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Background Aberrant activation of Wnt/β-catenin signaling is commonly found in colorectal cancers (CRCs) and is the prime event involved in the rapid proliferation of tumor cells in patients with advanced CRC. However, the limited effects of current therapeutics are unsatisfying, which highlights the importance of novel interventions in CRC chemo-treatment. We designed a highly potent small-molecule inhibitor CWP232228, which antagonizes binding of β-catenin to T cell factor in the nucleus. Thus, the present study aimed to explore the possibility of a selective small molecule β-catenin inhibitor, CWP232228, as a potential therapeutic drug in the treatment of CRCs. Methods We observed that CWP232228 at a concentration of as low as 1.0 μm induced significant cytotoxic effectsand apoptosis in HCT116. Immunoblot analysis showed that CWP232228 treatment increased the release of cytochrome C, which led to the activation of apical (caspase-9) and effector caspases (caspase-7 and -3) resulting in the increased cleavage of PARP. Results In addition, we observed that CWP232228 caused cell cycle arrest via attenuating the expressions of cyclin D2, D3, and survivin. Thus, we validated decreased expressions of Wnt/β-catenin targeted cell cycle progression regulators, aurora kinase A, c-Myc, cyclin D1, and microphthalmia-associated transcription factor. Conclusions We confirmed that CWP232228 targets β-catenin via decreased promoter activities, nuclear expressions of β-catenin. Lastly, we found CWP232228 also inhibited growth of xenografted colon cancer cells in NOD-scid IL2Rgammanull mice. Collectively, results in the current study showed a possibility for CWP232228 as a potential therapeutic drug in CRCs. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Purpose: To examine the long-term outcome of Stage I, II, and III patients treated with curative radiotherapy for Hodgkin’s disease at the University of Minnesota Hospital, with particular focus on long-term treatment-related complications and the need for long-term surveillance after treatment. Methods and Materials: A total of 210 Stage I, II, and III patients (98 female, 112 male) treated at the University of Minnesota since 1970 were included in this study. All patients were laparotomy staged. Between 1970 and 1974, 35 high-risk patients (i.e., patients with large mediastinal mass, and/or hilar disease, and/or splenic involvement) and 40 low-risk patients were treated with standard field radiotherapy. From 1975 on, 67 high-risk patients received radical radiotherapy because of poor outcomes with standard radiotherapy, and 68 low-risk patients received standard radiotherapy. Salvage chemotherapy was given to 62 patients who recurred. Median follow-up for all patients was 15.6 years (range 0.35–26.5 years). Long-term complications after treatment were assessed using standardized incidence ratios (SIR) and mortality ratios (SMR), with particular focus on cardiac complications and secondary malignancies. Results: By study end, 70% of the patients are alive and 70% had never recurred. Complications included 33 second malignancies and 75 cardiovascular events. Patients treated for Hodgkin’s disease had about 7 times the risk of dying from cardiac problems (SMR = 7.2) and 10 times the risk of dying from a second malignancy (SMR = 10.3) compared to the general population. In terms of absolute risk, Hodgkin’s disease would cause seven additional deaths from secondary malignancies per year among 1000 patients and four additional deaths from cardiac problems. Conclusion: Hodgkin’s disease patients treated successfully with radiotherapy are at an increased risk for developing long-term treatment-related cardiac disease and/or second malignancies. Careful monitoring of these patients is essential to manage morbidity and minimize mortality from these complications. Suggestions for the establishment of worldwide surveillance programs for these patients are proposed.

