We want to evaluate the efficacy of helical tomotherapy (HT) for treating advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT).
We treated 35 patients for unresectable HCC combined with PVTT in whom other treatment modalities were not indicated. The tumor thrombi involved the main trunk of the portal vein in 18 patients (51.4%) and the first or second order branches in 17 patients (48.6%). A median dose of 50 Gy (range: 45–60 Gy) was delivered in 10 fractions. Capecitabine was given concomitantly at a dose of 600 mg/m2 twice daily during radiotherapy.
The responses were evaluated via computed tomography. There was a complete response (CR) in 5 patients (14.3%), partial response (PR) in 10 patients (28.6%), stable disease (SD) in 18 patients (51.4%) and progressive disease (PD) in 2 patients (5.7%). The Child-Pugh classification (A vs B) and the Japan integrated staging (JIS) score (2 vs 3) were statistically significant parameters that predicted the response of PVTT (p = 0.010 and p = 0.026, respectively). The median survival, one and two year survival rate of all patients was 12.9 months, 51.4% and 22.2%, respectively. The patients with tumor thrombi in the main portal trunk showed statistically inferior overall survival than patients with tumor thrombi in the portal vein branches (9.8 versus 16.6 months, respectively, p = 0.036). The responders’ median survival was 13.9 months, double 6.9 months as the median survival of the non-responders. No radiation induced liver disease or treatment related mortality was not appeared.
Hypofractionated radiotherapy with HT was effective not only for tumor response but also for survival in the advanced HCC patients with PVTT. And stricter patient selection by Child-Pugh classification and JIS score may maximize the potential benefits of this treatment.
Helical tomotherapy; Hepatocellular carcinoma; Portal vein tumor thrombosis
To retrospectively evaluate the outcome and toxicity of total lymphoid irradiation (TLI) based conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) patients who experienced an engraftment failure from prior HSCT or were heavily transfused.
Materials and Methods
Between 1995 and 2006, 20 SAA patients received TLI for conditioning of HSCT. All patients were multi-transfused or had long duration of disease. Fifteen (75%) patients had graft failure from prior HSCT. In 18 (90%) patients, the donors were human leukocyte antigen identical siblings. The stem cell source was the peripheral blood stem cell in 15 (75%) patients. The conditioning regimen was composed of antithymocyte globulin plus TLI with a median dose of 750 cGy in 1 fraction. The graft-versus-host disease (GVHD) prophylaxis used cyclosporine with methotrexate.
With a median follow-up of 10.8 years, graft failures developed in 6 patients. Among them, 3 patients received their third HSCT to be engrafted finally. The Kaplan-Meier overall survival rate was 85.0% and 83.1% at 5 and 10 years, respectively. The incidence of acute and chronic GVHD was 20% and 20%, respectively. None of the patients have developed a malignancy after HSCT.
In our study, TLI based conditioning in allogeneic HSCT was feasible with acceptable rates of GVHD in SAA patients who experienced graft failure from prior HSCT or was at a high risk of graft rejection. We achieved relatively better results of engraftment and survival with a long term follow-up.
Aplastic anemia; Total lymphoid irradiation; Hematopoietic stem cell transplantation
In the fission yeast Schizosaccharomyces pombe, the phx1+ (pombe homeobox) gene was initially isolated as a multi-copy suppressor of lysine auxotrophy caused by depletion of copper/zinc-containing superoxide dismutase (CuZn-SOD). Overproduction of Phx1 increased the synthesis of homocitrate synthase, the first enzyme in lysine biosynthetic pathway, which is labile to oxidative stress. Phx1 has a well conserved DNA-binding domain called homeodomain at the N-terminal region and is predicted to be a transcription factor in S. pombe. However, its role has not been revealed in further detail. Here we examined its expression pattern and the phenotype of its null mutant to get clues on its function.
