ACTN4 copy number increase as a predictive biomarker for chemoradiotherapy of locally advanced pancreatic cancer.

BACKGROUND: Several clinical trials have compared chemotherapy alone and chemoradiotherapy (CRT) for locally advanced pancreatic cancer (LAPC) treatment. However, predictive biomarkers for optimal therapy of LAPC remain to be identified.We retrospectively estimated amplification of the ACTN4 gene to determine its usefulness as a predictive biomarker for LAPC. METHODS: The copy number of ACTN4 in 91 biopsy specimens of LAPC before treatment was evaluated using fluorescence in situ hybridisation (FISH). RESULTS: There were no statistically significant differences in overall survival (OS) or progression-free survival (PFS) of LAPC between patients treated with chemotherapy alone or with CRT. In a subgroup analysis of patients treated with CRT, patients with a copy number increase (CNI) of ACTN4 had a worse prognosis of OS than those with a normal copy number (NCN) of ACTN4 (P=0.0005, log-rank test). However, OS in the subgroup treated with chemotherapy alone was not significantly different between patients with a CNI and a NCN of ACTN4. In the patients with a NCN of ACTN4, the median survival time of PFS in CRT-treated patients was longer than that of patients treated with chemotherapy alone (P=0.049). CONCLUSIONS: The copy number of ACTN4 is a predictive biomarker for CRT of LAPC.

Feasibility of endoscopic mucosal resection as salvage treatment for patients with local failure after definitive chemoradiotherapy for stage IB, II, and III esophageal squamous cell cancer.

Local failure after definitive chemoradiotherapy (CRT) for stage IB, II, and III esophageal cancer is one of the causes of poor outcome. Endoscopic mucosal resection (EMR) is an effective treatment for superficial esophageal cancer. However, its feasibility as a salvage treatment for local recurrent or residual tumors after definitive CRT for stage IB, II, and III esophageal cancer remains unclear. Between January 2000 and February 2008, 274 patients with stage IB, II, and III esophageal squamous cell cancer excluding T4 received definitive CRT at the National Cancer Center Hospital, Japan. Of these patients, nine patients with local recurrence after achieving complete response and two patients with residual tumor underwent salvage EMR. The technique of salvage EMR involved a strip biopsy method. We retrospectively reviewed the 11 patients (13 lesions). Characteristics of all 11 patients were as follows: median age of 69 (range: 45-78); male/female: 10/1; baseline clinical stage (Union for International Cancer Control 7th) IB/IIA/IIB/III: 1/3/7/0. The depth of resected tumor was limited to the mucosal layer in seven lesions and submucosal in six lesions. En bloc resection was performed on six lesions (46%). The vertical margin was free of cancer cells in 11 lesions (84.6%). No major complications, such as hemorrhage requiring blood transfusion and perforation, were experienced. At a median follow-up period of 38.9 months (range: 5.3-94 months) after salvage EMR, no recurrence was detected in six patients (54%). Local recurrence was detected in five patients (27%). Of these patients, two had lung metastasis simultaneously, and one was also detected lung metastasis 2 months after the detection of local recurrence. The 5-year survival rate after salvage EMR was 41.6%. Salvage EMR is a feasible treatment option for local recurrent or residual lesions after definitive chemotherapy and/or radiotherapy for stage IB, II, and III esophageal squamous cell cancer.

Radiation therapy for primary vaginal carcinoma.

Brachytherapy plays a significant role in the management of cervical cancer, but the clinical significance of brachytherapy in the management of vaginal cancer remains to be defined. Thus, a single institutional experience in the treatment of primary invasive vaginal carcinoma was reviewed to define the role of brachytherapy. We retrospectively reviewed the charts of 36 patients with primary vaginal carcinoma who received definitive radiotherapy between 1992 and 2010. The treatment modalities included high-dose-rate intracavitary brachytherapy alone (HDR-ICBT; two patients), external beam radiation therapy alone (EBRT; 14 patients), a combination of EBRT and HDR-ICBT (10 patients), or high-dose-rate interstitial brachytherapy (HDR-ISBT; 10 patients). The median follow-up was 35.2 months. The 2-year local control rate (LCR), disease-free survival (DFS), and overall survival (OS) were 68.8%, 55.3% and 73.9%, respectively. The 2-year LCR for Stage I, II, III and IV was 100%, 87.5%, 51.5% and 0%, respectively (P = 0.007). In subgroup analysis consisting only of T2-T3 disease, the use of HDR-ISBT showed marginal significance for favorable 5-year LCR (88.9% vs 46.9%, P = 0.064). One patient each developed Grade 2 proctitis, Grade 2 cystitis, and a vaginal ulcer. We conclude that brachytherapy can play a central role in radiation therapy for primary vaginal cancer. Combining EBRT and HDR-ISBT for T2-T3 disease resulted in good local control.

