Radiotherapy of breast cancer.

Adjuvant radiotherapy is an essential component of the treatment of breast cancer. After conservative surgery for an infiltrating carcinoma, radiotherapy must be systematically performed, regardless of the characteristics of the disease, because it decreases the rate of local recurrence and by this way, specific mortality. A boost dose over the tumour bed is required if the patient is younger than 50 years-old. Partial breast irradiation could be routinely proposed as an alternative to whole breast irradiation, but only in selected and informed patients. For ductal carcinoma in situ, adjuvant radiotherapy must be also systematically performed after lumpectomy. After mastectomy, chest wall irradiation is required for pT3-T4 tumours and if there is an axillary nodal involvement, whatever the number of involved lymph nodes. After neoadjuvant chemotherapy and mastectomy, in case of pN0 disease, chest wall irradiation is recommended if there is a clinically or radiologically T3-T4 or node positive disease before chemotherapy. Axillary irradiation is recommended only if there is no axillary surgical dissection and a positive sentinel lymph node. Supra- and infraclavicular irradiation is advised in case of positive axillary nodes. Internal mammary irradiation must be discussed case by case, according to the benefit/risk ratio (cardiac toxicity). Hypofractionation regimens (42.5Gy in 16 fractions, or 41,6Gy en 13 or 40Gy en 15) are equivalent to conventional irradiation and must prescribe after tumorectomy in selected patients. Delineation of the breast, the chest wall and the nodal areas are based on clinical and radiological evaluations. 3D-conformal irradiation is the recommended technique, intensity-modulated radiotherapy must be proposed only in specific clinical situations. Respiratory gating could be useful to decrease the cardiac dose. Concomitant administration of chemotherapy in unadvised, but hormonal treatment could be start with or after radiotherapy.

[Radiotherapy of breast cancer]. / Radiothérapie du cancer du sein.

In breast cancer, radiotherapy is an essential component of the treatment. After conservative surgery for an infiltrating carcinoma, radiotherapy must be systematically performed, regardless of the characteristics of the disease, because it decreases the rate of local recurrence and by this way, specific mortality. Partial breast irradiation could not be proposed routinely but only in very selected and informed patients. For ductal carcinoma in situ, adjuvant radiotherapy must be also systematically performed after lumpectomy. After mastectomy, chest wall irradiation is required for pT3-T4 tumours and if there is an axillary nodal involvement, whatever the number of involved lymph nodes. After neo-adjuvant chemotherapy and mastectomy, in case of pN0 disease, chest wall irradiation is recommended if there is a clinically or radiologically T3-T4 or node positive disease before chemotherapy. Axillary irradiation is recommended only if there is no axillary surgical dissection and a positive sentinel lymph node. Supra and infra-clavicular irradiation is advised in case of positive axillary nodes. Internal mammary irradiation must be discussed case by case, according to the benefit/risk ratio (cardiac toxicity). Dose to the chest wall or the breast must be between 45-50Gy with a conventional fractionation. A boost dose over the tumour bed is required if the patient is younger than 60 years old. Hypofractionation (42.5 Gy in 16 fractions, or 41.6 Gy en 13 or 40 Gy en 15) is possible after tumorectomy and if a nodal irradiation is not mandatory. Delineation of the breast, the chest wall and the nodal areas are based on clinical and radiological evaluations. 3D-conformal irradiation is the recommended technique, intensity-modulated radiotherapy must be proposed only in case of specific clinical situations. Respiratory gating could be useful to decrease the cardiac dose. Concomitant administration of chemotherapy in unadvised, but hormonal treatment could be start with radiotherapy.

[Observance and results of concurrent chemoradiotherapy after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil for locally advanced head and neck cancers]. / Observance et résultats de la chimioradiothérapie concomitante après chimiothérapie d'induction par docétaxel, cisplatine et 5-fluoro-uracile pour les cancers de la tête et du cou localement évolués.

