSS was carried out before and after the treatment. Temporal and spatial parameters of the hyoid excursion and laryngeal elevation during swallowing were analyzed by two-dimensional motion analysis. The SM group (n = 25) revealed a significant increase in maximal anterior hyoid excursion distance (mean ± SEM = 1.56 ± 0.52 mm, p = 0.008) and velocity (8.76 ± 3.42 mm/s, p = 0.017), but there was no significant increase laryngeal elevation. The SI group (n = 25), however, showed a significant increase in maximal superior excursion distance (2.09 ± 0.78 mm, p = 0.013) and maximal absolute excursion distance (2.20 ± 0.82 mm, p = 0.013) of laryngeal elevation, but no significant increase in hyoid excursion. There were no significant differences between the two groups with respect to changes in maximal anterior hyoid excursion distance (p = 0.130) and velocity (p = 0.254), and maximal distance of superior laryngeal elevation (p = 0.525). EST on the suprahyoid muscle induced an increase in anterior hyoid excursion, and infrahyoid stimulation caused an increase in superior laryngeal elevation. Hyolaryngeal structural movements were increased in different aspects according to the stimulation sites. Targeted electrical stimulation based on pathophysiology is necessary.     

Macrophage migration inhibitory factor in head and neck squamous cell carcinoma: clinical and experimental studies

Purpose

The present in vivo/in vitro study was undertaken in order to evaluate the importance of macrophage migration inhibitory factor (MIF) in the progression of head and neck squamous cell carcinoma (HNSCC).

Methods

Tumor tissue expression (MIF immunostaining) and plasma levels (ELISA) of MIF were determined in HNSCC patients and correlated with tumor recurrence and metastasis, and overall survival. Furthermore, the impact of MIF expression on cell proliferation and anticancer drug sensitivity was examined in murine squamous carcinoma cell line SCCVII after MIF knockdown (MIF-KD).

Results

As revealed by quantitative analysis of MIF immunostaining, tumor progression was accompanied by an increase in mean optical density (MOD) and labeling index (LI). Likewise, an elevation of MIF serum levels was noted in HNSCC patients (n = 66) versus healthy individuals (n = 16). Interestingly, comparison of laryngeal carcinoma patients on the basis of MIF tissue expression (high expression, LI ≥ 47, versus low expression, LI < 47) disclosed a significant difference between disease-free survival curves for local and nodal recurrence, and overall survival curve. In vitro, MIF knockdown in murine SCCVII cells resulted in reduced cell proliferation and a decrease in cell motility. In mice inoculated with SCCVII cells, MIF-KD tumors grew more slowly and also appeared more sensitive to chemotherapy.

Conclusions

Both clinical observations and experimental data suggest that MIF plays a pivotal role in the progression of HNSCC.     

Self-Expanding Metal Stents (SEMS) for Preoperative Biliary Decompression in Patients with Resectable and Borderline-Resectable Pancreatic Cancer: Outcomes in 241 Patients

Background and Aim

Obstructive jaundice caused by distal biliary obstruction can present in up to 70 % of patients with localized cancer of the head of the pancreas. The aim of this study was to report our experience in using self-expanding metal stents (SEMS) for preoperative biliary decompression in patients with resectable and borderline resectable carcinoma of the pancreatic head.

Methods

We performed a retrospective study evaluating patients from two tertiary referral centers. Two-hundred and forty-one patients with resectable and borderline resectable pancreatic carcinoma underwent ERCP with metal biliary stent placement between September 2006 and August 2011. We assessed the effectiveness of SEMS to adequately decompress the biliary tree, procedural success, patient survival, stent patency, and stent-related complications.

