Flotillin-1 interacts with the serotonin transporter and modulates chronic corticosterone response.

Aberrant serotonergic neurotransmission in the brain is considered at the core of the pathophysiological mechanisms involved in neuropsychiatric disorders. Gene by environment interactions contribute to the development of depression and involve modulation of the availability and functional activity of the serotonin transporter (SERT). Using behavioral and in vivo electrophysiological approaches together with biochemical, molecular-biological and molecular imaging tools we establish Flotillin-1 (Flot1) as a novel protein interacting with SERT and demonstrate its involvement in the response to chronic corticosterone (CORT) treatment. We show that genetic Flot1 depletion augments chronic CORT-induced behavioral despair and describe concomitant alterations in the expression of SERT, activity of serotonergic neurons and alterations of the glucocorticoid receptor transport machinery. Hence, we propose a role for Flot1 as modulatory factor for the depressogenic consequences of chronic CORT exposure and suggest Flotillin-1-dependent regulation of SERT expression and activity of serotonergic neurotransmission at the core of the molecular mechanisms involved.

Differentiation of grain orientation with corrosive and colour etching on a granular bainitic steel.

This study presents a detailed verification of the etching methods with Nital and Klemm on a granular bainitic steel. It is shown that both methods allow the identification of the crystal orientation, whereas Klemm etching enables also a quantification of the apparent phases, as also retained austenite can be distinguished from the other bainitic microstructures. A combination of atom probe tomography with electron-back-scattered-diffraction showed that both etching methods emphasize the bainitic {100} crystal orientation. However, a cross-section produced by focused ion beam evidenced that Klemm etching leads to the formation of a topography of the different oriented bainitic crystals that directly affects the thickness and therefore the apparent colour of the deposited layer formed during etching.

Implementation of the Kids-CAT in clinical settings: a newly developed computer-adaptive test to facilitate the assessment of patient-reported outcomes of children and adolescents in clinical practice in Germany.

PURPOSE: To describe the implementation process of a computer-adaptive test (CAT) for measuring health-related quality of life (HRQoL) of children and adolescents in two pediatric clinics in Germany. The study focuses on the feasibility and user experience with the Kids-CAT, particularly the patients' experience with the tool and the pediatricians' experience with the Kids-CAT Report. METHODS: The Kids-CAT was completed by 312 children and adolescents with asthma, diabetes or rheumatoid arthritis. The test was applied during four clinical visits over a 1-year period. A feedback report with the test results was made available to the pediatricians. To assess both feasibility and acceptability, a multimethod research design was used. To assess the patients' experience with the tool, the children and adolescents completed a questionnaire. To assess the clinicians' experience, two focus groups were conducted with eight pediatricians. RESULTS: The children and adolescents indicated that the Kids-CAT was easy to complete. All pediatricians reported that the Kids-CAT was straightforward and easy to understand and integrate into clinical practice; they also expressed that routine implementation of the tool would be desirable and that the report was a valuable source of information, facilitating the assessment of self-reported HRQoL of their patients. CONCLUSIONS: The Kids-CAT was considered an efficient and valuable tool for assessing HRQoL in children and adolescents. The Kids-CAT Report promises to be a useful adjunct to standard clinical care with the potential to improve patient-physician communication, enabling pediatricians to evaluate and monitor their young patients' self-reported HRQoL.

Small-cell lung carcinoma: an analysis of 194 consecutive patients.