SU-E-T-216: TPS QC Supporting Program by a Third-Party Evaluation Agency in Japan.

PURPOSE: To equalize the quality of radiation therapy in Japan by supporting quality control of radiation treatment planning system. METHODS: Center for Cancer Control and Information Service in National Cancer Center supports the QA-QC of the cancer core hospitals in Japan as a third-party evaluation agency. Recently, a program for assessing the quality of treatment planning system (TPS) began as a part of our QA-QC supporting activities. In this program, a questionnaire about TPS was sent to 45 prefectural cancer core hospitals in Japan. The object of this questionnaire is to assess the proper commissioning, implement and applications of TPSs. The contents of the questionnaire are as follows; 1) calculate MUs which deliver 1000 cGy to the point of SSD = 100 cm, 10 cm depth with field sizes ranging from 5×5 to 30 × 30 cm2 , and obtain doses at several depths for the calculated MUs, 2) calculate MUs which deliver 1000 cGy to the point of SSD = 100 cm, 10 cm depth for wedge fields whose angles are from 15 to 60 degrees, and obtain doses at several depths with the MUs, 3) calculate MU which deliver 1000 cGy to the point of STD = 100 cm, 10 cm depth with 10×10 cm2 field size and obtain doses at several depths with the MU. RESULTS: In this program, 179 beam data from 44 facilities were collected. Data were compared in terms of dose per MU, output factor, wedge factor and TMR. It was found that 90% of the data agreed within 2%. CONCLUSIONS: The quality of the treatment planning system was investigated through the questionnaire including the information of essential beam data. We compared 179 beam data in TPSs sent from 44 facilities and 90% of the data showed good agreement.

Adjuvant pelvic irradiation in patients with pathologic T2b carcinoma of the uterine cervix.

Patients with cervical cancer are subject to postoperative adjuvant therapy if the histopathologic examination reveals parametrial involvement. This study evaluated the patterns of failure in patients with pathologic parametrial invasion (pT2b) treated with adjuvant pelvic irradiation. Between April 1985 and March 1997, 45 patients with pT2b cervical cancer were treated with postoperative pelvic irradiation. The median age was 52 years. Preoperative clinical stages were stage Ib in 8 patients, IIa in 4, and IIb in 33. Twenty-three patients had lymph node metastasis. The median total dose of whole pelvic radiation therapy was 50 Gy. Occurrence of pelvic failure or distant metastasis according to the nodal status was examined. None of the 22 patients without lymph node metastasis developed distant metastasis. Among the 23 node-positive patients, 6 developed distant metastasis as an initial failure site. The 5-year overall survival of the entire group was 78%. The actuarial distant metastasis-free rates at 5 years were 73% and 100% for those with and without pelvic lymph node metastasis, respectively (P = 0.016). Results support previous evidence for chemoradiation in patients with pelvic lymph node metastasis. However, it appears that the role of systemic chemotherapy for node-negative pT2b patients is yet to be established.

Risk factors for massive hemoptysis after endobronchial brachytherapy in patients with tracheobronchial malignancies.