Results

Two-hundred and forty-one patients were evaluated [123 male, mean age (±SD) 67.4 ± 9.8 years; resectable 174, borderline resectable 67]. Patients with borderline-resectable cancer underwent neoadjuvant therapy and restaging before possible curative surgery. Successful placement of a metal biliary stent was achieved in all patients and improved jaundice. Patients were followed for mean duration of 6.3 months. The overall survival was 49 % at 27 months. Fourteen (5.8 %) patients experienced stent occlusion; the mean time to stent occlusion was 6.6 (range 1–20) months. Immediate complications included: post-ERCP pancreatitis (n = 14), stent migration (n = 3), and duodenal perforation (n = 3). Long-term complications included stent migration (n = 9) and hepatic abscess (n = 1). A total of 144/174 patients deemed to have resectable cancer at time of diagnosis underwent curative surgery. Due to disease progression or the discovery of metastasis after neoadjuvant therapy, only 22/67 patients with borderline-resectable cancer underwent curative surgery.

Conclusions

SEMS should be considered for patients with obstructive jaundice and resectable or borderline resectable pancreatic cancer, especially if surgery is not planned immediately as a result of preoperative chemoradiation. These stents appear to be safe and effective.     

Prognostic value of ERCC1 in head and neck carcinoma treated with definitive or adjuvant radiotherapy

Purpose

To evaluate the prognostic significance of excision repair cross-complementation group 1 (ERCC1) expression in head and neck carcinoma patients treated with definitive radiotherapy (DR) or adjuvant radiotherapy (AR).

Methods

ERCC1 expression was assessed by immunohistochemical staining. A total of 48 patients were assessed.

Results

High ERCC1 expression was found in 23 patients (48 %). More ERCC1-positive tumours were detected in patients treated with DR than in patients treated with AR (73 vs. 36 %, respectively, p = 0.03). ERCC1 expression had no impact on overall survival neither in the whole cohort of patients (p = 0.16) nor in each particular treatment group (AR p = 0.98; DR p = 0.21).

Conclusions

ERCC1 expression had no predictive value in head and neck carcinoma patients treated with DR or AR. There might be difference in ERCC1 positivity that comes out of whether the assessment is done on biopsy or surgical specimens.     

Electroacupuncture Elicits Dual Effects: Stimulation of Delayed Gastric Emptying and Inhibition of Accelerated Colonic Transit Induced by Restraint Stress in Rats

Acupuncture has been used for treating functional gastrointestinal (GI) disorders. Animal studies have demonstrated that acupuncture antagonized various stress-induced responses. We investigated the effects of electroacupuncture (EA) at ST-36 (Zusanli; lower limb) on stress-induced alteration of GI motor activities. Solid gastric emptying was significantly delayed by restraint stress (29.6±2.4%; n=7) compared to that of controls (60.0±2.5%; n=8). Delayed gastric emptying was significantly improved by EA at ST-36 (47.2±1.8%). Intracisternal (IC) injection of corticotropin releasing factor (CRF; 1 μg) delayed gastric emptying to 25.4±3.1%, which was also improved by EA at ST-36, to 53.0±7.1% (n=8). The stimulatory effect of EA on stress-induced delayed gastric emptying was abolished by atropine (17.6±1.9%) but not by guanethidine (42.2±2.3%). Colonic transit was significantly accelerated by restraint stress (GC=7.2±0.3; n=8) compared to that of controls (GC=5.2±0.2; n=8). Accelerated colonic transit was significantly reduced by EA at ST-36 (GC=4.9±0.3). IC injection of CRF accelerated colonic transit (GC=6.9±0.2), which was also normalized by EA at ST-36 (GC=4.7±0.2). The inhibitory effect of EA on stress-induced acceleration of colonic transit was not affected by guanethidine (GC=4.6±0.3). In conclusion, EA at ST-36 showed dual effects: stimulation of stress-induced delayed gastric emptying and inhibition of stress-induced acceleration of colonic transit. The stimulatory effect of EA on stress-induced delayed gastric emptying is mediated via cholinergic pathways. The inhibitory effect of EA on stress-induced acceleration of colonic transit is independent of the sympathetic pathway.     