Fluorescence from the Phx1-GFP expressed from a chromosomal fusion gene demonstrated that it is localized primarily in the nucleus, and is distinctly visible during the stationary phase. When we replaced the N-terminal homeobox domain of Phx1 with the DNA binding domain of Pap1, a well-characterized transcription factor, the chimeric protein caused the elevation of transcripts from Pap1-dependent genes such as ctt1+ and trr1+, suggesting that Phx1 possesses transcriptional activating activity when bound to DNA. The amount of phx1+ transcripts sharply increased as cells entered the stationary phase and was maintained at high level throughout the stationary phase. Nutrient shift down to low nitrogen or carbon sources caused phx1+ induction during the exponential phase, suggesting that cells need Phx1 for maintenance function during nutrient starvation. The Δphx1 null mutant showed decreased viability in long-term culture, whereas overproduction of Phx1 increased viability. Decrease in long-term survival was also observed for Δphx1 under N- or C-starved conditions. In addition, Δphx1 mutant was more sensitive to various oxidants and heat shock. When we examined sporulation of the Δphx1/Δphx1 diploid strain, significant decrease in the formation of meiotic spores was observed.
Phx1 is a transcriptional regulator whose synthesis is elevated during stationary phase and by nutrient starvation in S. pombe. It supports long-term survival and stress tolerance against oxidation and heat, and plays a key role in the formation of meiotic spores.
To evaluate the prognostic impact of the lymph node ratio (LNR: the ratio of positive lymph nodes to the total number of lymph nodes examined) on disease recurrence and survival among rectal cancer patients who received curative surgery and postoperative chemoradiotherapy (CRT).
Between 1995 and 2008, 124 patients with pathologic T3-4 or node-positive rectal cancer underwent curative surgery and postoperative CRT. Postoperative radiotherapy was delivered at a median dose of 50.4 Gy (range, 45 to 59.4 Gy) for 6 weeks. Chemotherapy consisted of a bolus injection of 5-fluorouracil and leucovorin in the first and last week of radiotherapy (91.9%) or daily capecitabine during radiotherapy (8.1%). Further adjuvant chemotherapy was administered after chemoradiation.
The median follow-up was 5.1 years. In the multivariate analysis, pathologic N (pN) stage and lymphovascular invasion were significantly associated with disease-free survival and disease-specific survival (p<0.05). However, when the LNR with a cutoff value of 0.2 was included as a covariate in the model, the LNR was highly significant (p<0.001), and the pN stage lost its significance (p>0.05).
The LNR predicts recurrence and survival more accurately than pN stage. The pN stage and the LNR should be considered together when estimating the risk of disease recurrence among rectal cancer patients.
Rectal neoplasms; Lymph nodes; Combined modality therapy
This study evaluated the prognostic impact of the lymph node ratio (LNR; i.e., the ratio of positive to dissected lymph nodes) on recurrence and survival in breast cancer patients with positive axillary lymph nodes (LNs).
The study cohort was comprised of 330 breast cancer patients with positive axillary nodes who received postoperative radiotherapy between 1987 and 2004. Ten-year Kaplan-Meier locoregional failure, distant metastasis, disease-free survival (DFS) and disease-specific survival (DSS) rates were compared using Kaplan-Meier curves. The prognostic significance of the LNR was evaluated by multivariate analysis.
Median follow-up was 7.5 years. By minimum p-value approach, 0.25 and 0.55 were the cutoff values of LNR at which most significant difference in DFS and DSS was observed. The DFS and DSS rates correlated significantly with tumor size, pN classification, LNR, histologic grade, lymphovascular invasion, the status of estrogen receptor and progesterone receptor. The LNR based classification yielded a statistically larger separation of the DFS curves than pN classification. In multivariate analysis, histologic grade and pN classification were significant prognostic factors for DFS and DSS. However, when the LNR was included as a covariate in the model, the LNR was highly significant (p<0.0001), and pN classification was not statistically significant (p>0.05).
