Laurent H. Schwartz

Kidney mobility during respiration

Radiotherapy treatment planning needs optimum definition of the target volume in its relative position to normal tissue. The motion of the kidneys during respiration has not been well quantified. They move in a tilted coronal and sagittal plane. Using fast MRI while patients held their breath we quantified the movements of the kidneys. Fourteen patients volunteered for the study. Nine MRI images of the kidneys for one volunteer were done: three in the axial plane (all in deep inspiration) and six in the coronal plane (three in deep inspiration, three in deep expiration). The maximal vertical motion of the superior pole from its end-expiratory to its end-inspiratory position is 39 mm (43 mm for the inferior pole). In deep inspiration or deep expiration the positions of the right and left kidneys appear reproducible. The mean deviation of kidney movement is less than 4 mm in all three dimensions (range, 0-6.9). For tumors close to the kidney, we advocate respiration gated radiation therapy so as to minimize the movement of this very radiosensitive structure.

Radiation therapy in the treatment of difficult giant cell tumors

Thirteen patients with giant cell tumors of bone have been treated by radiation therapy because surgery was not feasible or unacceptably disfiguring. Seven patients were treated for primary giant cell tumors of the bone, four for recurrent disease, and three for metastasis (one presented with both distant metastasis and local recurrence after primary surgery). The follow-up time ranged from 18 months to 13 years, with a mean of 6.5 years. All patients except one are alive. Local control was achieved in 11 patients (85%). One patient whose tumor was located in the sacrum had no gross response and at 5 months was subjected to a partial sacrectomy. A second patient had local regrowth 1 year after treatment; salvage surgery was successful. There have been no long-term complications of radiation therapy. This study confirms that for patients with giant cell tumor of bone, radiation therapy offers an effective alternative to complex or difficult surgery and constitutes a good treatment method to medically inoperable patients.

Total-body irradiation and cataract incidence: A randomized comparison of two instantaneous dose rates

PURPOSE To assess the influence of instantaneous total-body irradiation dose rate in hematological malignancies, we randomized 157 patients according to different instantaneous dose rates. METHODS AND MATERIALS Between December 10, 1986 and December 31, 1989 157 patients have undergone a total-body irradiation before bone-marrow transplantation according to two different techniques: either in one fraction (1000 cGy given to the midplane at the level of L4, and 800 cGy to the lungs) or in six fractions (1200 cGy over 3 consecutive days to the midplane at the level of L4, and 900 cGy to the lungs). Patients were randomized according to two instantaneous dose rates, called LOW and HIGH, in single-dose (6 vs. 15 cGy/min) and fractionated (3 vs. 6 cGy/min) TBI groups; there were 77 cases for the LOW and 80 for the HIGH groups, with 57 patients receiving single-dose (28 LOW, 29 HIGH) and 100 patients receiving fractionated total-body irradiation (49 LOW, 51 HIGH). RESULTS As of July 1992, 16 (10%) of 157 patients developed cataracts after 17 to 46 months, with an estimated incidence of 23% at 5 years. Four (5%) of 77 patients in the LOW group, 12 (15%) of 80 patients in the HIGH group developed cataracts, with 5-year estimated incidences of 12% and 34%, respectively (p = 0.03). Ten (18%) of 57 patients in the single-dose group, and 6 (6%) of 100 patients in the fractionated group developed cataracts, with 5-year estimated incidences of 39% and 13%, respectively (p = 0.02). When the subgroups were considered, in the single-dose group, 3 (11%) of 28 LOW patients, and 7 (24%) of 29 HIGH patients developed cataracts, with 5-year estimated incidences of 24% and 53%, respectively; in the fractionated group, 1 (2%) of 49 LOW patients, and 5 (10%) of 51 HIGH patients developed cataracts, with 5-year estimated incidences of 4% and 22%, respectively (single-dose LOW vs. single-dose HIGH vs. fractionated LOW vs. fractionated HIGH, p = 0.006). There was no statistically significant difference in terms of 5-year estimated cataract incidence between the patients receiving steroids and those not (30% vs. 25%, p = 0.22). Multivariate analyses revealed that the instantaneous dose rate was the only independent factor influencing the cataractogenesis (p = 0.04). CONCLUSION We conclude that the total-body irradiation regimen (instantaneous dose rate and/or fractionation) may have an influence on the development of cataracts following bone-marrow transplantation.

pS2 expression in primary breast carcinomas: Relationship to clinical and histological features and survival

SummarypS2 protein expression has been reported to have prognostic significance in human breast carcinomas and to correlate with estrogen receptor positivity, although these findings have not been confirmed by all investigators. pS2 positivity was compared to various clinical and histologic parameters in a retrospective study of 290 patients (median follow-up 7.2 years) and significantly correlated with tumor grade and estrogen receptor content (p=0.001 and p=0.0007, respectively). Significant associations between pS2 positivity and lymph node metastases, T stage, histologic tumor type, and patient age were not observed. Univariate and multivariate analyses (controlling for estrogen receptor content, T and N stage) of the patient population at large showed that pS2 positivity was not predictive of disease-free or overall survival. Univariate analysis of lymph node negative patients demonstrated that both pS2 and estrogen receptor positivity were significantly associated with a better outcome. Multivariate analysis of these patients, however, showed that only estrogen receptor data had independent prognostic significance. This study suggests that immunohistochemical analysis for pS2 protein expression will not contribute additional prognostic information if the estrogen receptor content is known.

