Reproducibility of Deep-Inspiration Breath Hold treatments on Halcyon™ performed using the first clinical version of AlignRT InBore™: Results of CYBORE study.

Background and purpose: To investigate the reproducibility of deep-inspiration breath hold (DIBH) breast cancer treatments on Halcyon™ performed using the first clinical version of AlignRT InBore™ (Vision RT Ltd., London, UK), a Halcyon's SGRT dedicated solution. Materials and methods: The ease and feasibility of DIBH treatments was retrospectively investigated for the initial 22 left breast cancer patients treated on Halcyon™ using AlignRT InBore™. Setup time, Cone beam computed tomography (CBCT) imaging and analysis time as well as overall treatment time were recorded. Online and offline review of CBCT images was undertaken to verify the compliance of breast, heart, spine, sternum and diaphragmatic domes positions. Results: Mean duration of patient setup, CBCT analysis and overall treatment time were 4 min, 1.1 min and 14 min respectively. Online review of 520 CBCT acquisitions by therapists showed minimal positioning shifts with AlignRT InBore™ guidance with mean value of vertical, longitudinal, and lateral shifts of 1.7 mm, -1.7 mm, and -0.2 mm respectively. Meanwhile, offline review of 115 CBCTs by the radiation oncologist, showed reproducible breath hold (BH) with average deviation of breast, heart, spine, sternum and diaphragmatic domes respectively within 2.4 mm, 2.9 mm, 3.3 mm, 3.2 mm and 4.5 mm in magnitude. Conclusion: AlignRT InBore™ allows for accurate and reproducible DIBH on Halcyon™ with breast and heart organs' positions within 3 mm in magnitude of expected position and fully compliant with planning margins (5 mm anisotropic CTV-PTV margins).

Contact X-ray brachytherapy for rectal cancer: Past, present, and future.

The Papillon experience and the Lyon R96-02 trial have shown that contact X-ray brachytherapy of 50kV is efficient and safe to achieve long term local control and organ preservation for cT1 and early cT2-3 rectal cancers. The OPERA trial, using the Papillon 50™ machine, brings further support to this preservation strategy for selected T2T3ab lesions. Future trials using a contact X-ray boost will try to consolidate and enlarge its place in organ preservation for rectal cancers.

[Radiotherapy for ovarian carcinoma management: Literature review]. / Place de la radiothérapie dans le traitement des cancers ovariens : revue de la littérature.

Ovarian cancer is the fifth most common cancer in women in France with 4714 new cases in 2017. More than 70% of patients whose disease is initially locally advanced will present locoregional or distant recurrence. Therapeutic options in this situation are not consensual. They are based on chemotherapy possibly associated with an iterative cytoreductive surgery when it is bearable by the patient. The place of radiotherapy in the management of the disease is hidden in the vast majority of national or international standards. We conducted a general review of the literature to clarify the role of irradiation in the global management of ovarian cancers, particularly in recurrence.

[Adjuvant contact radiotherapy for conjunctival malignancies: Preliminary results of a series of 14 patients treated with the Papillon 50 machine]. / Radiothérapie de contact adjuvante des tumeurs malignes de la conjonctive : résultats préliminaires d'une série de 14 patients traités avec l'appareil Papillon 50.

PURPOSE: To evaluate the results of an adjuvant contact irradiation using 50kV photons after resection of conjunctival malignancies. MATERIALS AND METHOD: From 2012 to 2014, 14 patients (male: nine; female: five) have been treated by contact irradiation after resection of a malignant tumor of the conjunctiva (melanoma: five patients; malignant fibrous histiocytoma: one patient; carcinoma: eight patients) The treatment was performed using the Papillon 50 machine (Ariane). Three to four sessions were delivered, each giving a dose of 10Gy. The median follow-up in survivors was 33 months. RESULTS: The tolerance was good. A cataract was seen in one patient, and a moderate eye dryness in one. There was no corneal ulcer. One patient died of intercurrent disease. One patient with carcinoma recurred locally. CONCLUSION: Adjuvant contact radiotherapy provides a good local control after resection of conjunctival malignancies (melanoma, malignant histiocytofibroma, carcinoma). Thanks to its precision, this technique is well tolerated with a low rate of complications. Furthermore, it is delivered on an ambulatory basis.