Carcinoma in situ of the glottic larynx is a rare malignancy, comprising only 1% to 2% of laryngeal biopsy. The management of these lesions remains controversial. In this article, the authors present results and analysis of the management of 20 patients having these lesions treated by radiotherapy. A total of 20 patients who had carcinoma in situ of the glottis were treated with curative intent with radiotherapy at the Veterans Administration Medical Center, Minneapolis, Minnesota, U.S.A. from November 1972 through March 1993. Before radiotherapy, eight patients had only biopsies of the glottic larynx, five had one stripping procedure, and seven patients had two or three stripping procedures. Of the 20 patients, 19 are available for retrospective analysis, with a minimum follow-up of 4 years and a median follow-up of 7.3 years. Treatment was given to all patients by megavoltage units (cobalt 60, 2; 4-mV linear accelerator, 18). Patients were treated using bilateral opposed wedged 6-cm x 6-cm fields, with a dose of 1.75 Gy per fraction to a total median dose of 68.4 Gy in 40 fractions over 56 elapsed treatment days. The Kaplan-Meier method was used for survival analysis. The 4-year disease-free survival was 95% after irradiation. The actuarial disease-free survival for 5 and 10 years was 95%. Surgical salvage failed in one patient who had a laryngectomy for recurrent invasive squamous cell carcinoma at 34 months after radiotherapy. Two patients developed severe shortness of breath because of laryngeal edema, which required tracheostomy. Sixteen patients reported subjective significant improvement of their voice quality, and four reported no change. Radiotherapy is an excellent choice for patients who have recurrent carcinoma in situ after undergoing stripping procedures or for those patients who live too far from a medical facility to allow close follow-up and repetitive surgical procedures. These results are comparable to those of other investigators who used radiotherapy with higher dose per fraction.

Changes in blood flow in rat liver by local heating of the left lateral lobe were studied. A small portion of the left lateral lobe was heated by capacitive application of 8 MHz RF with a 2 cm diameter electrode on the ventral surface and a 7 cm diameter electrode on the dorsal surface of upper body of rats. A circular area with diameter of about 1 cm in the left lateral lobe could be heated to relatively homogeneous temperatures. The temperature in the remaining part of the left lateral lobe as well as in the rest of liver tissue also increased to varying degrees during the local heating of the left lateral lobe. When heated at 39 degrees or 41 degrees C for 45 min, the arterial blood flow, as measured with the radioactive microsphere method, in the heated area, and that in the rest of the left lateral lobe as well as in the whole liver initially increased during the first 30 min and then started to decline. During a 45 min heating at 43 degrees C, the arterial blood flow in the heated area slightly increased for 15 min and then significantly decreased thereafter. The arterial blood flow in the rest of the liver tissue also increased during the first 15 min of a 43 degrees C heating and began to decline. Histological examination of liver heated at 43 degrees C for 30 min showed wedge-shaped infarctions early on, which appeared to be organized into scar tissue by 7 days after heating. The concentrations of glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH) in the serum significantly increased 2 hr after heating the small portion of the left lateral lobe at 43 degrees C for 30 min and began to decrease thereafter although the serum level of GOT and GPT was still greater than the control value 24 hr after heating.

Toxic leukoencephalopathy syndromes are rare disorders of cerebral injury characterized by changes in the white matter and accompanying neurologic dysfunction. They have been reported in association with a variety of clinical etiologies, most commonly including severe hypertension, cranial irradiation, and environmental toxins. However, they have also been described in conjunction with immunosuppressive and chemotherapeutic agents. There has been one case of fatal leukoencephalopathy reported following CHOP chemotherapy for non-Hodgkin lymphoma. We report a second case of fatal necrotizing leukoencephalopathy following the administration of CHOP chemotherapy.