PURPOSE: Retrospectively evaluate the safety, feasibility and efficacy of concomitant chemoradiotherapy after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil for locally advanced head and neck cancers. PATIENTS AND METHODS: Patients' data from three radiotherapy centres in South of France, with locally advanced head and neck cancers, and treated between December 2007 and July 2013 by concomitant chemoradiotherapy, after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil, were analysed. Adverse effects were graduated according to CTCAE v3.0 criteria. Overall survival and disease-free survival were calculated according to Kaplan-Meier method. RESULTS: One hundred and sixty-eight patients, mostly oropharynx (38%) T4 (46%) N2 (54%) tumors, received, after induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil, a concomitant chemoradiotherapy with platin or cetuximab, which delivered 66 to 70Gy. Grade 3-4 adverse effects were less frequent in the group of patients who received cisplatin (with or withour 5-fluoro-uracil) at 100mg/m(2) each 21 days compared to cetuximab (radiomucositis: 32.5% vs 61%, P=0.018; radioepithelitis: 13% vs 61 %, P<0.0001). Chemopotentiation was incomplete for 21% of patients without impacting survival. Two years overall survival and disease-free survival were respectively of 81% and 64%. Lymph nodes status and WHO status significantly influenced these survivals (overall survival 84% if N<3 vs 56% if N3, P=0.017 and 85 % if WHO status ≤ 1 vs 50% if WHO status>1, P=0.006; disease-free survival 66% if N<3 vs 47% if N3, P=0.046). CONCLUSION: The association of induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil and concomitant chemoradiotherapy shows satisfying results with an acceptable toxicity. The terms of the chemopotentiation and its superiority to a single concomitant chemoradiotherapy treatment still remain to be clarified.

[Adenoid cystic carcinoma of the head and neck: a retrospective series of 169 cases]. / Carcinomes adénoïdes kystiques ORL : étude rétrospective multicentrique de 169 cas.

PURPOSE: Adenoid cystic carcinoma represents 1% of head and neck cancers. Adenoid cystic carcinomas are slow growing tumours with high potential for local recurrence. Treatment usually associates radiotherapy and surgery, but the role of radiotherapy remains unclear. We report a retrospective multicentric study of the management and prognostic factors of 169 adenoid cystic carcinomas of head and neck. PATIENTS AND METHODS: Between 1982 and 2010, 169 patients with adenoid cystic carcinoma of the head and neck were referred to the Cercle des oncologues radiothérapeutes du Sud departments of radiotherapy either for primary untreated tumour (n=135) or for a recurrence of previously treated tumour (n=34). The site of adenoid cystic carcinoma was: parotid gland (n=48, 28.4%), minor salivary gland (n=35, 20.7%), submandibular gland (n=22, 13%), sinus cavities (n=22, 13%), other (n=42, 24.9%). Tumour stages were: T1 (12.4%); T2 (14.2%); T3 (12.4%); T4 (41.4%) and Tx (19.5%). Lymph node involvement was 13% and distant metastasis 8.9%. For adenoid cystic carcinomas of the parotid gland, major nerve involvement was evaluated. Preferential site of metastasis was the lung (87.5%). Treatments were: surgery alone (n=27), surgery and adjuvant radiotherapy (n=89), surgery and adjuvant chemoradiotherapy (n=12), exclusive chemoradiotherapy (n=13), exclusive radiotherapy (n=14), other associations (n=5) and no treatment (n=7). Radiotherapy was delivered through photons (n=119), neutrons (n=6), both (n=4). Two patients had a brachytherapy boost. Median prescribed doses to T and N were respectively 65 Gy and 50 Gy for the 119 photons treated patients. RESULTS: Mean follow-up was 58 months (range 1-250 months). As of December 1, 2010, 83 patients were alive with no evolutive disease (49%), 35 alive and had recurred, 18 had uncontrolled evolutive disease, 28 had died of adenoid cystic carcinoma and 5 of intercurrent disease. Overall survival and disease free survival were respectively 72% and 72% at 5 years, 53% and 32% at 10 years; 5 and 10-year freedom from local recurrence were 81% and 52% respectively. Nerve involvement was found in 17/48 parotid gland adenoid cystic carcinomas. The Cox model including all patients, showed that surgery (P<0.001), surgical margins (P=0.015), nerve involvement (P=0.0079), length of radiotherapy (P=0.018), and tumour location (P=0.041) were associated with disease free survival. CONCLUSION: In this large series of adenoid cystic carcinoma of head and neck with a majority of T3-T4 tumours, 10-year survivals were achieved for 50% of patients. Radiotherapy did not impact survival.

Distinctive clinical and histologic features in cutaneous melanoma with copy number gains in 8q24.