Capecitabine, irinotecan, oxaliplatin (CAPIRINOX) and concomitant irradiation in advanced rectal cancer: the Lyon R-02-01 phase I trial.

AIMS: To determine the feasibility of radiotherapy-associated capecitabine, irinotecan and oxaliplatin administration at five dose levels for the treatment of locally advanced rectal cancer, with or without metastasis. PATIENTS AND METHODS: This was a bicentric phase I trial, including patients with locally advanced rectal cancer, with or without metastasis. Chemotherapy comprised capecitabine (1100, 1300 or 1500 mg/m2/day, every day), irinotecan (30, 40 or 50mg/m2, once per week for 6 weeks) with the addition of oxaliplatin (40 mg/m2 at level 4 or 50 mg/m2 at level 5, once per week for 6 weeks). Radiotherapy at 46 Gy plus a boost of 4 Gy was administered concomitantly. RESULTS: Twelve patients received four levels of dose. As a supplement to radiotherapy, the combination of capecitabine and irinotecan at the respective doses of 1500 mg/m2/day and 50 mg/m2/week was feasible and well tolerated. The addition of oxaliplatin to this combination provoked toxicity (grade 3/4 vomiting, diarrhoea) for two-thirds of the patients. CONCLUSION: A treatment associating radiotherapy (46 Gy+4 Gy) with concomitant chemotherapy comprising capecitabine (1500 mg/m2/day, every day) and irinotecan (50 mg/m2/week, for 5 weeks) was feasible and well tolerated. The addition of oxaliplatin to these doses was prohibitory to the continuation of treatment due to unacceptable toxicity.

French experience with contact X-ray endocavitary radiation for early rectal cancer.

This paper is an overview of the French experience with contact X-ray radiation for rectal cancer. The analysis was mainly carried out on 50 years of experience in Lyon or since 1980 in the Centre Hospitalier Universitaire Lyon Sud. The results obtained in Dijon and Nancy are also reported. In early rectal cancer, contact X-ray radiation can play an important role in three different situations: (1) small T1 less than 2 cm: adjuvant contact X-ray radiotherapy after local excision; (2) T2 N0 or large T1: first-line contact X-ray radiotherapy combined with external beam radiotherapy (+/- chemotherapy) followed by surgery (anterior resection or local excision); (3) early T3 N0 in frail patients: the same approach as for T2 N0 with, in case of clinical complete response, local excision or follow-up.

[Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases]. / Essai comparatif randomisé en double aveugle clodronate oral 1 600 mg/j versus placebo chez des patientes avec métastases osseuses de cancer du sein.

One hundred forty-four patients with breast cancer and osteolytic bone metastases were randomized to receive either oral clodronate 1,600 mg/d (73 patients) or placebo (71 patients), in addition to either chemotherapy or hormonal therapy, for up to 12 months. Patients were withdrawn from the study when the 12 months of treatment had been achieve or a new bone event occurred, which was defined as: hypercalcemia (> 3 mmol/l), increase in, or onset of new bone pain due to metastases, requirement of radiotherapy for bone pain relief, pathological fractures (including vertebral collapse, spinal cord compression) or death due to bone metastases. Patients are well balanced according to age, performance status, bone condition, except for fractures, more frequent in the clodronate group (25% vs 12%). Of the 137 evaluable patients, 69 received oral clodronate and 68 placebo. Clodronate significantly delayed the median time to onset of new bone events compared to placebo, respectively 244 days and 180 days (p = 0.05). Hypercalcemia did not occur in the clodronate group but was observed in four placebo-treated patients. Clodronate-treated patients had a significant reduction in pain intensity compared to placebo (p = 0.01; measured using a visual pain scale) and significantly fewer patients receiving clodronate required analgesics (p = 0.02). The evaluation of global efficacy by physicians and patients indicated that clodronate was more efficacious than placebo (respectively p = 0.02 and p = 0.01). No significant difference in incidence of adverse effects was observed between the two groups. Clodronate therapy significantly delayed the occurrence of new bone events in these patients with bone metastases from breast cancer and adds to treatment of malignant osteolysis.