BACKGROUND: Massive and mostly fatal hemoptysis is a frequently reported morbidity after endobronchial brachytherapy (EBB) for tracheobronchial malignancies. However, to the authors' knowledge, it remains controversial whether this morbidity is related directly to EBB. To investigate whether massive hemoptysis is related to EBB, the authors retrospectively analyzed risk factors for massive hemoptysis after EBB. METHODS: Thirty-six patients (30 men and 6 women) with a mean age of 70 years underwent high-dose rate EBB for tracheobronchial malignancy using a cobolt-60 (Co-60) afterloading machine. EBB was performed as primary therapy in 6 patients and as salvage treatment for recurrent disease in 30 patients. EBB was delivered to the tracheal lesions in 15 patients and to the main bronchial lesions in 21 patients. EBB was combined with external beam radiation therapy (EBRT) in 24 patients, with laser photocoagulation in 3 patients, and with EBRT plus laser photocoagulation in 5 patients. The dose of EBRT delivered with the EBB ranged from 16-69 grays (Gy), with a mean dose of 37 Gy. RESULTS: At a mean follow-up of 18 months, 33 of the 36 patients had died. Eight of the 33 patients had no evidence of local disease at the time of death. Seven patients died of massive hemoptysis. The cumulative rate of massive hemoptysis was 29.4% at 2 years. According to univariate analysis, no statistically significant correlation with massive hemoptysis was observed for EBRT dose delivered in combination with EBB, EBB fractional and total doses, EBB length, and the sum of all the EBRT doses including that used for the initial treatment. Local failure or persistent malignancy (P = 0.033) and delivery of laser photocoagulation (P = 0.032) were found to be statistically significantly associated with massive hemoptysis. Direct contact between the EBB applicator and the tracheobronchial walls at the vicinity of the great vessels was observed in 16 patients and was found to be statistically significantly associated with massive hemoptysis (P = 0.003). In six patients, the applicator was in direct contact with two or more tracheobronchial walls at the vicinity of the great vessels; all these patients died of massive hemoptysis. CONCLUSIONS: Direct contact between the EBB applicator and the tracheobronchial walls at the vicinity of the great vessels was one of the significant risk factors for massive hemoptysis. To prevent massive hemoptysis, a specific spacer should be employed to maintain a safe distance between the applicator and the bronchial wall.

Genetics, experience, and host-plant preference in Eurosta solidaginis: implications for host shifts and speciation.

Host-associated mating is crucial in maintaining the partial reproductive isolation between the host races of Eurosta solidaginis (Diptera: Tephritidae), a fly that forms galls on Solidago altissima and S. gigantea. (We refer to flies reared from S. gigantea as gigantea flies and those reared from S. altissima as altissima flies.) We measured the host preference of males and females of both host races, F1 hybrids between the host races, F2, and backcrosses to both host races. Male and female altissima flies and female gigantea flies had high host fidelity, whereas male gigantea flies had low host fidelity. This result suggests that there may be gene flow between the host races due to nonassortative mating that occurs when male gigantea mate with altissima females on S. altissima. This indicates assortative-mating mechanisms in addition to host-associated mating are required to produce the partial reproductive isolation between the host races that has been observed. Nongenetic factors had no influence on host preference. Larval conditioning did not influence host preference: reciprocal F1 hybrids reared in S. altissima and S. gigantea both preferred S. gigantea. Adult experience had no impact on host preference: females preferred their natal host plant regardless of which host they encountered first as an adult. The hypothesis that maternal effects influence preferences was rejected because male and female flies did not show a consistent preference for the host plant of their mother. We also found no evidence that preference was a sex-linked trait because F1 and backcrosses to the host races with different combinations of X chromosomes from the two host races preferred S. gigantea. Our results indicate that host preference is not determined by a large number of genes because preference of hybrids did not correspond to the proportion of the genome derived from each host race. The strength of the ovipuncture preference for S. gigantea by gigantea females, the females of both reciprocal F1 hybrids, the backcross to gigantea, and F2s indicates that preference is inherited nonadditively at a limited number of loci. The F1 female hybrids, however, had a weaker host preference for S. gigantea than the pure gigantea host race, indicating that there may be incomplete dominance or modifier loci. Males had different host preference patterns than females, with individual male gigantea and male F1 hybrids usually exhibiting preference exclusively for S. gigantea or S. altissima. One hypothesis explaining the difference in host preference between males and females is that the same gene influences both female and male host preference, but it is a sex-influenced gene. Thus, males carrying the gene for S. gigantea preference have an intermediate host preference, whereas females have a strong host preference to S. gigantea. In summary, we found that the host preference that produces host-associated mating is inherited nonadditively at a relatively small number of loci on autosomal genes. This mode of inheritance meets the assumptions of models of sympatric speciation, indicating that the host races could have evolved in sympatry.

