Pyrimidine-2,4-dione targets STAT3 signaling pathway to induce cytotoxicity in hepatocellular carcinoma cells.

Signal transducer and activator of transcription 3 (STAT3) is a tumorigenic transcription factor that is persistently activated in various human cancers including hepatocellular carcinoma (HCC). Therefore, STAT3 is considered as a prominent target to counteract the uncontrolled proliferation of cancer cells. In the present report, pyrimidine-2,4-diones (N-methyluracil derivatives) (MNK1-MNK14) were synthesized in an ionic liquid (BMIm PF6) medium employing a ligand-free Suzuki-Miyaura cross-coupling process. Among the 14 derivatives, compound MNK8 showed good cytotoxicity towards both the tested cell lines and did not display a toxic effect against normal hepatocytes (LO2). MNK8 significantly increased the Sub-G1 cell count in both cell lines and the cytotoxic effect of MNK8 was found to be mediated through the suppression of constitutive phosphorylation of STAT3Y705. It also decreased the DNA interaction ability of nuclear STAT3 in HCC cells. MNK8 downregulated the levels of apoptosis-related proteins (such as Bcl-2, cyclin D1, survivin) and increased cleaved caspase-3 inferring the apoptogenic effect of MNK8. It also reduced the CXCL12-triggered cell migration and invasion in in vitro assay systems. Overall, MNK8 has been demonstrated as a new inhibitor of STAT3 signaling cascade in HCC cells.

Tympanoplasty with and without cortical mastoidectomy - a comparative study.

Perfimttion of the tympanic membrane is nature's may of maintaining the middle far vntilation under the pressure of inflammatory process in the tempanomastoid cleft. An attempt at reconstruction with the possibility of infection lurking in and around the mastoid air cells may seem futile. Vow the quntinn arises as to whether a cortical Mastoidectomy is essential before an attempt at reconstruction is made. Our experience with one hundred and twenty patients is presented here. Our study shovn that conicul mastoidectomy does not signifieantly improve the results in well-selected ears.

Early-stage breast cancer: local control after conservative surgery and radiation therapy with immediate interstitial boost.

Two hundred forty-five women (250 breasts) with early-stage breast cancer were treated between June 1982 and June 1990 with lumpectomy, immediate (boost) interstitial iridium-192 to 15-20 Gy, and external-beam irradiation to the entire breast to 45-50 Gy. There were 123 stage I cancers (T1N0M0), 123 stage II cancers (36 T1N1, 50 T2N0, 33 T2N1, four T3N0), and four stage III cancers (two T2N2, two T3N1). At a median follow-up of 69 months (range, 26-122 months), there were 14 recurrences in the treated breasts. Four were at the site of primary disease, eight were in other quadrants, and two were in both. With immediate interstitial boost, the 11-year actuarial recurrence rate in the breast is 7.7% and the recurrence rate at the site of primary disease is 3.2%.

Prostate cancer: results of external irradiation.

From 1975 to 1982, 205 patients with local prostate cancer were treated at the radiation oncology department, the University of Kansas Medical Center, Kansas City, Kansas. Patients' median age was 73 years. All of the patients were staged according to American Urologic staging criteria. Twenty-eight patients had stage A2 cancer, 91 patients had stage B cancer, and 86 patients had stage C cancer. All patients were treated using megavoltage radiation (dosage range: 6000 cGy to 7100 cGy). The follow-up period ranged from a minimum of 8 years to a maximum of 15 years (median: 9.4 years). The clinical local control was 96% for stage A2, 94% for stage B, and 90% for stage C disease. The overall and disease-free survival rates were 71% and 60%, respectively. Fourteen patients developed moderate complications with one patient (0.5%) requiring surgical intervention. The local control and survival rates reported in this study are comparable with surgical results, suggesting that external beam irradiation in prostate cancer is safe and effective.

Management of advanced squamous cell carcinomas of the maxillary sinus.

From 1970 to 1988, 41 cases of advanced maxillary sinus cancers were treated at the University of Kansas Medical Center. Local control for the 37 evaluable patients was achieved in 21 (57%). Local control by radiation therapy alone was achieved in ten of 19 (53%) patients compared with eight of 14 (57%) treated with a combination of surgery and radiation therapy. A dose greater than 6500 cGy correlated with better local control in patients treated with radiation therapy alone. Neck node failure occurred in three of 35 (8%) patients when not electively treated. Neck metastasis either at presentation or at a later stage reduced survival. The overall absolute survival for the entire group at 5 years was 35%. A combination of preoperative radiation therapy and surgery is recommended for patients with advanced-stage maxillary sinus cancer. Radiation therapy is an equally good alternative for those who are not surgical candidates or refuse surgery.