A patient is diagnosed with an unknown primary of the head and neck when metastatic disease is present in the cervical lymph node or nodes and no primary lesion is detected by thorough physical examination, directed biopsies of suspicious or most likely primary sites, and imaging studies. The optimal management of patients who have this syndrome is still unclear and controversial. We report our results and analysis of the management of 24 patients with this syndrome. From 1976 through 1992, 24 patients who had metastatic squamous cell carcinoma in the cervical lymph nodes were seen in our medical center. A thorough search did not detect a primary lesion in any of them. Patients underwent radical neck dissection of the involved neck; 23 had unilateral and I had bilateral neck disease. Postoperative radiotherapy was delivered to both sides of the neck and to the potential primary mucosal and submucosal sites. The relation between clinical N stage, histologic findings of numerous involved lymph nodes, presence of extracapsular tumor extension, and survival were statistically analyzed. The Kaplan-Meier method was used for the survival analysis. The p values of log-rank test for the comparison of the two groups 1) N1 and N2 versus N3, and 2) presence of extracapsular tumor extension versus its absence are less than 0.005, with extracapsular tumor extension versus nonextracapsular tumor extension slightly smaller. The 5- and 10-year disease-free survival rate for the entire group was 54.2% (70.5% for N1 and N2, and 14.2% for N3). Three patients had locoregional failure, two in the primary sites, one in the nasopharynx, and the other in the oropharynx (the latter also had recurrent disease in the undissected neck). In 8 patients, distant metastases developed 7 to 38 months after radiotherapy. All 11 patients (45.8%) who had recurrent disease had advanced clinical N stage, microscopic findings of numerous involved lymph nodes, and prominent extracapsular tumor extension to the surrounding soft tissue and blood vessels. The high incidence of distant metastases shortly after treatment suggests a hematogenous spread before treatment in patients who had extensive nodal and extranodal disease. Our long-term disease-free survival beyond ten years seems to indicate combined treatment modalities, including radical neck dissection with postoperative radiotherapy of the neck, and the potential primary site in patients with N2 and N3 disease (our N1 group is too small for analysis). Further improvement of cure rate can be expected in the future with early detection and treatment.

The usefulness of precooling subcutaneous tissue in the hyperthermic treatment of deep-seated human tumors with capacitive application of radio-frequency (RF) was investigated. A capacitive hyperthermia unit operated at 8 MHz of radiofrequency was used to heat deep-seated human tumors. The electrode surfaces were covered with flexible vinyl sheets and the space between the electrode and the vinyl sheets perfused with 0.4% saline. The temperature of the saline was controlled by circulating the saline through built-in heat exchangers. The depth of heating was controlled by pairing electrodes of different diameters. When subcutaneous fat was less than 1 cm thick, various deep-seated tumors could be heated to a therapeutic temperature without significant discomfort in the subcutaneous tissue as long as the skin was properly cooled with the cold saline bolus. However, the same cooling method could not prevent the occurrence of pain in subcutaneous tissue in obese patients. The pain usually developed when the temperature of subcutaneous fat 1-2 cm below the skin surface exceeded 42 degrees C. We observed that cooling the human skin surface with 10 degrees C bolus for 20 min could substantially lower the temperature of fat as deep as 2.0-2.5 cm. Therefore, when the subcutaneous tissue was precooled with 10 degrees C saline for 20 min or longer before heating, it was possible to prevent successfully the overheating of subcutaneous fat as thick as 2.0-2.5 cm and to raise the temperature of deep-seated tumors to therapeutic levels.