The treatment of small-cell lung carcinoma (SCLC) requires the careful combination of chemotherapy and radiation therapy. To understand the factors involved in the outcome of these patients, the authors undertook a study of patients treated for limited stage SCLC. The charts of 194 consecutive patients treated at our facilities between 1986 and 1994 were reviewed. All patients underwent thoracic radiation therapy (TRT), 50% received prophylactic cranial irradiation (PCI), and all but one received chemotherapy. The probability of survival at 5 years was 14%, and the disease-free survival (DFS) was 17%. Patients receiving a combination of platinum and etoposide (PE) and Cytoxan (Bristol-Myers, Evansville, IN, U.S.A.), Adriamycin (Adria Laboratories, Dublin, OH, U.S.A.), and Vincristine (Eli Lilly, Indianapolis, IN, U.S.A.) (CAV) experienced a DFS at 3 years of 31%, versus 14% for CAV only and 18% for PE only (p = 0.004). In a multivariate survival analysis, only PCI (p = 0.001), having received PE and CAV (p = 0.01), and response to treatment (p = 0.001) were significant. Radiation dose and field size did not influence outcome. The combination of PE and CAV chemotherapy produced the best results in our series. Unanswered questions regarding the optimal TRT dose, field size, and timing of TRT await the results of ongoing randomized trials.

Prostate imaging may not be necessary in nonpalpable carcinoma of the prostate.

OBJECTIVES: Stage T1c carcinoma of the prostate is defined as a nonpalpable carcinoma (NPC-P) that is not visible by imaging and is identified by needle biopsy performed because of elevated prostate-specific antigen (PSA) concentrations. The purpose of this study was to define the incidence of normal findings on transrectal ultrasound (TRUS) and/or endorectal coil magnetic resonance imaging (EMRI) among patients with NPC-P, as well as to investigate the value of differentiating patients with Stage T1c disease from all other patients with NPC-P. METHODS: The records of 2211 patients diagnosed with prostate carcinoma between 1988 and 1995 were reviewed to identify 291 men with NPC-P. TRUS and EMRI reports were analyzed with regard to the presence and laterality of hypoechoic nodules or low-signal areas reported on T2-weighted images, respectively. Ninety percent of patients (n = 262) had at least six prostate biopsies, 185 patients (64%) underwent both TRUS and EMRI, 224 (77%) had TRUS, and 251 (86%) had an EMRI study. RESULTS: Results were considered normal in 101 (47%) of 214 patients undergoing TRUS, in 58 (23%) of 249 undergoing EMRI, and in 22 (12%) of 185 undergoing both TRUS and EMRI. For the side of the prostate with positive biopsy results, correlation with imaging abnormalities was better for EMRI than for TRUS (39% versus 24%). There was no significant difference in mean PSA value, distribution of Gleason score, or unilateral versus bilateral positive biopsy results among patients with normal versus abnormal findings on both TRUS and EMRI. CONCLUSIONS: (1) Only 12% of men with NPC-P have no TRUS or EMRI abnormalities, fulfilling the criteria for Stage T1c prostate carcinoma. (2) Those patients with Stage T1c disease do not differ from patients with NPC-P up-staged by TRUS or EMRI, with regard to pretreatment PSA levels, Gleason scores, and the probability of having bilateral rather than unilateral positive biopsy results. (3) The value of classifying patients with NPC-P into Stage T1c versus higher stages of prostate carcinoma on the basis of imaging should be questioned.

Effect of edema on the post-implant dosimetry of an I-125 prostate implant: a case study.

PURPOSE: To investigate the effect of post-implant edema on the CT-based calculation of the total dose delivered by an I-125 prostate implant. MATERIALS AND METHODS: CT scans of a transperineal I-125 prostate implant were obtained 1 and 39-days post-implant. Changes in the prostate dimensions were determined from changes in the spatial distribution of the I-125 seeds. The total dose delivered to the target volume was computed from each CT scan, and the results compared. RESULTS: The volume of the prostate decreased by approximately 17% during the 38-day interval between the first and second CT scans. As a result, the radiation dose computed from the second CT scan was 13% higher. CONCLUSION: Post-implant edema can cause a significant underestimation of the radiation dose delivered by an I-125 prostate implant. Similar analysis should be carried out among a larger cohort of patients to confirm or refute these observations.

A phase I study of weekly cisplatin and whole abdominal radiation for the treatment of stage III and IV endometrial carcinoma: a Gynecologic Oncology Group pilot study.