Vascular responses to the multiple overlapped paclitaxel-eluting stents for the treatment of bare-metal in-stent restenotic lesions: angiographic and intravascular ultrasound analysis from the TAXUS-V ISR Trial

BackgroundAlthough effective coverage of coronary diffuse in-stent restenosis (ISR) lesions has warranted the use of multiple drug-eluting stents, the vessel response to paclitaxel-eluting stent (PES) overlap is not fully understood.Methods and materialsIn the TAXUS-V ISR, i.e., comparing PES versus brachytherapy for the treatment of bare-metal ISR, angiographic analyses at 9-month follow-up were available in 184 ISR lesions treated with PES.ResultsIn-stent late loss in entire stented segment of multiple PES (n=50) was 0.45±0.48 mm, whereas that of single PES (n=134) was 0.3±0.47 mm, P=.06. No aneurysm was observed at overlapping PES segments at 9 months. Stent thrombosis up to 9 months was observed in one in each group (single PES, 0.7% vs. multiple PES, 1.8%; P=.47). In a subset of 30 patients, volumetric intravascular ultrasound analysis demonstrated that in-stent net volume obstruction was 12.3±12.4 in single PES (n=20) and 14.9±9.8 in multiple PES (n=10), P=.60. The changes of vessel and lumen at the overlapping PES segment were similar to those of the adjacent 5-mm segments (Δminimum lumen area, mm²: ?1.2±1.0, ?1.1±1.1, ?0.8±0.9, P=.48; Δvessel volume, mm³/mm: ?0.2±1.4, 0.1±1.7, 0.3±1.3, P=.37; proximal, overlap, distal segment, respectively). There was no late incomplete stent apposition at overlapping PES segments.ConclusionsNo in vivo evidence of adverse local vessel response at the site of overlapping PES for the treatment of bare-metal ISR has been demonstrated.     

Concurrent use of vinorelbine and gefitinib induces supra-additive effect in head and neck squamous cell carcinoma cell lines

Purpose Squamous cell carcinoma of the head and neck (HNSCC) remains a clinical challenge because of the high rate of locoregional disease recurrence. Standard treatment includes surgery, radiation, chemoradiation or a combination of these approaches. New therapies are needed to achieve improved survival, quality of life and organ function in these patients. A novel molecular targeted therapy incorporated into our current treatment strategies may have a significant role in the treatment of HNSCC. The aim of this study was to evaluate the sensitivity of HNSCC cell lines to vinorelbine combined with gefitinib in vitro. Methods Six recently established cell lines were used: UT-SCC-9, -11, -19A, -29 and -34 (laryngeal SCC) and UT-SCC-33 (oral cavity SCC). Chemosensitivity was tested using the 96-well plate clonogenic assay. The vinorelbine concentrations used varied between 0.4 and 1.0 nM and the gefitinib concentrations varied between 0.05 and 1.6 μM. Survival data were fitted to the LQ model, and the area under the curve (AUC) value was obtained with numerical integration. The type of interaction was determined by comparing the AUC ratio of the two drugs to the survival fraction (SF) of gefitinib alone. Results In the current study the combination of vinorelbine and gefitinib had a clear supra-additive or additive cytotoxic effect on the HNSCC cell lines. Conclusions This finding is encouraging as a proof of the possible benefit of combing an EGFR targeting compound with a cell cycle specific drug and warrants further studies of available combinations in vitro.     

Plasma tumor necrosis factor-α and C-reactive protein as biomarker for survival in head and neck squamous cell carcinoma

Purpose

Tumor TNM staging is the main basis for prognosis and treatment decision for head and neck squamous cell carcinoma (HNSCC) despite significant heterogeneity in terms of outcome among patients with the same clinical stage. In this study, a possible role of plasma interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte–macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) as biomarkers for survival of HNSCC patients was investigated.

Methods

In this prospective study, plasma levels of IL-2, IL-6, GM-CSF, TNF-α and CRP in patients (n = 100) and controls (n = 48) were analyzed.

Results

Significantly elevated levels of CRP and TNF-α (p < 0.001) were found in the patients. Combination of upregulated CRP and TNF-α in the patient plasma was significantly related to shorter patient survival, independent of clinical stage.

Conclusions

Our findings indicate that CRP and TNF-α might be suitable as biomarkers in combination with tumor TNM staging for predicting survival and individualized treatment of HNSCC patients. Plasma CRP and TNF-α analysis are simple, rapid, cost effective and suitable for clinical practice.     