Cutaneous melanoma may be quite heterogeneous in its clinical, histologic, and molecular features. Yet, the current classification of melanoma is limited to 4 main subtypes on the basis of clinical and histopathologic features and has shown limited impact on clinical management including prognostication and treatment. Advances in our understanding of the driving molecular pathways in melanoma and the importance of the mitogen-activated protein kinase pathway have shown that specific activating mutations in oncogenes may correlate with characteristic clinical and histologic features. We evaluated 40 melanoma cases with gains in MYC at 8q24, and we show that their characteristic features include aggressive clinical course, occurrence in nonchronically sun-damaged skin, amelanotic clinical and histopathologic appearance, a nodular or primary dermal growth pattern by histology, frequent epidermal consumption, and infrequent association with a precursor nevus. The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) mutation status was also determined. The presence of these mutations was comparable to frequencies previously reported from nonchronically sun-damaged skin. However, the BRAF mutant cases did not show histopathologic features considered characteristic of BRAF mutant melanoma. Considering these distinct clinical and histopathologic features and the possible role as a theragnostic tool, it may be of value to consider 8q24 status in cutaneous melanoma in addition to the mutation status of BRAF in future studies integrating molecular findings into the classification system for cutaneous melanoma.

[3D conformal radiation therapy and hormonal therapy for localized prostate cancer: is age a limiting factor?]. / La radiothérapie conformationnelle associée à l'hormonothérapie du cancer de prostate localisé: l'âge est-il un facteur limitant ?

No study on side effects had showed that conformal radiation therapy for prostate cancer is more harmful in patients older than 70 years to patients younger. The aim of this study was to evaluate acute and late toxicities of conformal radiotherapy, with high dose for localized prostate cancer in patients older than 70 years and compared to patients younger than 70 years. Between 1996 and 2009, 104 patients were treated with radiation therapy and hormonal therapy for localized cancer prostate. Median follow-up was 105 months (9-300). Acute (occurred at ≤ three months) and late side effects of 55 patients older than 70 years (median age: 75 [71-92]) were graded according to the CTCAE 3.0 criteria and compared to the younger population. Median dose to the prostate was 75.6 Gy (67-80) in both groups. There were no significant differences in acute and late side effects between age groups. For patients above 70 years, the incidence of grade II or higher acute and late side effects were respectively 27 and 22% for urologic symptoms and 13 and 16% for rectal symptoms. The frequency of grade III late symptoms was low and ranged between 0 and 6% for the evaluated symptoms, irrespective of age group. Older patients had a better biochemical recurrence-free survival than younger patients (86 versus 77% at four years, P=ns). High dose 3D conformal radiotherapy for localized prostate cancer was well tolerated in patients older than 70 years. Age is not a limiting factor for conformal radiation therapy and hormonotherapy for older patients.

[Postoperative radiotherapy of uterine sarcoma: a multicentric retrospective study]. / Radiothérapie postopératoire dans les sarcomes utérins: étude rétrospective multicentrique.

PURPOSE: Surgery is the treatment of choice for localized uterine sarcomas. We conducted a retrospective study to define prognostic factors. PATIENTS AND METHODS: We studied 111 cases of patients treated by adjuvant radiotherapy for uterine sarcoma in seven French centers. The median decline was 31 months. We conducted a univariate analysis to identify factors correlated with local recurrence. The statistically significant factors were studied in multivariate analysis by Cox model. RESULTS: The median dose of external beam radiotherapy was 45 Gy. Forty-three percent of patients had vaginal vault brachytherapy and 21 % chemotherapy. Only 6.3 % of patients had complications of acute grade III and 8.1 % of long-term sequelae of radiotherapy. The survival rate at 5 years was 74.6 %. They noted 12.6 % of isolated locoregional recurrences, against 29.7 % for distant recurrences, 80 % were pulmonary. Factors correlated with the risk of locoregional relapse were menopausal status (P = 0.045) and surgical margins suspicious or not healthy (P = 0.0095). The chemotherapy did not improve overall survival or disease free survival but the numbers were low. CONCLUSION: The postoperative radiotherapy provides good local control in this disease. Brachytherapy is sometimes done, but it does not improve local control. Chemotherapy is not a standard localized stage but the rate of metastatic recurrence calls for the development of strategies involving systemic treatment with radiotherapy.

[Evaluation of immediate breast reconstruction and radiotherapy: factors associated with complications]. / Reconstruction mammaire immédiate après mastectomie suivie de radiothérapie: facteurs de risque de complications.