Testicular neoplasms: seminoma.

From 1969 to 1984, 58 patients with a diagnosis of testicular seminoma were seen and treated at the University of Kansas Medical Center. The median age was 34 years (range of 20 to 62 years). The American Joint Committee on Cancer Staging System was followed: stage I (34 patients); stage II (6); stage III (8); and stage IV (10). Forty-two patients had typical seminoma, and 16 had anaplastic histology. Nine patients had elevated B subunit of human chorionic gonadotropin, and nine had a history of cryptorchidism. Fifty-six patients received radiation treatment, and seven received chemotherapy with or without radiation. The median follow-up was 7 years (range 3 to 16 years). The overall disease-free (absolute) survival according to stage was: stage I, 91% (100%); stage II, 66% (80%); stage III, 75% (85%); and stage IV, 50% (50%). There were no late complications. The survival for patients with anaplastic histology or with elevated B subunit of human chorionic gonadotropin was not significantly different from that of typical seminoma.

Dosimetric analysis in brachytherapy of carcinoma of the cervix.

Brachytherapy plays an essential role in the definitive radiation treatment of cervical carcinoma. The dosimetry of intracavitary irradiation is complex in that the optimum doses that can be delivered are dictated not only by the volume and extent of tumor but also by the close vicinity of dose-limiting structures, such as the small and large intestines, rectum, and bladder. To facilitate understanding of the relationships between the various dosimetric parameters involved, a retrospective analysis of 50 randomly chosen intracavitary insertions with Cesium-137 in 41 patients performed at our institution between 1975 and 1985 was carried out. All 50 cases utilized Fletcher-Suit-Delcos applicators and only the insertions using three sources in the tandem and one in each of the ovoids were included in this analysis. Using the AP and lateral radiographs and the lymphatic trapezoid, the reference points were obtained and transferred digitally to the treatment planning computer, and computerized dosimetry performed. In addition to the specified reference points, points were added and modified to obtain more complete information. The doses at the specified points were normalized to the average dose at AT, a reference point 2 cm superior to external os and 2 cm lateral to the tandem, and expressed as a percentage. It was noted that the average dose at the closest bladder point was 103 +/- 41% of the dose at AT, the maximum rectal dose 77 +/- 29% of the dose at AT and the maximum small bowel dose 65 +/- 16% of that at AT. The analysis of percent contribution of various sources to different reference points revealed that the dose to point AT was equally contributed to by all sources; bladder and rectal doses were mainly contributed to by the lowermost uterine and ovoid sources. Our analysis may provide a model for optimizing brachytherapy in cervical carcinoma.

Treatment options in early breast cancer.

Conservative management of early breast cancer with limited surgical excision and radiotherapy is now being accepted as a viable alternative to mutilating surgical procedures. In this paper, the major steps in the historical development of conservative management are traced, and the results of the current randomized trials are summarized. An innovative method used at the University of Kansas Medical Center delivers a "boost" dose to the tumor bed with interstitial Ir-192 immediately following resection of the primary tumor mass. The results obtained in terms of local control and cosmesis with this technique are presented, and the current state of the art is discussed.

Primary orbital lymphomas.

Between 1950 and 1982, seventeen patients with primary orbital lymphoma were treated at the University of Kansas Medical Center. There were 10 males and 7 females with a median age of 61 years. Four patients had bilateral disease, seven patients had disease involving the conjunctiva, and in ten patients, the disease involved paraocular structures. Fourteen patients received radiation with a median dose of 3500 cGy (range 2250 cGy to 4250 cGy) given in about 3 1/2 to 5 weeks. Median follow-up was 10 years (range 5 to 31 years). Local control was 100% and 5-year survival was 76%. Three patients are living with no evidence of lymphoma; three patients died from progression of the disease, and others died from unrelated causes. Radiation treatment for localized primary orbital lymphomas appears to be the primary treatment of choice.

Cosmetic results in early breast cancer treated with lumpectomy, peri-operative interstitial irradiation, and external beam radiation.