Absence of cervical radiation myelitis after hyperfractionated radiation therapy with and without concurrent chemotherapy for locally advanced, unresectable, nonmetastatic squamous cell carcinoma of the head and neck

Purpose: To evaluate the risk of developing radiation myelitis after a cervical spinal cord dose of 50.6 Gy given via 1.1 Gy b.i.d. fractionation during a prospective, randomised trial of hyperfractionated radiation therapy (HFX RT) to a total dose of 77 Gy given in 70 fractions of 1.1 Gy b.i.d., with and without concurrent low-dose, daily cisplatin (CDDP) for head and neck cancer. Methods: Of 130 patients with locally advanced, unresectable, nonmetastatic squamous cell carcinoma of the head and neck (SCC H&;N) who entered a prospective, randomised trial, 101 patients received 50.6 Gy to a portion of their spinal cord and survived >1 year following the beginning of therapy. Forty-five patients were treated with HFX RT alone and fifty-six patients also received CDDP. Results: None of these 101 patients developed cervical radiation myelitis. Therefore, it was not possible to investigate the influence of potentially contributing factors on the occurrence of radiation myelitis, such as interfraction interval, cord length, and administration of concurrent CDDP. Conclusions: Given the increasing number of studies with both altered fractionated regimens and concurrent radio-chemotherapy in SCC H&;N, new studies with more patients are needed to gain better insight into the risks of developing cervical radiation myelitis.     

Sublethal damage repair after fractionated irradiation in endometrial cancer cell lines tested with the 96-well plate clonogenic assay

Two long-established and seven newly established endometrial adenocarcinoma cell lines were tested for their capacity to repair sublethal damage after fractionated irradiation. Cell survival was determined with the 96-well plate clonogenic assay based on limiting dilutions. Total radiation doses of 0.75 Gy, 1.25 Gy, 2.50 Gy, 5.00 Gy and 7.50 Gy were used either as a single dose or divided into two or three equal fractions with a 24 h interval. Survival data were fitted to the linear quadratic model, and the area under the survival curve (AUC), equivalent to the mean inactivation dose, was obtained with numerical integration. The amount of sublethal damage repair (SLDR) was expressed as an area-under-the-curve (AUC) ratio comparing survivals from fractionated-dose with those from single-dose experiments. SLDR capacity of the cell lines expressed as an AUC ratio varied between 1.00 and 1.59, and the mean was 1.17. Two highly radiosensitive cell lines were found to be SLDR-deficient, but most of the cell lines studied had some SLDR capacity. We have earlier shown that endometrial cancer cell lines as a group are more radiosensitive than squamous-cell carcinoma (SCC) lines. Data obtained in this study suggest that the capacity for SLDR in these cell lines is rather limited compared with the majority of SCC lines tested. This finding underlines further the high radioresponsiveness of endometrial cancer.Abbreviations SLDR sublethal damage repair - SCC squamous-cell carcinoma - AUC area under the curve This study was financially supported by the Southwestern Division of the Finnish Cancer Society and the Turku University FoundationPresented at the Fourth Biennial Meeting of the International Gynecologic Cancer Society, Aug 29-Sep 2 1993, in, Stockholm, Sweden     

Intraoperative radiotherapy for resectable and unresectable pancreatic carcinoma

Eighty patients with pancreatic carcinoma were treated by intraoperative radiotherapy (IORT) with or without surgical resection of the tumor, and the results were compared with those of 111 patients treated by surgery alone. For resectable patients, the radiation dose was 30 Gy and the average field sizes were 8 or 10 cm; for unresectable patients, these values were 20–30 Gy and 6 or 8 cm, respectively. No side effects of IORT were observed. In 49 resectable stage III patients, the IORT group (n=16) had a higher survival rate than the non-IORT group (n=33); i.e., 1-year survival rates of 44.6% vs 23% and 2-year survival rates of 37.2% vs 7.7% after surgery (P<0.05). However, there was no significant difference in survival rate between the IORT group (n=28) and the non-IORT group (n=29) in 57 resectable patients in stage IV. In unresectable patients, the IORT group (n=31) (P<0.05) had a higher survival rate than the non-IORT group (n=38) (P<0.05). The palliative effect of IORT on abdominal or back pain was evaluated in 15 patients who had such symptoms and did not undergo tumor resection. Overall, pain decreased or disappeared in 13 of these patients (87%).     