A Gynecologic Oncology Group Phase I study was designed to evaluate the toxicity of whole abdominal radiation therapy with concurrent weekly cisplatin in patients with surgical International Federation of Gynaecology and Obstetrics (FIGO) Stage III and IV endometrial carcinoma. Cisplatin 15 mg/m2 was given once weekly during radiation therapy to the whole abdomen with a pelvic boost and optional para-aortic radiation. All eight patients received the prescribed dose of radiation therapy. Cisplatin chemotherapy was halted in one patient due to increased serum creatinine after three cycles. Acute adverse effects were within acceptable limits, with one patient admitted to the hospital after completion of treatment for diarrhea. Hematopoietic toxicity was clinically unimportant. Serious late toxicities included one radiation enteritis requiring a bowel resection and chylous ascites in one patient. There was no late renal damage reported. This regimen appears to be tolerated acutely and the late toxicities were similar to those seen with whole abdominal radiation therapy alone.

Potential underdosing with the use of electron beam therapy in patients with cervical adenopathy and advanced head and neck cancer.

To define the adequacy of electron beam therapy in the treatment of N1-N3 head and neck cancer, 24 patients with primary head and neck cancers and N1-N3 cervical adenopathy received primary radiation therapy with or without chemotherapy for definitive control of their disease. All patients underwent computerized tomography (CT) to assist in the design of treatment to the posterior neck with electron beams after photon therapy to the level of spinal cord tolerance. Treatment with electrons to the posterior neck in patients with N1 disease was adequate in 92% (11/12) of patients. However, in patients with N2 and N3 disease, electron beam treatment failed, because of spinal cord tolerance problems, to cover the disease adequately in 92% (11/12). It is concluded that CT should be employed routinely in patients with N1-N3 neck disease to determine the proper electron energy prescription. For some patients, electron beam may not be appropriate, making it necessary to use individual planning to treat adequately the neck disease and avoid the spinal cord.

Potential underdosing with the use of electron-beam therapy in patients with cervical adenopathy and advanced head and neck cancer.

To define the adequacy of electron-beam therapy in the treatment of N1-N3 head and neck cancer, 24 patients with primary head and neck cancers and N1-N3 cervical adenopathy received primary radiation therapy with or without chemotherapy for definitive control of their disease. All patients underwent computerized tomography (CT) to assist in the design of treatment to the posterior neck with electron beams after photon therapy to the level of spinal cord tolerance. Treatment with electrons to the posterior neck in patients with N1 disease was adequate in 92% (11/12) of patients. However, in patients with N2/N3 disease, electron beam failed, because of spinal-cord tolerance problems, to adequately cover disease in 92% (11/12). It is concluded that CT should be routinely employed in patients with N1-N3 neck disease to determine the proper electron-energy prescription. For some patients, electron beam may not be appropriate, making it necessary to use individual planning to treat adequately the neck disease and avoid the spinal cord.

Radiation therapy and combined chemo-irradiation in advanced and recurrent endometrial carcinoma.

The advent of surgical staging for endometrial carcinoma has identified multiple combinations and degrees of various risk factors. Therefore, it is obvious that questions regarding adjuvant treatment in advanced disease must be generally stated and the answers, when available, may not be specifically applicable to individual patients. Hopefully ongoing and future prospective trials will help to resolve questions about the proper role of RT and/or chemo-irradiation and the proper technique and treatment volume when RT is used.

The role of radiotherapy in the treatment of breast cancer: results of perioperative implantation.

Between 1982 and 1993, 620 of 938 patients with pathologically staged I-II breast cancer were treated at the time of reexcision (perioperatively), with an iridium-192 (Ir-192) implant to the tumor bed to give 2000 cGy to the 30 to 40 cGy/ph isodose line. This was followed by 4500 cGy to the entire breast at 180 cGy/d for 25 fractions. The local control for the 620 patients at 5 and 10 years was 93 and 89%, respectively. The actuarial survival at 5 and 10 years was 92 and 81%. The cosmetic results were good to excellent for 87% of the patients. Chemotherapy had no impact on local control in this study. Ir-192 implant is especially useful for deep tumors, making possible more flexibility in the techniques used to boost the tumor volume. Perioperative implantation has increased the accuracy of placing the boost dose, shortened the overall treatment time, and, for some patients, eliminated the need for rehospitalization and anesthesia.