The LNR predicts recurrence and survival more accurately than pN classification in our study. The pN classification and LNR should be considered together in risk estimates for axillary LNs positive breast cancer patients.
Breast neoplasms; Lymph nodes; Prognosis
We evaluated the long-term effect of stereotactic body radiation therapy (SBRT) for primary small hepatocellular carcinoma (HCC) ineligible for local therapy or surgery.
Forty-two HCC patients with tumors ≤ 100 cc and ineligible for local ablation therapy or surgical resection were treated with SBRT: 30-39 Gy with a prescription isodose range of 70-85% (median 80%) was delivered daily in three fractions. Median tumor volume was 15.4 cc (3.0-81.8) and median follow-up duration 28.7 months (8.4-49.1).
Complete response (CR) for the in-field lesion was initially achieved in 59.6% and partial response (PR) in 26.2% of patients. Hepatic out-of-field progression occurred in 18 patients (42.9%) and distant metastasis developed in 12 (28.6%) patients. Overall in-field CR and overall CR were achieved in 59.6% and 33.3%, respectively. Overall 1-year and 3-year survival rates were 92.9% and 58.6%, respectively. In-field progression-free survival at 1 and 3 years was 72.0% and 67.5%, respectively. Patients with smaller tumor had better in-field progression-free survival and overall survival rates (<32 cc vs. ≥32 cc, P < 0.05). No major toxicity was encountered but one patient died with extrahepatic metastasis and radiation-induced hepatic failure.
SBRT is a promising noninvasive-treatment for small HCC that is ineligible for local treatment or surgical resection.
To evaluate the incidence of genitourinary mycoplasmas and the efficacy of antibiotics in women with overactive bladder (OAB) symptoms.
Materials and Methods
Women with OAB symptoms (micturition ≥8/24 hours and urgency ≥1/24 hours) for ≥3 months were screened for Mycoplasma hominis (M. hominis), Ureaplasma urealyticum (U. urealyticum), and Chlamydia trachomatis (C. trachomatis). Specimens from urethral and cervical vaginal swabs were examined for M. hominis and U. urealyticum by using the Mycoplasma IST2 kit and for C. trachomatis by using PCR. Women with positive results were treated with a 1 g dose of azithromycin. Persistent infection was treated with doxycycline. Changes in a 3-day bladder diary, Patient Perception of Bladder Condition (PPBC), and International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) were evaluated 4 weeks after negative conversion. Patient satisfaction was assessed.
Of 84 women screened, 42.8% were positive (U. urealyticum, 40.5%; M. hominis, 7.1%; C. trachomatis, 3.6%; two organisms, 8.3%). After treatment, 82.7% obtained negative conversion, and their median number of micturition episodes decreased from 10.6/24 hours to 8.1/24 hours (p=0.002). PPBC and domain scores of the ICIQ-FLUTS (filling and quality of life) significantly improved. About 87.5% women with negative conversion were satisfied with the treatment.
Considering diagnostic tests and treatment for genitourinary mycoplasmas might be beneficial before invasive workup or treatment in women with OAB symptoms.
Chlamydia trachomatis; Mycoplasma hominis; Overactive urinary bladder; Ureaplasma urealyticum
Helical tomotherapy, an advanced intensity-modulated radiation therapy with integrated CT imaging, permits highly conformal irradiation with sparing of normal tissue. Capecitabine, a pro-drug of 5-FU that induces thymidine phosphorylase can achieve higher levels of intracellular 5-FU when administered concurrently with radiation. We evaluated the feasibility as well as the clinical outcome of concurrent administration of capecitabine with tomotherapy in patients with advanced pancreatic cancer.
Nineteen patients with advanced pancreatic cancer including primarily unresectable disease and recurrence after curative surgery were included in the study. Two planning target volumes (PTV) were entered: PTV1 is gross tumor volume; and PTV2, the volume of the draining lymph nodes. The total doses to target 1 and target 2 were 55 and 50 Gy, respectively. Capecitabine at 1600 mg/m2/day was administered on each day of irradiation.