Survival after myocardial infarction in rats: captopril versus losartan

Objectives. This study sought to compare the effects of angiotension-converting enzyme inhibition versus angiotensin II receptor blockade on survival in rats with myocardial infarction.Background. The effects of speciifc nonpeptide angiotensin receptor blocking agents on survival after myocardial infarction are unknown.Methods. Rats with a moderate to large myocardial infarction were treated with captpril (2 g/liter drinking water, n= 87) or losartan (2 g/liter drinking water, n= 96). Therapy was initiated immediately after coronary artery ligation and continued for 1 years.Results. Uncensored median survival in captopril-treated rats that survived at least 48 h was 201.5 days versus 236.0 days for losartan-treated rats (p = 0.066). Median survival censored for rats with lung infections was 201.5 days in captopril-treated rats versus 243.0 days for losartan-treated rats (p = 0.028). Conscious hemodynamic measurements and remodeling data obtained at 1 year in the surviving rats (n = 5 for captopril; n = 9 for losartan) revealed no differences in heart weight, left ventricular pressure, dP/dt, cardiac index, time constant of relaxation or any variable of left ventricular remodeling. The only differences (mean ± SD) were an increase in heart rate (293 ± 19 vs. 260 ± 15 beats/min, p < 0.05) and a decrease in peak developed pressure (153 ± 21 vs. 180 ± 16 mm Hg, p < 0.05) in the losartan-treated rats.Conclusions. We conclude that in this experimental model of heatr failure, there was no difference between survival after angiotensin II receptor blockade with losartan and with angiotensin-converting enzyme inhibition with captopril.     

Interleukin-6 and granulocytic elastase levels following laparoscopic cholecystectomy

Interleukin-6 (IL-6) levels have been shown to correlate well with the magnitude of surgical stress. Serum IL-6 and plasma granulocytic elastase levels, 24 h after surgery, were determined in 12 patients who underwent open major surgery [MS group; esophageal carcinoma (n=5), gastric carcinoma (n=3), colorectal carcinoma (n=4) 5 patients who had open cholecystectomy [OC group] and 17 patients who had laparoscopic cholecystectomy [LC group]. IL-6 levels correlated significantly with the duration of surgery (r=0.685,P < 0.01) and with intraoperative blood loss (r=0.583,P < 0.02). However, there was no significant correlation between granulocytic elastase and the duration of surgery or blood loss. Plasma IL-6 levels in the LC group (21±3 pg/ml) were significantly lower than those in the OC group (47±5 pg/ml) and the MS group (186±36pg/ml) (P<0.05;P<0.01). However, there was no significant difference in granulocytic elastase levels between the LC group (318±8μg/l), the OC group (360±130 gmg/ml), and the MS group (701±344 μg/l). Increased IL-6 levels correlated well with increased duration of surgery. The lower IL-6 levels following laparoscopic cholecystectomy may therefore be indicative of lower surgical stress associated with laparoscopic cholecystectomy.     

The actuarial survival analysis of the surgical and non-surgical therapy regimen for chronic thromboembolic pulmonary hypertension

Aim To characterize the in-hospital mortality and the actuarial survival of surgical and non-surgical therapy regimen in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Methods A retrospective cohort study was conducted in 504 patients with CTEPH, who were treated surgically (n = 360), or non-surgically (n = 144) in Anzhen Hospital from February 1989 to August 2007. The patients in surgical group received a standard pulmonary thromboendarterectomy (PTE), while those in non-surgical group were given thrombolytic therapy. The actuarial survival of the two groups was determined with the Kaplan–Meier survival curves. Univariate analysis and multivariate binary logistic regression and Cox proportional hazard analysis were used to identify the risk factors for the in-hospital and late deaths. Results The in-hospital mortality for the surgical group and non-surgical group were 4.44% and 3.50%, respectively. For the proximal type of CTEPH, the actuarial survival at 10 and 15 years of the surgical group and non-surgical group were 94.60 ± 2.38%, 90.96 ± 4.24% and 81.4 ± 7.14%, 56.43 ± 14.7%, respectively (χ² = 12.33, P = 0.0004). For the distal type of CTEPH, the actuarial survival at 10 and 15 years of the surgical group and non-surgical group were 71.78 ± 4.66%, 29.57 ± 15.1% and 69.84 ± 7.78%, 32.59 ± 13.7%, respectively (χ² = 0.03, P = 0.874). Conclusion The PTE procedure has statistically superiority over thrombolytic therapy for the proximal type of CTEPH in terms of actuarial survival; however, for the distal type of CTEPH, the PTE procedure provides no benefits with regard to actuarial survival.     