A phase I study of a new polyamine biosynthesis inhibitor, SAM486A, in cancer patients with solid tumours.

Because tumour cell proliferation is highly dependent upon up-regulation of de-novo polyamine synthesis, inhibition of the polyamine synthesis pathway represents a potential target for anticancer therapy. SAM486A (CGP 48664) is a new inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), more potent and specific than the first-generation SAMDC inhibitor methylglyoxal (bis) guanylhydrazone (MGBG). Preclinical testing confirmed promising antiproliferative activity. In this phase I study, SAM486A was given 4-weekly as a 120 h infusion. 39 adult cancer patients were enrolled with advanced/refractory disease not amenable to established treatments, PS

[Local excision and adjuvant radiotherapy for rectal adenocarcinoma T1-2 N0]. / Exérèse locale et radiothérapie adjuvante des adénocarcinomes rectaux T1-2 N0.

AIM: To study retrospectively the relapse rate, the functional results and the survival rate in patients with rectal carcinoma treated with local excision and adjuvant radiotherapy. METHODS: Between 1980 and 1995, 43 patients were treated. All cancers were infiltrating tumours except 4 high grade dysplasias with positive margins. The pT classification was: pT1 (n=34), pT2 (n=4), pT3 (n=1). In 4 cases the depth of penetration of the tumor into the bowel wall was not evaluable. The endo-anal excision was performed by surgery (n=20) or by endoscopy (n=23). Only the tumor bed was irradiated in 35 cases (contact x-ray therapy: 30, interstitial iridium implant: 5) and in 8 cases the whole rectum was irradiated with external beam radiotherapy (+/- endocavitary irradiation). RESULTS: Median follow-up was 72 months. Four malignant relapses were observed (local: 1, perirectal lymphatic: 2, distant metastasis: 1). The overall 5- and 10-year survival rates were 80 and 68%, respectively. A total of 41 patients preserved a normal sphincter (95%). The anal function was evaluated as excellent or good in all the cases. No severe radiation toxicity was observed. CONCLUSION: Small rectal carcinomas T1 N0 can be effectively treated in most cases by local excision and postoperative radiation therapy. A close multidisciplinary collaboration is necessary to achieve an optimal result.

Phase I and pharmacological study of weekly administration of the polyamine synthesis inhibitor SAM 486A (CGP 48 664) in patients with solid tumors. European Organization for Research and Treatment of Cancer Early Clinical Studies Group.

A single-agent dose-escalating Phase I and pharmacological study of the polyamine synthesis inhibitor SAM 486A was performed. A dosing regimen of four weekly infusions followed by 2 weeks off therapy was studied. Fifty patients were entered into the study. Dose levels studied were 1.25, 2.5, 5, 8, 16, 32, 48, 70, 110, 170, 270, and 325 mg/m2/week. Pharmacokinetic sampling was done on day 1, and trough samples were taken weekly during the first treatment cycle. Pharmacodynamic sampling was done on days 1 and 22. At 325 mg/m2/week, dose-limiting toxicity was seen (one patient each with grade 4 febrile neutropenia, grade 3 neurotoxicity, and grade 3 hypotension with syncope and T-wave inversions on electrocardiogram). The recommended dose for further testing was set at 270 mg/m2/week. Infusion time was increased from 10 to 180 min due to facial paresthesias and flushing and somnolence. Drug exposure increased linearly with dose. Mean +/- SD t1,2 at 70-325 mg/m2 doses was 61.4+/-26.2 h, with a large volume of distribution at steady state. In peripheral blood leukocytes, a clear relationship between dose and inhibitory effect on S-adenosylmethionine decarboxylase or changes in intracellular polyamine pools was not recorded. SAM 486A can be administered safely using a dosing regimen of four weekly infusions followed by 2 weeks off therapy. The recommended dose for Phase II studies using this regimen is 270 mg/m2/week.