OBJECTIVES: To determine prospectively the factors associated with reconstruction failure (i.e. requiring expander removal) and capsular contracture in patients undergoing mastectomy and immediate two-stage breast reconstruction with a tissue expander and implant, and radiotherapy for breast cancer. This is a multi-institutional prospective nonrandomized trial. PATIENTS AND METHODS: Between 2/1998 and 9/2006, we prospectively evaluated 141 consecutive patients who received 141 implants after mastectomy and underwent chest wall radiotherapy (46 to 50 Gy in 23 to 25 fractions). Patients were evaluated after 24 to 36 months by two senior physicians (radiation oncologist and surgeon). RESULTS: Medical follow-up was 37 months. Baker 1 and 2 capsular contracture was observed in 67.5% of patients, Baker 3 and 4 in 32.5%. There were 32 reconstruction failures. In a univariate analysis, the following factors were associated with Baker 3 and 4 capsular contracture: surgeon, use of hormonotherapy and smoking, of which only one remained in the multivariate analysis: surgeon. In a univariate analysis, the following factors were associated with reconstruction failure: tumor size T3 or T4, smoking, pN+ axilla. Three factors remained associated with reconstruction failure in a multiple logistic regression: large tumors T3/T4, smoking and pN+ axilla. CONCLUSIONS: Mastectomy, radiotherapy and immediate breast reconstruction with a tissue expander and implant should be considered when breast conserving surgery has been denied. Adequate patients can be easily selected by using three factors of favourable outcome.

[Ductal carcinoma in situ: role of the boost]. / Radiothérapie des carcinomes canalaires in situ: impact du complément d'irradiation du lit tumoral.

Ductal carcinoma in situ is defined as breast cancer confined to the ducts of the breast without evidence of penetration of the basement membrane. Local treatment quality represents one of the most prognostic factors as half of recurrences are invasive diseases. The main goal of adjuvant radiotherapy after conservative surgery is to decrease local recurrences and to permit breast conservation with low treatment-induced sequelae. Several randomized trials have established the impact of 50 Gy to the whole breast in terms of local control. Nevertheless, no randomized trial is still available concerning the role of the boost in this disease. In this review, we present updated results of the literature and we detail the French multicentric randomized trial evaluating the impact of a 16 Gy boost after 50 Gy delivered to the whole breast in 25 fractions and 33 days. This protocol will start inclusions in October 2008.

[Radiosurgery and brain radio-induced carcinogenesis: update]. / Radiochirurgie et carcinogenèse radio-induite cérébrale. Le point actuel.

The use of radiosurgery Gamma-knife for many benign tumors and diseases has increased significantly over the last two decades. The long-term potential carcinogenic risk has not been evaluated until recently. The definition of radio-induced tumors was based on Cahan's criteria: it must occur in the previously irradiated field, with a sufficiently long interval from irradiation, it must be pathologically different from the primary tumor, not be present at time of irradiation and no genetic predisposition for second tumor. The brain is one of most sensitive tIssues and no minimal dose has been established. Even doses as low as 1 Gy have been associated with second tumor formation and relative risk between 1.57 and 8.75. This relative risk increases to 18.4 for an interval time between 20 and 25 Years. Many publications emphaze the risks after larger-field, fractionated radiotherapy with low non-cell-killing dose delivered to central nervous system. Furthermore, therapeutic radiation doses for benign tumors associated with a long life (parasellar tumors, meningioma) were implicated in carcinogenesis. Incidence of radiation-associated tumors is linked to different factors such as age and individual genetic susceptibility. At this time and to our knowledge, 3 radiation-associated gliomas and 5 malignant acoustic neurinomas have been reported in the literature. Moreover, these second tumors met some but not all Cahan criteria. We also report 2 cases from our radiosurgical experience and discuss these points. Long time follow-up is needed to observe the crude incidence of radiation-induced tumors at 5 to 30 Years. The relative risk is estimated less than 1 and must be announced to each patient before the radiosurgical procedure and counterbalanced wit the 1% annual risk of mortality from bleeding of untreated MAV or the 1% mortality rate of benign tumors after surgery alone.

[Target-volume and critical-organ delineation for conformal radiotherapy of prostate cancer: experience of French dose-escalation trials]. / Délimitation des volumes-cibles et des organes critiques pour la radiothérapie conformationnelle du cancer de la prostate: expérience des essais français d'escalade de dose.

The delineation of target volume and organs at risk depends on the organs definition, and on the modalities for the CT-scan acquisition. Inter-observer variability in the delineation may be large, especially when patient's anatomy is unusual. During the two french multicentric studies of conformal radiotherapy for localized prostate cancer, it was made an effort to harmonize the delineation of the target volumes and organs at risk. Two cases were proposed for delineation during two workshops. In the first case, the mean prostate volume was 46.5 mL (extreme: 31.7-61.3), the mean prostate and seminal vesicles volume was 74.7 mL (extreme: 59.6-80.3), the rectal and bladder walls varied respectively in proportion from 1 to 1.45 and from 1 to 1.16; in the second case, the mean prostate volume was 53.1 mL (extreme: 40.8-73.1), the volume of prostate plus seminal vesicles was 65.1 mL (extreme: 53.2-89), the rectal wall varied proportionally from 1 to 1, 24 and the vesical wall varied from 1 to 1.67. For participating centers to the french studies of dose escalation, a quality control of contours was performed to decrease the inter-observer variability. The ways to reduce the discrepancies of volumes delineation, between different observers, are discussed. A better quality of the CT images, use of urethral opacification, and consensual definition of clinical target volumes and organs at risk may contribute to that improvement.