A modified 60C teletherapy unit for total body irradiation

PURPOSE A modified teletherapy unit to achieve total body irradiation with a vertical beam in a conventional treatment room. METHODS AND MATERIALS A standard 60C teletherapy unit has been modified to achieve total body irradiation with a vertical beam in a conventional treatment room. Patients are treated in prone and supine positions. Removal of the adjustable collimator assembly of this standard machine provides a circular field of 196 cm in diameter at 167 cm from the source. Second, the machine has been elevated by about 50 cm on a metallic base to enlarge irradiation field to obtain 248 cm in diameter at 210 cm from the source, and to encompass tall patients under better conditions. A special lead conical beam flattening filter, 10-mm thick at the center, was designed to compensate the spatial inhomogeneity of the beam. An instantaneous dose rate of 6.10(-2) Gy/min is attained at the L4 level (midplane) in an average 20-cm thick patient with a source activity of 5099 RHM (air kerma rate of 44.8 Gy.h-1.m2). Between February 2, 1984 and December 27, 1990, 244 total body irradiations were performed either by single dose (n = 69, 10 Gy were given to midplane at L4 level in about 6 to 8 h, 8 Gy to the lungs), or by fractionated dose (n = 175, 12 Gy were given in 6 fractions over 3 consecutive days to midplane at L4 level, 9 Gy to the lungs). RESULTS The dose distribution is similar than the ones obtained by a linear accelerator with patients lying on their sides. CONCLUSION Patients were treated in a comfortable and highly reproductible position. Organ shielding was easily achievable. This could be a less expensive and reasonable alternative to linear accelerator.

A PRELIMINARY COMPARATIVE TREATMENT PLANNING STUDY FOR RADIOTHERAPY OF AGE-RELATED MACULOPATHY

PURPOSE We present a comparative planning of different approaches for external radiotherapy in age-related maculopathies. MATERIALS AND METHODS Calculated dose distributions and dose-volume histograms for (a) bilateral irradiation with 6 MV photons, (b) a single lateral-oblique beam using either photons, electrons or protons and (c) an anterior circular proton beam. RESULTS For lateral photon or electron beams the dose to the lens is usually lower than 10% of the dose to the macula. The entrance doses for bilateral photon beams are about 50% which increase up to 100% at the orbital bone. About 5 mm of optic nerves are irradiated at the maximal dose while the optic chiasma is spared. A single photon beam gives 50% of the dose to the fellow eye. The electron beam spares the fellow eye but gives a rather inhomogeneous dose to the target volume. For a lateral proton beam, 4 mm of optic nerve receives 90% of the dose, the skin dose is at least 70% of the dose to the macula and the lens and the fellow eye are spared. An anterior proton beam gives 90% of the dose to 1 mm of optic nerve and the 50% isodose approaches the periphery of the lens. CONCLUSION Doses to the critical structures can be dramatically diminished for all the techniques by reducing the beam size, but only if very precise set-up techniques are used. Proton beams are an attractive solution, but the impact of such a choice on the use of proton facilities and on the national health system should be carefully evaluated, as well as the risk of radio-induced secondary neoplasias.

Hypoxia Immunity, Metabolism, and Hyperthermia

Hypoxia is common in solid tumors and in many other disease states such as myocardial infarction, stroke, bone fracture, and pneumonitis. Once hypoxia has developed, the undernourished and hypoxic cells trigger signals in order to obtain new blood vessels to satisfy their increasing demands and to resolve hypoxia. The principal signal activated is an ancestral oxygen sensor, the hypoxia inducible factor (HIF). After its nuclear translocation, HIF triggers a series of mediators that recruit, into the hypoxic milieu, several immature myeloid, mesenchymal, and endothelial progenitors cells. Resident and recruited cells participate in the processes of neoangiogenesis, for resolving the hypoxia, while at the same time trigger an inflammatory reaction. The inflammatory reaction has as primary end point, the repair of the damaged area, but if an insufficient production of resolvins is produced, the inflammatory reaction becomes chronic and is unable to repair the damaged tissue. In this brief overview, we will show the differences and the similar events present in cancer, myocardial infarction, and stroke. Furthermore, the metabolic alterations produced in the tumor by hypoxia/HIF axis and the consequences on hyperthermic treatment are also discussed.