Treatment outcomes of adolescent acute lymphoblastic leukemia treated on Tokyo Children’s Cancer Study Group (TCCSG) clinical trials

There is no standard treatment for adolescents aged 15 years or older with acute lymphoblastic leukemia (ALL), although this age group has been reported as having a poorer prognosis compared to younger patients. We retrospectively analyzed the outcomes of three consecutive Tokyo Children’s Cancer Study Group ALL trials (1995–2006) of 373 patients aged 10 years or older, with particular focus on adolescents aged 15–18 years (older-adolescents n = 41), compared to those aged 10–14 years (younger-adolescents n = 332). The probability of event-free survival at 8 years was 67.5 ± 7.4 % for the older-adolescents and 66.5 ± 2.6 % for the younger-adolescents (p = 0.95). Overall survival was 70.7 ± 7.1 % for the older-adolescents and 74.3 ± 2.4 % for the younger-adolescents (p = 0.48). The differences between groups in relapse incidence, non-relapse mortality, and death rate during induction were not statistically significant, although the older-adolescents trended towards a higher frequency of having stem-cell transplantation during the first remission. In conclusion, our treatment strategy, which consists of intensive induction and block-type consolidation, provided improved outcomes for patients aged 15–18 years, comparable to those for patients aged 10–14 years.     

Adenosine receptor expression in an experimental animal model of myocardial infarction with preserved left ventricular ejection fraction

Adenosine, a purine nucleoside and a “retaliatory metabolite” in ischemia, is ubiquitous in the body and increases 100-fold during ischemia. Its biological actions are mediated by four adenosine receptors (ARs): A₁, A_2A, A_2B and A₃. The aim of this study was to determine possible myocardial alterations in AR expression in an experimental animal model of myocardial infarction (MI) with a preserved left ventricular (LV) ejection fraction. LV tissue was collected from sexually mature male farm pigs with MI (n = 6) induced by permanent surgical ligation of the left anterior descending coronary artery and from five healthy pigs (C). mRNA expression of A₁R, A_2AR, A_2BR, A₃R and TNF-α was determined by real-time PCR in tissue collected from border (BZ) and remote zones (RZ) of the infarcted area and from LV of C. BZ, RZ and samples of C were stained immunohistochemically to investigate A₃R immunoreaction. After 4 weeks a different regulation of ARs was observed. A₁R mRNA expression was significantly lower in the infarct regions than in controls (C = 0.75 ± 0.2, BZ = 0.05 ± 0.2, RZ = 0.07 ± 0.02 p = 0.0025, p = 0.0016, C vs. BZ and RZ, respectively). Conversely A₃R was higher in infarct areas (C = 0.94 ± 0.2, BZ = 2.85 ± 0.5, RZ = 3.48 ± 1.0, p = 0.048 C vs. RZ). No significant differences were observed for A_2AR (C = 1.58 ± 0.6, BZ = 0.42 ± 0.1, RZ = 1.37 ± 0.6) and A_2BR (C = 1.66 ± 0.2, BZ = 1.54 ± 0.5, RZ = 1.25 ± 0.4). A₃R expression was confirmed by immunohistochemical analysis and was principally localized in cardiomyocytes. TNF-α mRNA results were: C 0.41 ± 0.25; BZ 1.60 ± 0.19; RZ 0.17 ± 0.04. The balance between A₁R and A₃R as well as between A_2AR and A_2BR was consistent with adaptative retaliatory anti-ischemic adenosinergic changes in the infarcted heart with preserved LV function.     