Between 1970 and 1983, 179 patients with pathologically staged IA, IIA, and IIIA Hodgkin's disease were treated with curative radiotherapy. From 1970 to 1974, patients were treated with standard extended or total nodal field irradiation (Treatment Group 1). Since 1975, because of the high prevalence of recurrences in patients with large mediastinal mass and/or hilar disease and/or splenic involvement (LMM &/or H+ &/or S+), treatment was modified to include low-dose lung irradiation within the mantle field for those patients with LMM &/or H+ and low-dose liver irradiation within the infradiaphragmatic field for patients with S+ (radical XRT). Patients who did not have those characteristics were treated with standard radiotherapy (standard XRT). A total of 122 patients were treated from 1975 to 1983 (Treatment Group 2), of whom 61 received radical XRT and 61 received standard XRT. An analysis was done to evaluate whether the progressive-improvement in outcome since 1970 at the University of Minnesota Hospital resulted from the contribution of modified treatment or from progressive improvement in treatment overall. There was a statistical improvement in recurrence-free survival (RFS) in Treatment Group 2 (Tr Gr 2) compared to Treatment Group 1 (Tr Gr 1), with 10-year RFS of 80% versus 57% (p less than 0.001 for time to event). The improvement in RFS was attributed to treatment modification consisting of radical XRT for those patients with LMM &/or S+. There was no change in RFS for those patients without LMM &/or H+ &/or S+ who were treated in Tr Gr 1 and Tr Gr 2, with 10-year RFS of 78% versus 86% (p = 0.29), respectively. However, treatment results for patients with LMM &/or H+ &/or S+ improved considerably in the radical XRT group. Comparing standard versus radical XRT, 10-year RFS was 36% versus 78% (p = 0.001), and 10-year OS was 72% versus 92% (p = 0.034). Patterns of relapse also changed for patients with LMM &/or H+ &/or S+ who were treated with radical XRT. Rather than showing a high frequency of intrathoracic recurrence as was seen in those patients with LMM &/or H+ &/or S+ after standard XRT, the relapse pattern was similar to patients without LMM &/or H+ &/or S+. Salvage treatment was well tolerated for patients who failed after radical XRT. Delayed, life-threatening effects, such as pulmonary and cardiovascular complications and SMN, were equivalent for patients in Tr Gr 1 versus 2, and for those who received standard and radical XRT.(ABSTRACT TRUNCATED AT 400 WORDS)

Since Hodgkin's disease patients with large mediastinal masses frequently relapse in the intrathoracic area after regular mantle field irradiation, the feasibility and utility of low dose lung irradiation as an initial part of the supradiaphragmatic field was examined. Fifteen newly diagnosed patients with Hodgkin's disease and large mediastinal masses were treated with 1000–2000 rad to the lung as a part of extended field radiotherapy. All patients received radiotherapy aloe. Results of treatment were compared with those in 20 similar patients who were treated only with extended field irradiation. With a minimum follow-up of 24 months, only 2 patients (13%) who received lung irradiation have recurred and only one of these recurred in the Lung. In contrast 15 (79%) of the 19 complete responders who were treated without lung irradiation had relapsed by 24 months, 9 in the intrathoracic region. Recurrence-free survival was significantly longer in patients who received Lung irradiation. No increased frequency in serious complications has been experienced to date with low dose whole lung irradiation, compared with regular mantle field treatment. This study suggests that lung irradiation may be a feasible alternative to adjuvant combination chemotherapy when treating patients with Hodgkin's disease and large mediastinal masses.

The cytotoxicity of 5-thio-D-glucose (5-TG) and misonidazole (MISO) on hypoxic cells in vitro was compared, and the combined effect of these two compounds was investigated. The cytotoxicity of 5-TG on hypoxic SCK mammary carcinoma cells of mice was markedly greater than that of MISO. However, MISO was more toxic than was 5-TG to P815-X2 mastocytoma cells of mice. The elevation of temperature from 37.5 degrees C to 40.0 degrees C during incubation with drugs greatly enhanced the cell death. The thermal enhancement of cytotoxicity of 5-TG to mastocytoma cells appeared to be greater than that of MISO. Preliminary studies indicated that the combined effect of 5-TG and MISO is additive, suggesting the intracellular targets or cytocidal mechanisms of these two compounds may be different.