Population pharmacokinetics/toxicodynamics (PK/TD) relationship of SAM486A in phase I studies in patients with advanced cancers.

SAM486A (previously termed CGP 48664), a potent inhibitor of S-adenosylmethionine decarboxylase, is under clinical development for the treatment of advanced refractory malignancies. Hematological toxicity manifested by dose-dependent neutropenia has been observed in phase I studies. Population methods were used to investigate pharmacokinetics (PK) as a prognostic factor for safety end point (hematological toxicity) in patients with advanced cancers. SAM486A plasma concentrations and neutrophil counts were collected from three ascending-dose tolerability and PK studies (study 1: single 5-day continuous intravenous (IV) infusion with doses ranging from 24-700 mg/m2/cycle; study 2: 10-minute to 3-hour IV infusion once weekly with doses ranging from 16-325 mg/m2/week; study 3: 1-hour IV infusion once daily for 5 days with doses ranging from 3.6-202.8 mg/m2/day). The PK of SAM486A were best estimated by a population linear three-compartment model with NONMEM (version 5) using data from 9 patients in studies 1 through 3. The population pharmacokinetic parameters (SD) were CL = 6.2 (0.4) l/h/m2, Q2 = 15.4 (1.5) l/h/m2, Q3 = 33.6 (5.3) l/h/m2, V1 = 9.5 (1.6) l/m2, V2 = 672 (52) l/m2, and V3 = 39.9 (8.3) l/m2, and the corresponding intersubject variability was 45.4%, 74.0%, 85.3%, 80.1%, 37.0%, and 103%, respectively, where CL is total body clearance, Q2 and Q3 are intercompartmental clearances, and V1, V2, and V3 are the volumes of distribution in central and peripheral compartments, respectively. The intrasubject variability was 24.0%. The cumulative AUC before the onset of neutrophil nadir count (AUC) and the duration of exposure over threshold SAM486A concentrations in the range of 0.05 to 0.1 microM based on Bayesian PK parameter estimates significantly correlated with absolute neutrophil count nadir (< 5 x 10(9)/l). AUC showed the best correlation (R2 = 0.72) with absolute neutrophil count nadir by an inhibitory sigmoid Emax model and also correlated with percent decrease in neutrophil count from baseline to nadir by a simple Emax model (R2 = 0.53). Logistic regression analysis indicated that AUC and the duration of exposure over 0.05 to 0.1 microM, but not Cmax, were strong predictors of grade 4 neutropenia (< 0.5 x 10(9)/l). Drug exposure parameters such as AUC derived from population analysis may be used clinically as a useful predictor of drug-induced neutropenia.

Prostate-specific antigen: A surrogate endpoint for screening new agents against prostate cancer?

BACKGROUND: An endpoint for clinical trials of prostate cancer which simplifies traditional endpoints (response of measurable lesions, progression rates, and death) is urgently needed. This is especially true for hormone-unresponsive disease, for which many new drugs are presently in a development phase. This paper presents a rationale for the use of prostate-specific antigen (PSA) in clinical trials of progressive prostate cancer under endocrine treatment. METHODS: The study is based on 84 patients who progressed after radical prostatectomy or node dissection, of whom 24 showed increasing PSA levels under subsequent endocrine treatment. An average linear relationship between (log-transformed) PSA and time and a subject-specific deviation from this average relationship were assessed. The predictive value of the subject-specific parameters of the linear fit with respect to time to prostate cancer-specific death was determined. The outcomes of the fitting procedure were used to calculate sample sizes for future studies (duration, 6 months) using PSA increase over time in hormone-unresponsive prostate cancer as a marker for treatment efficacy. RESULTS: The average PSA doubling time in this population was 4 months (corresponding time constant = 0.25). The assessed variance of the time constants equalled 0.04; the overall residual variance equalled 0.265. The subject-specific rate of change of the log-transformed PSA value in hormone-unresponsive prostate cancer was a highly significant predictor of prostate cancer-specific death. This suggests the potential usefulness of PSA as an endpoint in trials of hormone-unresponsive prostate cancer. Depending on conditions chosen (e.g, desired power and changes in log PSA slope), 18-70 participants per arm will be necessary in future phase III studies. A suggestion (algorithm) for the use of PSA in drug development is presented. CONCLUSIONS: Relatively small PSA-based trials in patients with hormone-unresponsive prostate cancer are possible if a similar patient population is utilized. As long as surrogacy is not established, such studies cannot be considered conclusive with respect to effectiveness of treatment, but are likely to be useful as a screening tool for new drugs. Experimental confirmation in human prostate cancer model systems of synergism between PSA decrease and tumor control by a given test treatment is likely to enhance the level of certainty of PSA-based drug evaluation.