Epidermal growth factor receptor-targeted therapy potentiates lovastatin-induced apoptosis in head and neck squamous cell carcinoma cells

Purpose Mevalonate metabolites are vital for a variety of key cellular functions with the biosynthetic products including cholesterol and farnesyl and geranylgeranyl isoprenoids. Inhibition of this pathway using lovastatin induces a potent apoptotic response in a specific subset of human tumor-derived cell lines, including head and neck squamous cell carcinomas (HNSCC). In this study, we evaluated the potential of a number of chemotherapeutics that demonstrate activity in HNSCC, including an inhibitor of epidermal growth factor receptor (EGFR) to potentiate the cytotoxic effects of lovastatin.Methods We evaluated the cytotoxic effects of combining a variety of chemotherapeutics with lovastatin using the MTT assay and flow cytometry. The MCF-7 lovastatin-resistant breast adenocarcinoma cell line and the lovastatin-sensitive HNSCC cell lines SCC9 and SCC25 were tested. Expression levels of EGFR and ligand activated EGFR following lovastatin treatment were analyzed by Western blotting.Results Pretreatment or concomitant treatment of 10 M lovastatin did not significantly augment the effects of a variety of chemotherapeutic agents tested in these cell lines. Co-administration with actinomycin D or cycloheximide, drugs that inhibit RNA and protein synthesis, respectively, inhibited lovastatin-induced apoptosis in these cell lines. This suggests a requirement for the cellular functions disrupted by these chemotherapeutic agents in lovastatin-induced apoptosis of HNSCC cells. In contrast to the chemotherapeutics analyzed, the AG1478 tyrosine kinase inhibitor of the EGFR demonstrated additive cytotoxic effects in combination with lovastatin in HNSCC cells. Mevalonate metabolites may regulate EGFR function, suggesting that lovastatin may inhibit the activity of this receptor. Indeed, lovastatin treatment inhibited EGF-induced autophosphorylation of the EGFR in the SCC9 and SCC25 cell lines. Pretreatment of SCC9 and SCC25 cell lines for 24 h with 10 M lovastatin, conditions that demonstrated significant inhibition of EGF-induced EGFR autophosphorylation, induced significant additive effects in combination with AG1478.Conclusion These results demonstrated the ability of EGFR pathway inhibitors to potentiate lovastatin-induced apoptosis and suggested that lovastatin may target the EGFR pathway in HNSCC cells.Abbreviations HNSCC head and neck squamous cell carcinoma - EGFR epidermal growth factor receptor - 5-FU 5-fluorouracil - HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A - ActD actinomycin D - CHX cycloheximide     

Single HCC smaller than 2 cm: surgery or ablation

Purpose

For hepatocellular carcinoma (HCC), surgical resection and radiofrequency ablation (RFA) are accepted as effective treatments. To clarify the long-term outcome in patients with small HCC, we analyzed data from a nationwide survey of Japan.

Methods

Between 2000 and 2003, a total of 2,550 patients who had undergone resection (n = 1,235) or RFA (n = 1,315) for single small HCC (≤2 cm) were registered to the database of the Liver Cancer Study Group of Japan (LCSGJ).

Results

After a median follow-up period of 37 months, disease-free survival after resection was significantly better than after RFA (1-year, 91 vs. 87%; 2-year, 46 vs. 25%; P = 0.001), but overall survival after resection and RFA were similar (98 vs. 99%; 94 vs. 95%, P = 0.28). In the patients of Child–Pugh class A, disease-free survival was significantly better after resection (n = 1,056) than after RFA (n = 965) (P = 0.001), while overall survival was not significantly different (P = 0.16). In the patients of Child–Pugh class B, both disease-free and overall survival were almost similar (P = 0.63 and P = 0.66) after resection (n = 136) and RFA (n = 303).

Conclusions

For single small HCC (≤2 cm), surgical resection provides better disease-free survival than does RFA. Longer follow-up is needed to regard this indication as conclusive.