In 1970, a policy for the treatment of Stage IIIA Hodgkin's disease patients at the University of Minnesota, which included complete staging procedures and extended field or total nodal irradiation (TNI), was introduced. Evaluation of the results 4 years later indicated that certain patients, especially those with large mediastinal masses and/or hilar disease, or who were spleen positive, were having higher recurrence rates than patients without these characteristics. In 1974, a new approach to treatment for patients with large mediastinal masses or spleen positive disease was instituted which involved treating the whole lung or hemi lung in patients with large mediastinal masses and/or hilar disease, and the liver in patients who had positive spleens. The results of this treatment modification are reported in this study. Long term follow-up reveals that this approach has led to a recurrence free survival and overall survival similar to that noted in patients treated with combined modality treatment without the obvious risk of subsequent leukemia related to combination chemotherapy and radiotherapy. In addition, the complications of the treatment are tolerable and do not demonstrate an increase over patients not treated in this manner. Radical radiation therapy is recommended as a treatment of choice for Stage IA, IIA, and IIIA patients with or without splenic involvement, and with or without hilar disease and/or large mediastinal masses with appropriate radiation field modification to adjust for disease extent.

Nineteen patients with localized non-Hodgkin's lymphoma large cell type classified by the international formulation in group D (5) and group G (14) were treated with extended field radiation therapy. These patients have been followed for 168 months with range from 12 to 168 months from initiation of treatment. In G category of the formulation, the overall survival is 83 per cent at 5 and 10 years and recurrence-free survival is 75 per cent at 10 years. Sixteen of the patients were stage I and three were stage II. Two patients died without evidence of recurrence. Four patients recurred and two of these died of disease. Thirteen of the 19 patients are alive and recurrence free. Bulk of disease had no apparent influence on the response to irradiation. We believe that the early pathological stage large cell lymphoma of the G and D type international formulation are appropriate candidates for radical radiation therapy and benefit from this approach to treatment.

The thermal profile was investigated in agar phantoms and in human tumors heated capacitively with 8 MHz RF. Deep and homogeneous heating could be achieved in a large homogeneous phantom of 25 cm diameter and 24 cm thick when heated with a pair of 25 cm diameter electrodes, coupled to both bases of the phantom. When the size of the two electrodes was not the same, the region near the smaller electrode was preferentially heated. It was, therefore, possible to control the depth of heating by choosing properly sized electrodes. Therapeutic temperature (greater than 42 degrees C) could be obtained in 7 out of 9 small, as well as, bulky superficial human tumors as large as 8 X 8 X 10 cm. Indications are that heating of some deep-seated human tumors might be achieved by the capacitive method, provided that subcutaneous fat layer is cooled by temperature controlled bolus and large electrodes are used. The effect of the anatomical structure on the power deposition in the human body during capacitive heating should be further investigated.

In an attempt to reduce the incidence of hypothyroidism following irradiation of the neck, we administered oral L-thyroxine in doses sufficient to suppress serum TSH to 20 patients receiving radiation therapy for Hodgkin's disease or other lymphomas. L-thyroxine was discontinued when radiation therapy was completed. Twenty similar patients who did not receive L-thyroxine during radiation therapy served as a control group. After a mean follow-up period of 33 months, seven patients (35%) in the L-thyroxine group developed elevation of serum TSH and were started on chronic L-thyroxine therapy. In the control group, after mean follow-up of 19 months, five patients (25%) developed elevation of TSH and were started on chronic L-thyroxine. We conclude that suppression of serum TSH during neck irradiation does not prevent subsequent thyroid dysfunction.

For patients undergoing extended and inverted Y field irradiation for the treatment of Hodgkin's disease, it is desirable to know the ovary and fetus dose accurately. Using a phantom loaded with thermoluminescent LiF dosimeters, doses as a function of distance from the edge of the field were measured for typical mantle, periaortic and inverted Y fields. In addition, ovarian dose for situation (1) ovaries located at midline behind uterus, and (2) ovaries displaced bilaterally to the iliac wings were measured and compared. Our results show that in situation (1) the dose is higher by a factor of 3 as opposed to situation (2). In addition, we show that the use of additional blocking to shield the patient from collimator leakage reduces the fetal dose significantly for mantle field irradiation. Our results indicate that Clarkson's algorithm can be applied with reasonable accuracy to estimate doses for points well outside the irradiated volume.