Phase I clinical and pharmacokinetic study of S9788, a new multidrug-resistance reversal agent given alone and in combination with doxorubicin to patients with advanced solid tumors.

PURPOSE: The objectives of this phase I study were to evaluate the toxic effects and the maximum tolerated dose (MTD) of S9788, a new modifier of multidrug resistance (MDR), when given alone and in combination with doxorubicin to patients with advanced solid tumors; to achieve a potentially active plasma concentration of S9788; and to study the pharmacokinetics of both drugs. METHODS: A total of 26 patients (median age 58 years) entered the study. S9788 was given alone as a 30-min infusion at day 1 and in combination with a 50-mg/m2 bolus of doxorubicin at days 8 and 29. Dose levels of S9788 were escalated from 8 to 96 mg/m2 according to the modified Fibonacci scheme. Plasma samples were taken predose as well as during and up to 48 h after the beginning of infusion for S9788 and doxorubicin quantitation. Fractionated urine samples were also collected for up to 24 h for S9788 determination. RESULTS: The dose-limiting side effects of S9788 consisted of bradycardia, sometimes associated with faintness or dizziness. The MTD of S9788 was 96 mg/m2. No enhancement of doxorubicin toxicity was observed. One partial response (duration 140 days) was observed at 96 mg/m2 in a patient with multiple lung metastases from a refractory urothelial carcinoma. Pharmacokinetic studies were performed in 24 patients. Since the mean apparent elimination half-life of S9788 was 46 +/- 23 h and the last plasma sampling time was 48 h, only model-independent parameters were considered. Plasma levels of S9788 were below the limit of quantitation (4 x 10[-3] microM) before each drug administration. S9788 plasma levels of up to 3.7 microM could be obtained with this administration schedule. The urinary elimination of the unchanged drug was negligible, whatever the collection period. In spite of the large inter- and intraindividual variability, plasma pharmacokinetics of S9788 given as a 30-min i.v. infusion were linear up to 96 mg/m2 and were not modified by doxorubicin administration. Doxorubicin pharmacokinetic parameters did not seem to be influenced by S9788 coadministration. CONCLUSION: The dose-limiting toxicity of S9788 consisted of bradycardia or clinical symptoms suggesting a vasovagal impact such as faintness or dizziness. The MTD of S9788 was 96 mg/m2. The pharmacokinetic parameters of doxorubicin in this study were close to those usually described and were not influenced by escalation of the S9788 dose. No pharmacokinetic interaction was observed between S9788 and doxorubicin. The clinical tolerability of the combined treatment is in good agreement with the pharmacokinetic findings, since no enhancement of doxorubicin toxicity was observed.