[Multicenter study on dose escalation with conformal and conventional radiotherapy for the treatment of localized prostatic cancer. Preliminary results of tolerance and quality of life]. / Etude multicentrique d'escalade de dose par radiothérapie conformationnelle pour le traitement du cancer localisé de la prostate. Résultats préliminaires de la tolérance et de la qualité de vie.

OBJECTIVE: To study the safety of conformal radiotherapy dose escalation up to 80 Gy for curative treatment of prostate cancer. MATERIAL AND METHODS: A multicentre trial sponsored by the PHRC include 164 patients under the age of 75 years with stage T1b-T3 N0 M0 prostatic adenocarcinoma, between 1995 and 1998. The prostate was treated at 5 dose levels: 18 patients at 66 Gy, 28 at 70 Gy, 49 at 74 Gy, 48 at 78 Gy, 21 at 80 Gy. The acute and delayed toxicity was graded according to a multidisciplinary glossary. Quality of life was evaluated before and one year after treatment using the EORTC QLQ-C30 questionnaire and additional questions. RESULTS: 89% and 55% of mild or moderate gastrointestinal and urinary adverse effects were observed during treatment, respectively. At long-term follow-up, of the 162 evaluable patients, 12.3% presented grade 2 adverse effects and 2.5% presented grade 3 adverse effects (1 case of haematuria, 2 urethral strictures, 1 bladder neck lesion) with no significant difference between the various dose levels. Two successive quality of life questionnaires were available for 119 patients: tiredness, pain and dyspnoea increased in parallel, but non-significantly in the groups receiving conventional doses or high doses. The proportion of patients reporting sexual activity without endocrine therapy decreased from 48% before treatment to 35% one year later. The proportion of patients with no clinical or laboratory signs of progression was higher in the high-dose group. CONCLUSION: No significant difference was observed between conventional dose levels and high dose levels in terms of toxicity or quality of life. As the adverse effects were acceptable, a randomized trial comparing 70 Gy and 80 Gy has been initiated.

Combined brachytherapy and surgery for early carcinoma of the uterine cervix: analysis of extent of surgery on outcome.

PURPOSE: The aim of this retrospective study was to evaluate the survival data and rates and patterns of complications and recurrences for patients who had early uterine cervix carcinoma and underwent brachytherapy and subsequent surgery. METHODS AND MATERIALS: Between January 1990 and December 1997, 192 women with cervical carcinoma (Stages IA2 with vascular invasion [n = 28], IB1 [n = 144], and IIA [n = 20]) underwent brachytherapy, delivering 60 Gy and then hysterectomy with external iliac lymphadenectomy. Piver class I, II, and III hysterectomies were performed on 136, 38, and 18 patients, respectively. Adjuvant chemoradiotherapy was delivered to patients with positive lymph nodes. RESULTS: The median follow-up time was 61 months. After brachytherapy, a pathologically complete response (CR) was observed in 137 (71.3%) of 192 women. The distribution of CRs according to tumor stage was as follows: Stage IA2, 24 (85.7%) of 28; Stage IB1, 105 (72.9%) of 144; and Stage IIA, 8 (40%) of 20. Patients with Stage IB1 cancer had 13 lymph node metastases (9%), as did 6 with Stage IIA disease (30%). Pelvic recurrences occurred in 9 (4.6%) of the 192 patients; in 3, local relapses were associated with relapses at distant sites. Ten patients had systemic relapses (5.2%). Recurrences at distant sites were more frequent (p < 0.02) in partial responders, and other recurrences were more frequent in patients with lymph node metastases (p < 0.04). The overall 5-year disease-free survival rate was 91.2% (96.2% for Stage IA2, 91% for Stage IB1, and 84.4% for Stage IIA cancers). The class of hysterectomy did not influence the outcome. Late complications occurred in 28 patients (Grade 1, 24 [12.5%]; Grade 2, 4 [2%]; and Grade 3, 1 [0.5%] of 192 patients). CONCLUSIONS: Combined treatments resulted in high local control and low morbidity rates in patients with early-stage cervical carcinoma. Limited surgery seemed to be adequate after intracavitary therapy.

Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms.

PURPOSE AND OBJECTIVE: Late rectal bleeding is a potentially dose limiting complication of three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer. The frequency of late rectal bleeding has been shown to increase as the prescription dose rises above 70 Gy. The purpose of this study is to identify features of the cumulative dose-volume histogram (DVH) for the rectal wall that correlate with late rectal bleeding after 3D-CRT for prostate cancer. METHODS AND MATERIALS: Follow-up information on rectal bleeding is available for 261 and 315 patients treated using 3D-CRT at Memorial Sloan-Kettering Cancer Center for Stage T1c-T3 prostate cancer with minimum target doses of 70.2 and 75.6 Gy, respectively. All patients in this study were treated with a coplanar 6-field technique (2 lateral and 4 oblique fields). Patients were classified as having rectal bleeding if they bled (> or = Grade 2) before 30 months, and nonbleeding (< or = Grade 1) if they were without bleeding at 30 months, using the RTOG morbidity scale. Rectal bleeding was observed in 13 and 38 of the patients treated at 70.2 and 75.6 Gy, respectively. Treatment plans were analyzed for 39 nonbleeding and 13 bleeding patients receiving 70.2 Gy, and 83 nonbleeding and 36 bleeding patients receiving 75.6 Gy. Dose-volume histograms (DVHs) for the anatomic rectal wall were calculated. Average DVHs of the bleeding and nonbleeding patients were generated, and a permutation test was used to assess the significance of differences between them, for each dose group. The confounding effect of total rectal wall volume (V(RW)) was removed by calculating the average differences in DVHs between all combinations of bleeding and nonbleeding patients with similar V(RW)s. Finally, multivariate analysis using logistic regression was performed to test the significance of the DVH variables in the presence of anatomic, geometric, and medical variables previously found to correlate with rectal bleeding in a companion analysis of the same patients. RESULTS: The area under the average percent volume DVH for the rectal wall of patients with bleeding was significantly higher than those of patients without bleeding in both dose groups (p = 0.02, 70.2 Gy; p < 0.0001, 75.6 Gy). However, small V(RW)s were associated with rectal bleeding (p = 0.06, 70.2 Gy; p < 0.01, 75.6 Gy), resulting in an increase in average percent volumes exposed to all doses for patients with rectal bleeding. For patients with similar V(RW)s, rectal bleeding was significantly correlated with the volumes exposed to 46 Gy in both dose groups (p = 0.02, 70.2 Gy; p = 0.005, 75.6 Gy, tolerance in V(RW): 5 ccs). For the 75.6 Gy dose group, the percent volume receiving 77 Gy was significantly correlated with rectal bleeding (p < 0.005). Bivariate analysis using logistic regression, including V(RW) together with a single DVH variable, showed good agreement with the above analysis. Multivariate analysis revealed a borderline significant correlation of the percent volume receiving 71 Gy in the 70.2 Gy dose group. It also showed that the DVH variables were highly correlated with geometric and dosimetric variables previously found to correlate with rectal bleeding in multivariate analysis. CONCLUSION: Significant volume effects were found in the probability of late rectal bleeding for patients undergoing 3D-CRT for prostate cancer with prescription doses of 70.2 and 75.6 Gy. The percent volumes exposed to 71 and 77 Gy in the 70.2 and 75.6 Gy dose groups respectively were significantly correlated with rectal bleeding. The independent correlation of small V(RW) with rectal bleeding may indicate the existence of a functional reserve for the rectum. The independent association with larger percent volumes exposed to intermediate doses ( approximately 46 Gy) seen in both dose groups may indicate that a large surrounding region of intermediate dose may interfere with the ability to repair the effects of a central high dose region.

Facial reanimation surgery utilizing the Mitek anchor system: A case report.

A flaccid hemi-face is frequently the most noticeable and cosmetically unacceptable consequence of facial nerve palsy, whether due to trauma, Bell's palsy or other etiologies. A variety of face-lift and reanimation techniques have been utilized in the past, but with time, these frequently require further surgery. We describe the use of Mitek (Norwood, MA) suture anchors for cheek resuspension in a patient with facial palsy. This system is composed of a drill guide, drill, inserter, and anchor. Although the titanium alloy anchors come in multiple sizes, the Mini GII Anchor is typically most appropriate for use in facial procedures. The actual size of the Mini GII Anchor is 1.8 mm in diameter and 5.4 mm in length. Two small arched prongs extend from the body of the anchor, and an eyelet at the superior surface is used for suture placement. When placed into a pre-drilled hole with the insertion tool, the prongs extend, effectively fixing the anchor in place. The drill guide protects adjacent soft tissues during the drilling process and allows drilling to a predetermined fixed depth. Sutures attached to the anchor may then be used for soft tissue fixation to bone.