Twenty six measurable lesions were evaluated. Overall in-field response rate was 42.3%; partial responses were achieved in 53.3% of the pancreatic masses, 28.6% of distant metastatic lesions and 25.0% of regional lymph nodes. The median duration of follow-up after tomotherapy was 6.5 months. None of the lesions showed in-field progression. Treatment was well tolerated with only minor toxicities such as grade 1 nausea (one patient), grade 1 hand-foot syndrome (one patient) and grade 1/2 fatigue (three patients).
Helical tomotherapy with concurrent capecitabine is a feasible option without significant toxicities in patients with advanced pancreatic cancer. We achieved excellent conformal distribution of radiation doses and minimal treatment-related toxicities with promising target volume responses.
We have assessed the efficacy and safety of Escherichia coli extract (ECE; Uro-Vaxom®) which contains active immunostimulating fractions, in the prophylactic treatment of chronically recurrent cystitis. Forty-two patients with more than 2 episodes of cystitis in the proceeding 6 months were treated for 3 months with one capsule daily of ECE and observed for a further 6 months. The primary efficacy criterion was the number of episodes of recurrent cystitis during the 6 months after treatment compared to those during the 6 months before treatment. At the end of the 9-month trial, 34 patients (all women) were eligible for statistical analysis. Their mean age was 56.4 yr (range, 34-75 yr), and they had experienced recurrent urinary tract infections for 7.2±5.2 yr. The number of recurrences was significantly lower during the 6-month follow-up period than during the 6 months preceding the trial (0.35 vs. 4.26, P<0.001). During the follow-up, 28 (82.4%) patients had no recurrences and 4 (11.8%) had 1 each. In patients who relapsed, ECE alleviated cystitis symptoms, including painful voiding, frequency and urgency. There were no serious adverse events related to the study drug. Our study demonstrates the efficacy and safety of ECE in the prophylactic treatment of chronically recurrent cystitis.
Cystitis; Immunization; Escherichia coli; OM-8930; Prevention and Control
The underlying molecular and cellular mechanisms of radiation pneumonitis (RP) are very complex. Several biological factors need to be considered together with the well known dosimetric parameters for understanding the molecular events in developing RP in lung cancer patients. The aim of this study was to correlate the variations of the cytokine levels in lung cancer patients during radiation therapy (RT) with the occurrence of symptomatic RP.
Thirty-four lung cancer patients who received three-dimensional conformal radiation therapy were evaluated prospectively. Serial blood samples before, at the beginning, in the middle of, at the end of RT and 2 and 4 weeks after RT were analyzed for IL-1α, IL-6, IL-10, TNF-α and TGF-β1 by performing enzyme-linked immunosorbent assay. The predictive values of dosimetric factors for RP were evaluated, too.
Overall, 8 patients (23.5%) had grade ≥ 2 RP. By serial measurement of cytokines level, only the TGF-β1 level showed a correlation to the symptomatic RP. None of the other cytokines, IL-1α, IL-6, IL-10 and TNF-α level was correlated with the risk of RP. The mean pretreatment TGF-β1 level did not differ between RP and non-RP groups. However, during the period of radiation treatment, the TGF-β1 level began to increase at the end of RT in the RP group and became significantly higher 4 weeks after RT (p = 0.007). Using an ANOVA model for repeated-measures, we found significant associations between the changes of TGF-β1 during the time course of the RT and the risk of developing RP (p < 0.001). Most of the dosimetric factors showed a significant association with RP.
Our results show that the changes of TGF-β1 could be correlated with RP and the incorporation of the biological parameters into the dosimetric data could be useful for predicting symptomatic RP.