Blastic natural killer cell lymphoma arising from the mediastinum with terminal deoxynucleotidyl transferase expression.

Blastic natural killer (NK) cell lymphoma/leukemia is a relatively rare NK cell malignancy. We report the second case of blastic NK cell lymphoma arising from the mediastinum with an aggressive clinical course. The patient was a 63-year-old Japanese man with an anterior mediastinum tumor. The biopsy specimen showed diffuse proliferation of tumor cells with frequent mitotic figures and apoptotic bodies. Both angiocentric features and small foci of coagulative necrosis were found in this section. The tumor cells had medium to large nuclei with a fine chromatin pattern, inconspicuous nucleoli and scanty cytoplasm. The nuclear contour was oval to moderately irregular, showing slight pleomorphism as compared with typical lymphoblastic lymphoma. The tumor cells were positive for CD2, CD56 and terminal deoxynucleotidyl transferase, but negative for other T-cell antigens, B-cell antigens and myeloid markers. In situ hybridization for Epstein-Barr virus encoded small ribonucleic acid 1 was negative.

Target volume definition for upper abdominal irradiation using CT scans obtained during inhale and exhale phases.

PURPOSE: To evaluate the clinical utility of a treatment-planning technique involving the use of CT images obtained during both the static exhalation phase and static inhalation phase (two-phase planning). METHODS AND MATERIALS: Ten patients with pancreatic or liver tumors underwent CT scanning under static exhale and inhale conditions, after a period of mild ventilation. By setting image positions differently, we were able to treat the two-phase images as one dataset. Each gross tumor volume (GTV) was contoured separately and the mixed GTV was used for the two-phase treatment planning. Treatment plans were constructed to compare the two-phase plans with the plans constructed using static exhalation images. The shift of the center of the GTV and kidneys and the minimum dose of GTV were then calculated. RESULTS: The shift of the GTV ranged from 2.6 to 27. 3 mm and that of the kidneys from 2.2 to 24 mm. In some patients whose treatment was planned using exhalation planning, the minimum dose of GTV at inhalation was less than 90% of the isocenter dose. CONCLUSION: Two-phase planning is a simple technique that can visualize tumor and organ movement simultaneously using CT. It further defines adequate field margins around the tumor and prevents unexpected radiation exposure to critical organs. Routine use of this technique for upper abdominal irradiation is recommended.

Postoperative radiation therapy for stage IB-IIB carcinoma of the cervix with poor prognostic factors.

BACKGROUND: To investigate failure pattern and to evaluate the prognostic impact of lymph node metastasis in patients with cervical cancer treated with postoperative adjuvant pelvic irradiation. MATERIALS AND METHODS: Ninety-eight patients with FIGO IB to IIB cervical cancer were treated with radical hysterectomy, bilateral pelvic lymphadenectomy and postoperative radiation therapy. All the patients had at least one of the following pathologic risk factors for pelvic recurrence; 1) positive margins, 2) positive pelvic lymph nodes other than common iliac node, 3) deep stromal invasion more than 50% or parametrial invasion. RESULTS: The 5-year overall survival (OAS) rate for the entire patient group was 82%. Causes of the first failure were pelvic recurrence in 5 cases and distant metastasis in 15 cases. Fifteen of the 47 patients with positive pelvic lymph nodes developed distant metastasis, whereas distant metastasis was noted in only 1 of 51 patients without lymph node metastasis. The 5-year OAS rates for patients with and without pelvic lymph node metastasis were 76% and 89%, respectively (p = 0.018). CONCLUSION: Despite receiving postoperative pelvic irradiation, apparently lower survival was observed for node positive patients.

Treatment for pyothorax-associated lymphoma.

In eight patients with pyothorax-associated lymphoma (PAL), which resulted from artificial pneumothorax for the treatment of pulmonary tuberculosis, seven patients received radiotherapy and five showed no local recurrence. All four patients treated by primary chemotherapy had disease progression. Radiotherapy of 50 Gy with wide margins is recommended to treat PAL.

Radiotherapy for large hepatocellular carcinoma combined with transcatheter arterial embolization and percutaneous ethanol injection therapy.