Preoperative radiation therapy in clinical stage II endometrial carcinoma.

From 1980 to 1987, 30 patients with FIGO clinical Stage II carcinoma of the endometrium were treated with 5000 cGy preoperative pelvic radiation therapy at Thomas Jefferson University Hospital. Patients with gross cervical disease received additional intracavitary irradiation with a tandem and ovoids for a combined total dose of 7000 cGy to point A. All patients then underwent exploratory laparotomy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO). The 5-year actuarial survival for the entire group was 69%. The 5-year actuarial survival for the 8 patients with papillary serous, clear cell, and undifferentiated small cell carcinoma was 38%, with most patients failing in the upper abdomen. The 5-year actuarial survival for the remaining 22 patients was 82%. The only local failure occurred in the patient with an undifferentiated small cell carcinoma. Although preoperative pelvic radiation therapy together with TAH/BSO appears to offer excellent local control in all patients with Stage II endometrial carcinoma, additional treatment options should be considered for patients with papillary serous and clear cell histologies because of the poor survival and high failure rate in the upper abdomen.

Vertex field verification in the treatment of central nervous system neoplasms.

Increasing sophistication of computerized brain tumor treatment plans has enabled clinicians to devise increasingly complex field combinations to spare as much normal brain tissue as possible. These treatment plans often call for the use of a vertex field. This report describes a simple, useful technique for the verification of the vertex (or any non-coplanar) field on the treatment machine--a procedure that is impossible with conventional port film techniques.

Combined pre- and postoperative adjuvant radiation therapy for bladder cancer--a ten year experience.

From 1978 through 1987, 78 patients with carcinoma of the bladder were treated with combined pre- and postoperative adjuvant radiation therapy. All were given a single dose of pre-operative radiation therapy, 500 cGy, either on the day of or the day before cystectomy. Histological staging on the cystectomy specimens according to the TNM classification system was performed. Forty patients with Stage P2 (high grade III and IV), P3A, P3B, P4A, or N+ underwent planned high dose postoperative radiation therapy (4000-4500 cGy) in 5 weeks. The whole pelvis was treated with conventional fractionation of 180 cGy 5 days per week. Median follow-up was 52 months, with 36 months minimum follow-up. There was a 67% overall 5-year survival, and those with P1 and P2 (Grade I and II) had an 84% 5-year survival. Survival for patients with P2 tumor (Grade III and IV), P3A, P3B, and P4/N+ stages was 57%, 56%, 39%, and 50%, respectively. Bowel obstructions developed in 8% of patients who received no postoperative radiation therapy and 37% in those who did. Genitourinary complication rates were similar in both groups, 13% in the group that received no postoperative radiation therapy and 10% in the group that did. Although the planned approach of combined pre- and postoperative radiation therapy for unfavorable stages of bladder cancer is associated with a better than 50% 5-year survival rate (except in Stage P3B cancer), the bowel toxicity was unacceptably high.

Endometrial cancer with para-aortic adenopathy: patterns of failure and opportunities for cure.