The purpose of the present study was to evaluate the efficacy and safety of bipolar transurethral prostatectomy (TURP) using the Gyrus™ PlasmaKinetic System compared with conventional monopolar TURP. This study included 102 patients with benign prostatic hyperplasia (BPH) who underwent TURP from January 2003 to March 2005. In all, 49 consecutive patients had bipolar and 53 had monopolar TURP. All patients were assessed by preoperative and postoperative International Prostate Symptom Score (IPSS), uroflowmetry, transrectal ultrasonography, operative time, weight of resected tissue, change in serum sodium and hemoglobin, duration of catheter use, length of hospital stay, and complication rates. Significant improvement was seen postoperatively in both groups, and no difference was observed in the resection time, weight of resected tissue, change in serum sodium and hemoglobin, improvement of IPSS and peak flow rate (Qmax), or complication rates over the 12-month follow-up in both groups. There was, however, a significant difference in duration of catheter use and hospital stay. Duration of catheter use (2.28 days vs. 3.12 days) and hospital stay (3.52 days vs. 4.27 days) were shorter in the bipolar group (p = 0.012 vs. p = 0.034, respectively). Our results demonstrate that bipolar TURP using the Gyrus™ Plasma Kinetic System is as effective as conventional monopolar TURP with the additional advantage of reduced length of catheter use and hospital stay. Bipolar TURP is a promising new technique that may prove to be a good alternative to conventional TURP in the future.
Prostatic hyperplasia; transurethral resection of prostate
To evaluate the effect of the simulation method on recurrence among the patients who received radiotherapy after breast-conserving surgery (BCS) for early breast carcinoma.
Materials and Methods
Between 1995 and 2000, 70 patients with stage I-II breast carcinoma underwent breast-conserving surgery and adjuvant radiotherapy. Twenty nine patients (41.4%) were simulated with the 2D contour-based method (September 1995 to August 1997) and 41 patients (58.6%) were simulated with the 3D CT-based method (September 1997 to February 2000). To analyze the effect of the simulation method, the patient and treatment characteristics were compared.
The characteristics were similar for the patients between the 2D contour-based simulation group and the 3D CT-based simulation group. During a median follow-up period of 75 months, 4 (13.8%) of 29 patients who were treated with 2D simulation and 1 (2.4%) of 41 patients who were treated with 3D simulation group developed treatment failure. The five-year survival rates were 89.2% and 95.1% between the 2D and 3D simulation groups (p=0.196). The five-year disease free survival (DFS) rates were 86.2% and 97.5% between the 2D and 3D simulation groups (p=0.0636). On univariate analysis, age > 40 (p= 0.0226) and the number of dissected axillary lymph node ≥ 10 (p=0.0435) were independent predictors of improved 5-year DFS.
Although our data showed marginal significance for the DFS between the two groups, it is insufficient, due to the small number of patients in our study, to prove whether 3D CT-based simulation might improve the DFS and reduce the risk of recurrence when compared with 2D contour-based simulation. Further study is needed with a larger group of patients.
Breast neoplasms; Radiotherapy; Simulation; Recurrence
Recombinant activated coagulation factor VII (rFVIIa) is known to be effective in the management of acquired deficiencies of factor VII and platelet function defects. But recently, rFVIIa has been successfully used to treat ongoing bleeding in disseminated intravascular coagulopathy (DIC) condition. The patient reported here was suspected to be suffering from toxic hepatitis on admission. After percutaneous liver biopsy, bleeding occurred and did not stop even after right hepatic artery embolization. The patient developed a severe hemorrhage that resulted in hypovolemic shock, hemoperitoneum, and a massive subcapsular hematoma. The patient then developed DIC due to massive transfusion, as well as acute liver necrosis. The patient was given 400 μg/kg of rFVIIa. Recombinant factor VIIa was administered in an attempt to control the bleeding. This stabilized the hemoglobin levels of the patient. The patient gradually recovered in 4 months. In conclusion, this case suggests that rFVIIa can be successfully used for the hemostasis of uncontrolled bleeding in DIC.
Recombinant activated coagulation factor VII; Subcapsular hematoma