Prostate cancer radiosensitization in vivo with adenovirus-mediated p53 gene therapy.

An adenovirus 5 vector containing wild-type p53 cDNA (Ad5-p53) and a cytomegalovirus promoter was used to generate p53 transgene expression. Control vector (Ad5-pA) contained the poly-adenosine sequence. PC3 cells (2 x 10(6)) were injected s.c. into the legs of nude mice. Treatment with Ad5-p53 was initiated at a tumor volume of 200 mm3. Three intratumoral injections (days 1, 4, and 7) were given with 3 x 10(8) plaque-forming units, followed by 5 Gy pelvic irradiation (day 8) in one fraction using a cobalt-60 source. Tumor volume measurements were obtained every 2 days. LNCaP cells (2 x 10(6)) were injected orthotopically into the prostates of nude mice, and tumor weight was approximated using serum prostate-specific antigen (PSA) obtained from weekly tail vein bleedings. The target PSA for the start of the studies was 5 ng/ml. The intraprostatic injections of Ad5-p53 were done twice (days 1 and 2) and followed by 5 Gy pelvic irradiation on day 3. The PC3 tumor volume growth curves were log transformed and fitted using linear regression. The times (in days) for the tumors to reach 500 mm3 were calculated as 10.7 +/- 0.7 (+/- SE) for the saline control (no virus), 9.8 +/- 2.1 for Ad5-pA, 15.6 +/- 1.6 for Ad5-p53, 14.6 +/- 1.5 radiation therapy (RT; 5 Gy), 14.6 +/- 1.5 for Ad5-pA plus RT, and 31.4 +/- 5.3 for Ad5-p53 plus RT. The Ad5-p53 plus RT times were significantly different from the other groups. An enhancement factor of 3.4 was calculated, indicating supra-additivity. LNCaP tumor growth was determined via weekly serum PSA measurements. Treatment failure was determined using two PSA-based methods; a serum PSA of > 1.5 ng/ml or two rises in PSA during 6 weeks posttreatment. The results were similar using either end point. Treatment with Ad5-p53 plus 5 Gy resulted in significantly fewer PSA failures (<30%), as compared with Ad5-p53 alone (64-73%) and the other controls (approximately 80-100%) These results are also consistent with a supra-additive inhibition of tumor growth. Tumor growth in vivo was inhibited supra-additively when p53null and p53wildtype prostate tumors were treated with Ad5-p53 and 5 Gy radiation.

Adenoviral-mediated p53 transgene expression sensitizes both wild-type and null p53 prostate cancer cells in vitro to radiation.

PURPOSE/OBJECTIVE: The effect of adenoviral-mediated p53 transgene expression on the radiation response of two human prostate cancer cell lines, the p53(wild-type) LNCaP and p53(null) PC3 lines, was examined. The objective was to determine if this vector sensitizes cells to radiation independently of their p53 status. METHODS AND MATERIALS: A recombinant adenovirus-5 vector (RPR/INGN 201, Introgen Therapeutics, Houston, TX) containing a CMV promoter and wild-type p53-cDNA (Ad5-p53) was used to facilitate p53 transgene expression. A multiplicity of infection (MOI) of 10-40 viral particles per cell was used, based on Ad5/CMV/lacz infection and staining for the beta-galactosidase reporter gene product. Clonogenic assays were performed to evaluate the degree of sensitization to radiation of viral-transduced cells compared with irradiated nontransduced controls. The relative efficacy of these treatments to induce apoptotic cell death was determined using the TUNEL assay. RESULTS: The delivery of Ad5-p53 (10 MOI) reduced control plating efficiency from 36.5% to 0.86% in the LNCaP cell line and from 75.1% to 4.1% in the PC3 cell line. After correcting for the effect of Ad5-p53 on plating efficiency, the surviving fraction after 2 Gy (SF2) of gamma-irradiation was reduced over 2.5-fold, from 0.187 to 0.072, with transgene p53 expression in the LNCaP cell line. Surviving fraction after 4 Gy (SF4) was reduced over 4.5-fold, from 0.014 to 0.003, after Ad5-p53 treatment. In the PC3 cell line, Ad5-p53 (40 MOI) reduced SF2 over 1.9-fold from 0.708 to 0.367, and SF4 over 6-fold from 0.335 to 0.056. In both the LNCaP and PC3 cell lines, the combination of Ad5-p53 plus radiation (2 Gy) resulted in supra-additive apoptosis (approximately 20% for LNCaP and approximately 15% for PC3 at 50 MOI), above that seen from the addition of the controls; control vector Ad5-pA plus RT (0.15% for LNCaP and 1.44% for PC3), Ad5-p53 alone (28.6% for LNCaP and 21.7% for PC3), RT alone (0% for LNCaP and 0.23% for PC3), or Ad5-pA alone (0.1% for LNCaP and 0.29% for PC3). CONCLUSION: The clonogenic survival and apoptosis data demonstrate that p53 transgene expression sensitizes human prostate adenocarcinoma cells in vitro to irradiation. As this effect was observed in both the p53(wild-type) LNCaP and p53(null) PC3 lines, radiosensitization was independent of p53 status.