Patients with operable breast cancer were treated at the University of Kansas Medical Center with lumpectomy, peri-operative interstitial Iridium, and external beam radiotherapy, and concomitant adjuvant chemotherapy in a majority of node positive cases. Examination of the cosmetic results in 85 breasts followed for at least 2 years, at a median of 41 months revealed 20% to be excellent, 44% to be very good, 24% good, 9% fair, and 4% to have poor results. In this paper cosmesis is analyzed with reference to the size of the primary, its location, age of the patient, whether the patient received adjuvant chemotherapy, and whether the regional nodes were treated. In this group of patients, the size and the site of the primary, patient's age, and whether adjuvant chemotherapy was administered or not, did not adversely affect the aesthetic outcome. Treatment of the regional nodes gave a worse mean cosmetic score compared to the group in whom only the breast was treated (37.51 vs. 58.98 respectively, p less than 0.001). Among the 11 patients with fair/poor cosmesis, all had regional nodal treatment, 7/11 had inner quadrant lesions, and 7/11 had lesions greater than T1. Further follow-up and accrual would be needed to confirm our results and affirm if other factors would change.

Perioperative interstitial irradiation in the conservative management of early breast cancer.

Conservation of the breast in early breast cancer with limited resection and radiation is proving to be as effective as modified radical mastectomy in survival and in loco-regional control. Management at the University of Kansas Medical Center consists of an interstitial implant at the time of lumpectomy to facilitate perioperative irradiation with Iridium-192 to the tumor bed. An axillary node dissection is also performed at that time. Two to 3 weeks later external beam irradiation is delivered to the entire breast. One hundred and twenty-three breasts in 120 patients have been treated between June 1982 and June 1986. There were 49 pathological Stage I, 63 Stage II, 8 Stage III carcinomas, and 3 carcinomas in situ, consisting of 72 T1, 43 T2, 5 T3, and 3 TIS lesions. Patients have been followed for a median of 30 months. One patient had a "true" recurrence in the breast. Another patient developed recurrence in a different quadrant. Ninety percent of the patients had good to excellent cosmetic results, 7% were considered fair, and 3% had poor results. Seven patients developed mild arm edema, 4 were found to have moderate edema, and 1 had severe arm edema. Our preliminary results indicate that interstitial irradiation immediately after excision results in excellent local control, with very satisfactory cosmesis and no morbidity due to the simultaneous excision and irradiation.

Breast conservation treatment with perioperative interstitial irradiation.

Limited resection of the breast combined with radiation has proved to be as effective as more radical surgery in treating early breast cancer. At the University of Kansas Medical Center, the radiotherapy consists of an interstitial implant at the time of lumpectomy to deliver an interstitial boost dose to the tumor bed with iridium-192 immediately following the surgical procedure. An axillary node dissection is also performed at the time of lumpectomy. A dose of 2,000 cGy is delivered to the tumor bed between 40 and 60 h. Two to three weeks later, 4,500-5,000 cGy is delivered to the entire breast with external beam radiation over 5-5.5 weeks. One hundred breasts in 98 patients were so treated between June 1982 and February 1986, with 2 carcinomas in situ, 40 stage I, 51 stage II, and 7 stage III cancers, consisting of 2 TIS, 54 T1, 39 T2, and 5 T3 lesions. Locoregional control with a median follow-up of 31 months was 98%. One recurrence was in a different quadrant, and the other revealed predominantly the in situ component. Immediate implant did not compromise wound healing or cosmesis. The cosmetic result was graded as good to excellent in 88% of the breasts. Our preliminary results appear to suggest a better local control with immediate interstitial irradiation.

Intraoperative implantation radiation therapy plus lumpectomy for carcinoma of the breast.

The preponderance of evidence indicates that lumpectomy plus radiation therapy produces the same survival as modified radical mastectomy in patients with early breast cancer and further suggests that the local failure rate may be lower in the patients who undergo irradiation. In this series, patients were treated with immediate implantation of the tumor bed with iridium Ir 192. There have been two recurrences in the breast from 110 breast cancers (44% had a clinical stage greater than T1, and 41% had axillary-node involvement) in 107 patients followed up for four to 52 months (25.8 +/- 13.3 months [mean +/- SD]). These preliminary data suggest that local treatment failure can be minimized by aggressive, immediate intraoperative implantation of the tumor bed with iridium Ir 192.

Local recurrence in adenocarcinoma of the rectosigmoid colon after curative surgical resection.