Abstract 3832: Tolerance of oral lipoid acid and hydroxycitrate combination in cancer patients: first approach of the cancer metabolism research group

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: our previous publications demonstrate that lipoic acid (ALA) and hydroxycitrate (HCA) combination decreases the tumor growth in mice with either lung cancer, bladder cancer or melanoma. ALA is a well known treatment of the diabetic neuropathy but its interest in cancer is growing. In fact, ALA is a cofactor in mitochondrial energy metabolism and a potent regulator of the cells redox status with effects on P13K and AMPK signaling and related transcriptional pathways. These mechanisms increase its interest in cancer and aging relative diseases. HCA (garcinia extract) a weight loss supplement, a derivated citric acid, could act by competitively inhibiting the enzyme adenosine triphosphate citrate lyase. This could also be a way to inhibit tumor cells growth as other evoked mechanisms (increase of serotonin in the brain, inhibition of pancreatic alpha amylase and intestinal alpha glucosidase leading to a reduction in carbohydrate metabolism. So, both molecules target the abnormal metabolic pathways such as seen in cancer. There combination appears in mice to be more effective than their use alone. We report here the early clinical tolerance evaluation of a daily metabolic combination in humans associated with chemotherapy. Methods and patients(p.) Italian experience: median duration of 14,5 months (4 to 20 m),4 p.: 3 F, 1 M, median age 57 years (37 - 81 y), 1 breast cancer, 1 nasopharyngeal carcinoma, a pancreatic adenocarcinoma, a glioblastoma. Doses of ALA 1,2 g/d, HCA 1,2 g/d orally. AlL but one p. had concomitant chemotherapy. French experience: Jan 08 to Nov 11, 13 p. with local relapse and/or metastatic cancer with a combination of ALA -HCA, 7 M, 6 F, median age 45 y (28 –74) 2 colon, 1 lung, 1 hepatocarcinoma, 5 sarcomas, 1 neuro-endocrine. HCA was administered orally, 3 g / d (1 g x3/d). ALA 1,8 g /D (600 m g x3/d) and from Oct 11 increased to 6 g /d for 3 last 6 p. Median duration: 3 months (15 d - 5 m, 1 pt 20m). Results: This association was well tolerated with few clinical disturbances: vomiting, nausea, 5 patients had a gastric protective treatment and 2 because of corticotherapy. The increased dose of ALA was well tolerated. No hepatic toxicity found, no weight loss, no hypoglycemia. A problem was the bad and discontinued observance for patients in relation with the cost of these medicines, the difficulty to buy them (only by online pharmacy for ALA in France).The tolerance of HCA was mild because of gastric pain but patients continue the treatment. Conclusion: ALA - HCA a combination well tolerated is a promising treatment in cancer patients. The switch to IV ALA will permit to obtain higher blood peaks and better observance. Randomized clinical trials are necessary to evaluate the efficacy on tumor progression in correlation with pharmacologic studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3832. doi:1538-7445.AM2012-3832

La protonthérapie : aspects technologiques, applications cliniques et perspectives

Protontherapy certainly presents a ballistic advantage with in-depth dose distribution following a Bragg peak. Some fifteen health-care centres are presently applying this technique in the U.S. Europe and Japan. - Low-energy systems allow the treatment of tumours of the eye while higher energies are able to reach tumours deep in the trunk. - The present two major indications are the conservative treatment of ocular melanomas and the post-operative irradiation of sarcomas of the skull base and of the spinal canal. - Other treatments are presently being explored : carcinomas of the prostate ; tumours of the head and neck, of the central nervous system and of the liver.

Adenocarcinoma of the distal esophagus and gastroesophageal junction

In order to address this question, 128 patients with adenocarcinoma of the distal esophagus and G-E junction who were treated between 1980 and 1985 were reviewed retrOSPeCtiVelY. Ninety-eight patients who were free from demonstrable metastases were subjected to surgery, and 30 patients who were judged incurable were treated palliatively. The patient characteristics were as follows: The age ranged from 29-83 yrs; the sex ratio was 6:1 for male to female; and tumor stage included Tl in 10, T2 in 26, and T3-4 in 51. Lymph node involvement was noted in 46 of 48 patients with stage T3-4 lesion. Postoperative adjuvant therapies included postoperative radiotherapy CRT) in 21 and postoperative chemotherapy (CT) and RT in 27 Patients. Postoperative RT delivered 45-50 Gy in 1.8 Gy per fraction, 5 days per week to the tumor bed and regional lymph nodes. CT consisted of 5-FU 600 mg/m* day 1, mitomycin-C 10 mg/m* day 1. 7, 28, 35; Adriamycin 30 mg/m* day 1, 29; and