This study was performed to determine the effect of radiotherapy (RT) combined with transcatheter arterial embolization (TAE) and percutaneous ethanol injection (PEI) on large HCC. Between 1988 and 1996, 102 patients with unresectable, biopsy proven HCC underwent uniform pretreatment assessment followed by TAE and PEI. Of the 102 patients, 68 (67%) had more than 2 lesions in the liver, and the largest tumor sizes in each patient ranged from 3 to 8 cm in diameter. Immediately after TAE and PEI, external beam RT (36 to 70 Gy) was administered to the largest tumors only in 44 patients. The cause-specific 5-year survival rate for all patients was 39.9%. The 3-year survival rate of the RT group was better than that of the no RT group (81.1% vs. 54.6%). The cumulative local control rates of the largest treated tumors were 53.2% in the RT group and 32.7% in the no RT, respectively (p=0.006). When the survival rate was compared between patients with and without local control in the RT group, that of patients with local control was significantly better than that with local recurrences (p=0.048). No deaths or major treatment related complications occurred. RT combined with TAE and PEI did not clearly show improvement of the survival, however, it effectively controlled large HCC, and demonstrated minimal toxicity. This treatment may represent therapeutic option for some patients with unresectable large HCC.

[Easy graphical display of beam directions in three-dimensional converging radiation therapy: proposal for a radiation map].

In stereotactic radiosurgery, non-coplanar isocentric beams are employed to concentrate the dose distribution on the planning target volume (PTV). However, the directions of incident beams must be determined with great care by using a digitally reconstructed beam's eye view (BEV) to prevent the irradiation of organs at risk. We present a new method of 2-dimensional graphical representation (radiation map) to facilitate the understanding of 3-dimensional relationships between incident beams and critical organs. After determining the isocenter and beam diameter, beam directions and critical organs are projected onto the imaginary sphere centered on the isocenter. The coordinate of the beam directions and the organs at risk can be expressed by latitude and longitude on the sphere. The contours of the organs at risk are displayed with a margin of the the radius of the radiation beam. Mirror images of the critical organs are also displayed to prevent irradiation by the opposing beams. The radiation map could be produced within 5 minutes using a workstation. Radiation maps, like DVH, will be very useful in the evaluation of radiation treatment planning.

[Bleomycin, adriamycin, cyclophosphamide, vincristine, deacadron, etoposide (BACOD-E) chemotherapy for the treatment of non-Hodgkin's lymphoma: long-term survival rate and complications].

This study was performed to analyze the effect of Bleomycin, Adriamycin, Cyclophosphamide, Vincristine, Deacadron, Etoposide (BACOD-E) chemotherapy for patients with non-Hodgkin's lymphoma. Seventy patients with non-Hodgkin's lymphoma (stage I: 15, stage II: 23, stage III: 20, and stage IV: 12) were treated at the Department of Radiology, Chiba University Hospital, between 1987 and 1995. The response rates for treatment were CR: 63%, PR: 35%, and PD: 2%. The overall disease-free 5-year survival rate was 54%, and those for each stage were as follows: stage I: 78%, stage II: 55%, stage III: 51%, and stage IV: 28%. There were no significant differences between patients with and without B symptoms, or those with and without elevated LDH levels. Treatment associated deaths occurred in six patients. Two patients died due to side effects of chemotherapy during treatment, and one patient due to leukemia 2 years and 5 months after treatment. One patient died due to radiation pneumonitis, one patient due to heart failure, and one patient due to an unknown reason one month after treatment. This chemotherapy may be useful for patients with advanced disease or unfavorable prognostic factors such as B symptoms or elevated LDH. Moreover, the addition of radiation therapy may prolong survival.

Non-Hodgkin's lymphoma presenting with adrenal insufficiency and hypothyroidism: an autopsy case report.

A 55-year-old male presented with an initial manifestation of primary adrenal insufficiency, hypothyroidism. Computed tomography scans showed enlarged bilateral adrenal glands and thyroid. A pathological diagnosis of diffuse large cell, B cell lymphoma was made by a needle biopsy of the adrenal gland. He was treated with combination chemotherapy and adrenal and thyroid hormone replacement. The lymphoma subsequently involved the central nervous system. He died of pneumonia 8 months after the presentation of the first symptom. The postmortem examination demonstrated a complete regression of lymphoma in the bilateral adrenal glands and thyroid. This is an extremely rare case of coexistent lymphoma of the adrenal glands and the thyroid presenting with adrenal failure and hypothyroidism.