Between January 1975 and January 1982, 157 patients with a diagnosis of adenocarcinoma of the rectosigmoid colon underwent curative surgical resection. The median follow-up was three years (range, 2.5 to 9 years). Two patients were excluded from the study for staging purposes because they received preoperative radiation. The remaining patients were categorized in the following stages: carcinoma in situ-3; A-14; B(1)-14; B(2)-41; B(3)-8; C(1)-1; C(2)-70; and C(3)-4. The overall local recurrence rate was 41 percent. The local recurrence according to stage was as follows: stage A-1/14 (7 percent); B(1)-2/14 (14 percent); B(2)-15/38 (39 percent); B(3)-3/8 (38 percent); C(1)-0/1; C(2)-31/56 (55 percent); and C(3)-4/4 (100 percent). Seventeen patients in stages B(2) and C(2) received postoperative irradiation. Only two patients (2/17, or 12 percent) recurred locally. In this study the local recurrence rate for patients undergoing curative surgical resection only was very high, especially in patients with advanced stage of disease (B(2) to C(3)). There is evidence that postoperative radiotherapy could minimize the local failure rate.

Strontium 89 for palliation of bone metastases.

At the University of Kansas Medical Center, systemic use of strontium 89 ((89)Sr), a betaemitting radioisotope, was evaluated in the treatment of metastatic carcinoma to bone for relief of bone pain. Eighty-five patients were treated with systemic (89)Sr in the dosage of 30 to 40 µCi/kg. All patients had multiple bone metastases, the majority with primary breast or prostatic cancer. The response to treatment was evaluated by daily diary entries, changes in the amount of pain medication, periodic bone scans, and other laboratory values.In the patients who survived (47) and who were observed for three or more months, overall results showed 15 percent becoming pain free; 23 percent showed marked improvement with decreased consumption of pain medication; 53 percent showed mild but significant improvement in pain relief and decrease in pain medication requirement; and 9 percent showed no improvement. No patients noted a worsening of bone pain after the treatment. There was a combined favorable response in 91 percent (43/47) of patients with some meaningful palliation after (89)Sr therapy. This study, using (89)Sr systemic therapy, suggests that this isotope may be a valuable adjuvant therapy for palliation of pain from metastatic bone lesions.

Comparison of single, fractionated and hyperfractionated irradiation on the development of normal tissue damage in rat lung.

The effect of fractionated thoracic irradiation on the development of normal tissue damage in rats was compared to that produced by single doses. Animals received a single dose of 15 Gy, 30 Gy in 10 daily fractions of 3 Gy each (fractionation), or 30 Gy in 30 fractions of 1 Gy each 3 times a day (hyperfractionation). The treatments produced minimal lethality since a total of only 6 animals died between days 273 and 475 after the initiation of treatment, with no difference in survival observed between the control and any of the 3 treated groups. Despite the lack of lethality, evidence of lung damage was obtained by histological examination. At times less than 180 days after treatment, the lungs of animals receiving a single dose of 15 Gy displayed more severe changes than did animals from either fractionation group. At longer times after treatment (days 261 and 475), the histological appearances within each group were changed, collagen deposits and fibrosis being the most significant observations. Animals that had received either single doses or fractionated doses had more of the pulmonary parenchyma involved than did animals that had received hyperfractionated doses. We conclude that, in the rat lung model, a total radiation dose of 30 Gy fractionated over 14 days produces no more acute lethality nor damage to lung tissue than does 15 Gy delivered as a single dose. However, long-term effects as evidenced by deposits of collagen and development of fibrosis are significantly reduced by hyperfractionation when compared to single doses and daily fractionation.

Interaction of radiation, dihydroxyanthraquinone, and adriamycin on the induction of acute lethality in mice.

The acute lethality induced by combinations of radiations, Dihydroxyanthraquinone (DHAQ), and Adriamycin (ADR) was investigated in mice. Whole-body irradiation produced acute lethality, with an LD-50/30 of approximately 6.5 Gy. ADR and DHAQ produced LD-50/30's of 14 and 4 mg/kg, respectively. When 10 mg/kg doses were fractionated into 5 X 2 mg/kg daily doses, both drugs were equally or more efficient at producing mortality, 90% by day 30. When 4 Gy radiation was combined with 5 mg/kg ADR or 5 mg/kg DHAQ, a response no greater than that produced by drug alone was obtained. However, when 5 mg/kg ADR was administered concomitantly with 5 mg/kg DHAQ, there was a less-than-additive induction of lethality, resulting in only 21% mortality by day 30. Since this response is similar to that seen after ADR only, it would appear that the DHAQ-induced toxicity was protected against. Less-than-additive effects were also observed for combinations of 5 mg/kg ADR with either 2.5 or 10 mg/kg DHAQ; and combinations of 10 mg/kg ADR with either 2.5 or 5 mg/kg DHAQ. If ADR and DHAQ (at doses of 5 mg/kg) were combined but with a 1 day interval between drugs, the protective effect was lost and animals died earlier than after either agent alone. At present, no definite explanation is available for this unusual protective effect of ADR against acute lethality induced by DHAQ.