PURPOSE: To examine the outcome of patients with advanced endometrial cancer whose para-aortic involvement was diagnosed pathologically or lymphographically. METHODS AND MATERIALS: Fifty patients from four institutions were treated between 1959 and 1990 with preoperative, post-operative, and primary radiotherapy. Para-aortic disease was diagnosed pathologically in 26 patients and lymphographically in the remaining 24 patients. Pathologically diagnosed patients underwent debulking of grossly involved nodes. All patients received external beam treatment through pelvic and para-aortic portals. Median prescribed dose to the pelvic and para-aortic fields was 50 and 47 Gy, respectively. Those treated with primary or pre-operative irradiation also received intrauterine brachytherapy. RESULTS: The actuarial 5-year disease-free survival was 46% for all patients. Para-aortic failure was significantly decreased among patients undergoing lymph node resection (13% versus 39%, respectively). Relapse-free survival and pelvic control tended to improve among patients receiving surgery plus irradiation in comparison to those treated by irradiation alone. Distant metastases were most common among patients with high grade lesions. CONCLUSIONS: Long-term disease-free survival is achievable in endometrial cancer patients with para-aortic lymphadenopathy who are treated with extended-field radiotherapy. Cure is mot attainable among patients with well differentiated, early clinical stage disease who receive combined modality treatment. Survival and local failure are similar for radiologically and pathologically diagnosed patients; however, para-aortic failure as a component of local failure was increased in patients who did not undergo surgical debulking of the adenopathy.

Survival and failure analysis in stage II endometrial cancer using the revised 1988 FIGO staging system.

Fifty-one patients with Stage II endometrial carcinoma diagnosed between 1974 and 1987 were restaged according to the FIGO 1988 revisions for endometrial carcinoma. Patients were divided into Stage IIA, those patients with cervical glandular involvement without stromal invasion, and Stage IIB, those patients having stromal invasion of the cervix. Tumor grade was also assessed. Patients were treated with radiation therapy alone, pre-operative radiation therapy followed by a simple hysterectomy, or a simple hysterectomy followed by postoperative radiation therapy. The 5-year actuarial survival for Stage IIA was 86% and the 5-year actuarial survival for Stage IIB was 46% (p = 0.06). The 5-year local recurrence rate in each group was 9%. Stage IIA had a distant metastases rate of 14% whereas 44% of the patients in Stage IIB developed distant disease (p = 0.06) at 5 years. The grade of the tumor did not play a role in local recurrence. However, when tumor grade was analyzed with respect to distant disease, 14% of patients with grade 1 tumors developed distant metastases, 31% of patients with grade 2 tumors developed distant metastases, and most significantly, 63% of patients with grade 3 tumors developed distant metastases (p = 0.004). There was no statistically significant relationship between stromal invasion and tumor grade. This study concludes that grade is the greatest predictor of survival, with only 37% of grade 3 patients surviving at 5 years. As a predictor of survival, stromal invasion is of less significance than grade (p = 0.06 vs. p = 0.004). Death most often occurs because of distant metastases, and local failure is rare and is not dependent on the degree of cervical involvement or grade.

Stage IB glassy cell carcinoma of the cervix diagnosed during pregnancy and recurring in a transposed ovary.

A case report of glassy cell carcinoma of the cervix occurring during pregnancy is presented. Clinical staging was FIGO IB and treatment consisted of a radical hysterectomy, bilateral ovarian transposition, and postoperative pelvic radiation therapy. The patient had a relapse in one of the transposed ovaries. A review of ovarian conservation in Stage IB carcinoma of the cervix is discussed.

Mammographic findings after breast cancer treatment with local excision and definitive irradiation.

Following local excision and definitive irradiation of 163 breast cancers in 160 women, alterations in mammographic patterns were observed for up to 7 years. Skin thickening was observed in 96% of mammograms obtained within 1 year of completing therapy and was most pronounced in women treated with iridium implant, chemotherapy, or axillary dissection. In 76% of mammograms, alterations in the parenchymal pattern, including coarsening of stroma and increased breast density, were seen at 1 year. Neither skin nor parenchymal changes progressed after 1 year. Within 3 years of treatment the parenchymal density, which usually regressed, did not change in all patients. At 3 years skin thickness and the parenchymal pattern had returned to normal in less than 50% of the breasts of these women. Scars developed in approximately one-quarter of women. They were present on the initial post-treatment mammogram and remained unchanged on serial studies. Coarse, benign calcifications also developed in the breasts of about one-quarter of women. Microcalcifications developed in 11 breasts; biopsy specimens of six were benign. Benign microcalcifications may be related to therapy.