High dose rate brachytherapy for carcinoma of the cervix: risk factors for late rectal complications.

PURPOSE: To determine the incidence of late rectal complications in patients treated with high dose rate brachytherapy for FIGO Stage IIB, IIIB carcinoma of the uterine cervix, and to evaluate the treatment factors associated with an increased probability of treatment complications. METHODS AND MATERIALS: Records of 100 patients with FIGO IIB and IIIB cervical carcinoma treated with definitive irradiation using high dose rate intracavitary brachytherapy (HDR-ICR) between 1977 and 1994 were retrospectively reviewed. For each HDR-ICR session, 6-Gy isodose volume was reconstructed retrospectively and the relationship between probability of late rectal complications and several treatment factors, including a specific point dose and parameters representing isodose volume, were examined. Statistical analyses were performed to determine the treatment factors predictive of late rectal complications. RESULTS: Of patients treated for both stages, 33% and 38% had experienced moderate to severe (Grade 2-4) complications at 3 and 5 years, respectively. Mean value of depth (D) of 6-Gy isodose volume in HDR-ICR in patients with and without complication were 51 mm and 46 mm, respectively (p = 0.0070). A significant difference was noted in complication rate between patients with D > 51 mm and D < or = 51 mm (p = 0.0023). Cumulative Point S (2 cm dorsal from the midpoint of the ovoid sources) dose (p = 0.044), and single or total point S dose by HDR-ICR (p = 0.019, each) were significantly higher in patients who developed complication, whereas these factors did not significantly affect the probability of pelvic control. Multivariate analysis revealed that D was the independent predictor for the endpoint of actuarial complication rate (p = 0.047). No significant difference was noted in the product of L, D, and W value (L x D x W) between patients with less than Grade 2 rectal complication and those with Grade 2-4. CONCLUSION: Depth of 6-Gy isodose volume determined three dimensionally (3D) has the predictive value of late rectal complications. This suggests that the shape of the high dose area in HDR-ICR influences the incidence of late rectal complications regardless of its volume.

Squamous cell carcinoma of the maxillary sinus treated with radiation therapy and conservative surgery.

BACKGROUND: For patients with squamous cell carcinoma of the maxillary sinus, combined modality treatment is usually employed, involving radiation and en bloc radical surgery. In this study, local control was analyzed retrospectively in patients who underwent less aggressive piecemeal surgery. METHODS: Of the 37 patients irradiated between 1973 and 1992, 62% were classified as having T4 lesions. Thirty-two patients underwent surgery and radiation therapy; conventional fractionation radiation therapy was used in most cases. Thirty of these patients underwent piecemeal debulking of their tumors and simultaneous radiation therapy. RESULTS: Local recurrence free survival at 5 years was 59%, and orbital exenteration was performed on only 1 patient. T classification, the number of operations, and the presence of macroscopic residual disease each had a statistically significant impact on local recurrence. For the patients with macroscopic residual disease, more than 58 gray administered in conventional fractionation appeared to be necessary to improve local control. CONCLUSIONS: Combined with radiation therapy, conservative surgery with piecemeal debulking was an effective method of treatment for the patients in this study.

Local control of piriform sinus cancer treated by radiation therapy alone.

Local control rate by radical radiation therapy was analyzed in 33 patients with a piriform sinus cancer. Twenty-five patients (76%) were in stage T3 + T4. Local recurrence-free survival at 3 years was 49% in T1 + T2 and 25% in T3 + T4 (p = 0.01). In T1 + T2 lesions, a biologically effective dose for an acute reaction over 80 Gy and total treatment time less than 70 days appeared to improve local control. In T3 + T4 lesions, good radiation response assessed by the regaining of laryngeal mobility affected local control favorably. An esophageal involvement and destruction of the laryngeal cartilage as well as soft tissue extension precluded the possibility of local control by radiation therapy alone. In addition to the T-stage, other tumor factors should also be considered for predicting local control with radiation therapy.