TOR2 is part of two related signaling pathways coordinating cell growth in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae genes TOR1 and TOR2 encode phosphatidylinositol kinase homologs. TOR2 has two essential functions. One function overlaps with TOR1 and mediates protein synthesis and cell cycle progression. The second essential function of TOR2 is unique to TOR2 and mediates the cell-cycle-dependent organization of the actin cytoskeleton. We have isolated temperature-sensitive mutants that are defective for either one or both of the two TOR2 functions. The three classes of mutants were as follows. Class A mutants, lacking only the TOR2-unique function, are defective in actin cytoskeleton organization and arrest within two to three generations as small-budded cells in the G2/M phase of the cell cycle. Class B mutants, lacking only the TOR-shared function, and class C mutants, lacking both functions, exhibit a rapid loss of protein synthesis and a G1 arrest within one generation. To define further the two functions of TOR2, we isolated multicopy suppressors that rescue the class A or B mutants. Overexpression of MSS4, PKC1, PLC1, RHO2, ROM2, or SUR1 suppressed the growth defect of a class A mutant. Surprisingly, overexpression of PLC1 and MSS4 also suppressed the growth defect of a class B mutant. These genes encode proteins that are involved in phosphoinositide metabolism and signaling. Thus, the two functions (readouts) of TOR2 appear to involve two related signaling pathways controlling cell growth.

Salvage liver surgery of a chemorefractory ovarian choriocarcinoma.

A 41-year-old woman with pure ovarian choriocarcinoma and widespread liver metastases became refractory to standard cisplatin-based chemotherapy regimens. As metastatic disease was limited to the liver and operable, the patient underwent complete resection of three liver metastases. The serum human chorionic gonadotrophin level promptly returned to normal values. Pathologic studies demonstrated the presence of active residual disease composed of typical syncytiotrophoblastic and cytotrophoblastic cells and large mononucleated intermediate cells. The patient remained disease-free for more than 5 years after treatment. It is concluded that liver salvage surgery may cure patients with chemorefractory ovarian choriocarcinoma with metastases to the liver.

Endocavitary irradiation for early rectal carcinomas T1 (T2). A series of 101 patients treated with the Papillon's technique.

PURPOSE: This work is a retrospective analysis of a series of patients treated with endocavitary irradiation stressing the role of transrectal ultrasound (TRUS), which has been used routinely in the staging since 1987. METHODS AND MATERIALS: Between 1977 and 1993, 101 patients with infiltrating adenocarcinomas were treated. Clinical staging was 65 T1 N0 and 36 T2 N0. TRUS used in 36 patients showed: 22 UT1 N0, 10 UT2 N0, and 3 UT2 N1. Contact x-ray was delivered with a 50 kV radiotherapy unit. The median dose was 92 Gy (60-125) in five fractions, 55 days. In 28 patients a boost was given with 192Ir implant delivering a median dose of 25 Gy/21 h. RESULTS: Complete response was observed in all patients at the completion of treatment. Loco-regional failures were seen in 14 patients (local in 7 patients, nodal pararectal in 6 patients, and local + nodal in 1 patient). A curative salvage treatment was attempted in 13 patients and resulted in an ultimate pelvic control rate of 99 patients. Rectal preservation was possible in 92 patients. Overall and specific 5-year survival was 83.3% and 94.4%. No serious complication was observed. TRUS was more sensitive than digital rectal examination to detect involvement of pararectal metastatic nodes (N1). No loco- regional relapse was observed out of 22 UT1 N0. CONCLUSION: Endocavitary irradiation can cure early adenocarcinoma of the rectum without complication. TRUS appears as a significant improvement in the selection of patients amenable to this treatment. If restricted to UT1 N0 tumors, endocavitary irradiation should control locally more than 90% of these patients. Any UN1 is a contraindication for endocavitary irradiation alone.

Combined curative radiation therapy alone in (T1) T2-3 rectal adenocarcinoma: a pilot study of 29 patients.