Dose escalation with 3D-CRT in prostate cancer: French study of dose escalation with conformal 3D radiotherapy in prostate cancer-preliminary results.

PURPOSE: To evaluate the feasibility of dose escalation in a multi-institutional study in prostate cancer patients. METHODS AND MATERIALS: Between October 1995 and October 1998, 164 patients with localized adenocarcinoma of the prostate were treated with 3-dimensional conformal radiotherapy at one of five French institutions. The dose of radiation was escalated from 66 to 80 Gy (ICRU point). The maximum dose to the rectal wall was limited to 75 Gy. RESULTS: Results were compared in two groups, one (group 1) receiving the standard dose (n = 46 patients; 66 to 70 Gy) and the other (group 2) receiving the escalated dose (n = 118 patients; 74 to 80 Gy). There was no difference in the characteristics of patients between the two groups. The mean follow-up time was 32 months in group 1 and 17.5 months in group 2. No statistical difference between the two groups was observed in the incidence of late gastrointestinal and urinary toxicities. The probability of achieving a posttreatment prostate-specific antigen nadir of

Outpatient sequential high dose alkylation with stem cell support for patients with advanced breast cancer: a phase I-II study.

We evaluated the feasibility of administering, in an out-patient setting, a sequential high dose alkylating regimen with hematopoietic growth factor (HGF) and stem cell support to patients with advanced breast cancer. Peripheral blood stem cells (PBSC) were previously collected after chemotherapy and HGF. Two consecutive cycles of alkylating agents were planned: Thiotepa (T) then, 15 days later, BCNU (B). Three dose levels of each agent were administered in cohorts of consecutive patients: 400, 500 and 600 mg/m2 respectively. HGF and reinfusion of PBSC followed both cycles. Toxicity and response were evaluated according to the WHO recommendations. From April 1996 to August 1988, 30 women were enrolled: 8 in the first, 12 in the second and 10 in the third dose level. In all cases, B was administered after T with a median delay of 25 days because of grade 3/4 hematological toxicity. 4 patients did not receive B because of previous lung radiotherapy, persistent tricytopenia or insufficient PBSC collection. 19 patients with measurable lesions were considered for response. The objective response rate was 48% (11% CR, 37% PR). We recommended T and B at a dose of 600 mg/m2 to conduct a phase II study in metastatic breast cancer and even to administer B before T.

Activation of extracellular signal-regulated kinase (ERK) and Akt by human serotonin 5-HT(1B) receptors in transfected BE(2)-C neuroblastoma cells is inhibited by RGS4.

Regulator of G protein signaling (RGS) proteins are GTPase-activating proteins for heterotrimeric G proteins. One of the best-studied RGS proteins, RGS4, accelerates the rate of GTP hydrolysis by all G(i) and G(q) alpha subunits yet has been shown to exhibit receptor selectivity. Although RGS4 is expressed primarily in brain, its effect on modulating the activity of serotonergic receptors has not yet been reported. In the present study, transfected BE(2)-C human neuroblastoma cells expressing human 5-HT(1B) receptors were used to demonstrate that RGS4 can inhibit the coupling of 5-HT(1B) receptors to cellular signals. Serotonin and sumatriptan were found to stimulate activation of extracellular signal-regulated kinase. This activation was attenuated, but not completely inhibited, by RGS4. Similar inhibition by RGS4 of the protein kinase Akt was also observed. As RGS4 is expressed at high levels in brain, these results suggest that it may play a role in regulating serotonergic pathways.