AIM: Analysis of a pilot study including 29 consecutive patients with high surgical risk or refusal of colostomy treated with radiation therapy alone with curative intent. PATIENTS: Between 1986 and 1992, 29 patients were treated for infiltrating adenocarcinoma of the rectum. Median age was 72 years. Transrectal ultrasound staging was used in 24 patients (T1, 2; T2, 14; T3, 13; N0, 23; N1, 6). In 20 patients the lower border of the tumor was at 5 cm or less from the anal verge and in 19 patients the diameter exceeded 3 cm. CEA was elevated in seven cases. TREATMENT: Contact X-ray (50 kV) was given first (70 Gy/3 fractions). External beam radiation therapy used a three-field technique in the prone position. Accelerated schedule (39 Gy/13 fractions/17 days) with a concomitant boost "field within the field' (4 Gy/4 fractions). Six weeks later an iridium-192 implant was performed in 21 (20 Gy/22 h). RESULTS: Median follow-up time was 46 months. Overall and specific survival at 5 years was 68% (SE = 0.09) and 76% (SE = 0.08). Local control was obtained in 21/29 patients (72%). There was one grade 2 rectal bleeding and five grade 2 rectal necroses. The overall tolerance was good in these frail patients. DISCUSSION: For T2. T3 or T1 > 3 cm diameter rectal adenocarcinoma, where contact X-ray alone is not recommended, a combined treatment with radiation therapy alone is able to give good local control with acceptable toxicity. This treatment should be restricted to inoperable patients.

[Carcinoma of the oropharynx extended to the base of the tongue: radiosurgical treatment with intraoperative radiotherapy]. / Carcinomes de l'oropharynx étendus à la base de langue: traitement radiochirurgical avec radiothérapie intraopératoire.

Treatment by surgery and postoperative radiotherapy is classical for patients with locally advanced oropharyngeal carcinoma. The poor prognosis of these tumors is associated with the frequency of locoregional relapses, and the survival of the patients treated is more limited according to the initial degree of tumoral involvement of the base of the tongue, which is a critical zone: at this level, the surgical resection must not be too large for a good preservation of the function of the tongue; high doses of radiotherapy are also required here for a fair local tumor control. Intraoperative Radiotherapy (IORT) may be available for delivery of high boosting doses of radiotherapy locally in this target volume. Between March 1988 and March 1992, 39 patients were treated for T3-T4 locally advanced oropharyngeal carcinoma, with 1/4 to 1/2 of the base of the tongue involved; 30 patients were treated for a first localization. Surgery was done by transmaxillary buccopharyngectomy (followed by vascularized myocutaneous flap) for 31 patients with lateral tumors; for 8 patients with median tumor (valleculae), either a conservative susglottic laryngectomy (5 patients) or a total laryngectomy was indicated. Patients treated for the first time underwent also a bilateral node dissection. IORT delivered 20 Gy in the target volume of the resected base of the tongue (prescribed at 90% isodose depth) by the mean of an electron beam of 6 to 13 MeV, with a collimator of 4 or 5 cm of inner diameter. Postoperative radiotherapy was indicated for all patients treated with a first localization. After a minimal follow-up of 6 months, the global survival of 28 patients treated for their first localization was 49% at more than 3 years; 64% of patients treated were locally free of disease. In the same delay, and according to the quality of the surgical resection, the survival of patients treated was 67% and 58%, respectively, if non pathological level of resection was beyond 2 mm, or unless 2 mm from the tumor limit. No complication directly related to IORT was noted. These therapeutic results demonstrate the validity of IORT as a part of a radiosurgical treatment indicated for patients with locally advanced oropharyngeal carcinomas. A longer follow-up of patients treated with a first oropharyngeal tumor is warranted for confirmation of the gain on survival observed.

TOR controls translation initiation and early G1 progression in yeast.

Saccharomyces cerevisiae cells treated with the immunosuppressant rapamycin or depleted for the targets of rapamycin TOR1 and TOR2 arrest growth in the early G1 phase of the cell cycle. Loss of TOR function also causes an early inhibition of translation initiation and induces several other physiological changes characteristic of starved cells entering stationary phase (G0). A G1 cyclin mRNA whose translational control is altered by substitution of the UBI4 5' leader region (UBI4 is normally translated under starvation conditions) suppresses the rapamycin-induced G1 arrest and confers starvation sensitivity. These results suggest that the block in translation initiation is a direct consequence of loss of TOR function and the cause of the G1 arrest. We propose that the TORs, two related phosphatidylinositol kinase homologues, are part of a novel signaling pathway that activates eIF-4E-dependent protein synthesis and, thereby, G1 progression in response to nutrient availability. Such a pathway may constitute a checkpoint that prevents early G1 progression and growth in the absence of nutrients.