Local control in medically inoperable lung cancer: an analysis of its importance in outcome and factors determining the probability of tumor eradication.

PURPOSE: For patients who are medically unable to tolerate a surgical resection for technically resectable non-small-cell lung carcinoma, radiation therapy is an acceptable alternative. We report on the effect of achieving local control of the primary tumor on survival end-points, and analyze factors that may influence local control. METHODS AND MATERIALS: We reviewed the records of 152 patients with medically inoperable non-small-cell lung carcinoma treated at our institutions. All patients had technically resectable lesions and no evidence of metastatic disease. Treatment was delivered using megavoltage irradiation to doses ranging from 45 to 75 Gy. RESULTS: For patients with tumors 3 cm or less, locally controlling the tumor significantly improved survival (p = .0371). Patients with T1 tumors had a higher probability of survival and disease-free-survival than patients with larger tumors if the primary tumor was locally controlled, but this survival advantage disappeared if the tumor was not controlled. Overall, patients with smaller tumors had a lower incidence of distant spread, but this association was maintained only when the primary tumor was controlled (36 month risk of 10%, 23%, and 57% for tumors < 3 cm, 3-4.9 cm, 5 cm or greater, respectively, p = .0027). For patients whose tumors were not controlled, there was no significant difference in the risk of distant dissemination by tumor size. Higher radiation doses influenced local control and metastatic spread. We observed no influence of the initial field size in the risk of local control and in the probability of survival. CONCLUSION: Radical radiation therapy is an effective treatment for small (T1 or < 3 cm) tumors when treated to doses of 65 Gy or more, and should be offered as an alternative to surgery in elderly or infirm patients. New therapeutic strategies to improve the local control rate should be considered for larger tumors, through the use of hyperfractionated treatment, endobronchial "boost" irradiation, and sensitizing chemotherapy agents.

Orthotopic transplantation of partially hepatectomized liver in the pig.

One of the major technical obstacles to liver transplantation in children is to find a liver of appropriate size because of the rarity of child donors. To overcome this difficulty an experimental study was carried out using only a portion of the donor liver (right liver) transplanted orthotopically in pigs. A group of 15 allotransplants were performed. A left hepatectomy of the liver graft was performed ex situ and the right liver amounted to 55% of the whole liver. A total of 13 animals survived for more than 5 days (5 to 30 days, with an average of 16). Upon killing, the liver weight was considerably more than that of the part transplanted. The absence of technical complications suggests that this procedure is safe and feasible.

A randomized trial of OKT3-based versus cyclosporine-based immunoprophylaxis after liver transplantation. Long-term results of a European and Australian multicenter study.

A multicenter randomized trial was performed to compare two immunosuppressive protocols after first ABO-compatible liver transplantation. Forty six patients were randomized to a 14-day treatment with Orthoclone (OKT3) in association with steroids and azathioprine, cyclosporine being progressively introduced on day 11 posttransplant. Fifty patients were randomized to a standard protocol of cyclosporine with steroids and azathioprine. Minimum follow-up was 1 year and graft and patient survivals were updated for the purpose of the study. The cumulative 1-year incidence of acute rejection tended to be greater in the cyclosporine group (75%) than in the OKT3 group (67%), especially when patients who did not receive full-course treatment with OKT3 were excluded (59%). Renal function was better preserved during the first two postoperative weeks in the OKT3 group than in the control group but plasma creatinine levels were comparable in both groups thereafter. The incidence of severe infections was lower in the OKT3 group (13.6%) than in the cyclosporine group (32%). The 4-year incidences of patient and graft survival in the OKT3 group (69% and 61%, respectively) were not different from those in the cyclosporine group (62% versus 54%, respectively). Thus this prospective trial shows that OKT3 immunoprophylaxis is a safe alternative to cyclosporine immunoprophylaxis in unselected recipients of a first liver graft.

Clinical outcome and prognosis of patients with inflammatory breast cancer.

This report analyzes clinical factors affecting outcome in 26 patients with inflammatory breast cancer. Peau d'orange was the most common clinical finding at diagnosis (65%). A palpable breast mass (PBM) was noted in 65% with axillary lymph node involvement in 81% of patients. Eighteen patients were staged as stage IIIB and eight as stage IV. Initial metastases included supraclavicular nodes (five of eight), bones (one of eight), skin (one of eight), and liver (one of eight). All patients were treated with neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil, 18 patients; other, 8 patients). Partial response was the best clinical response attained in 38% of patients. Only one patient was treated with total mastectomy after neoadjuvant chemotherapy, and 19 patients received radiotherapy followed (2 patients) or not (17 patients) by mastectomy. The progression rate in stage IIIB patients was 78%, with distant sites of progression in 93% of patients and only 7% with local progression. Mean time-to-progression was 13 months (Kaplan-Meier estimates of 45% and 11% at 24 and 48 months, respectively). The median overall survival (OS) value of the entire population was 13.2 months (Kaplan-Meier estimates at 24 and 48 months of 21% and 12.5%). By Kaplan-Meier method and log-rank test, a better OS was correlated with stage IIIB (p = 0.002), a PBM at diagnosis (p = 0.01), and a favorable response to initial chemotherapy (p = 0.03). Our results confirm the better clinical outcome of patients with stage IIIB and PBM at diagnosis. They also support the role for combined treatment as the best modality approach for this disease. However, overall prognosis remained poor, with recurrence and death resulting from the disease.

Oral ftorafur plus intramuscular thiotepa as adjuvant chemotherapy in patients with breast cancer.

In this study, we evaluated the safety and efficacy of a combination of oral ftorafur administered together with intramuscular thiotepa as adjuvant chemotherapy for "early" breast cancer patients. A total of 30 patients with operated breast cancer were treated with 500 mg/m2 oral ftorafur for 10 consecutive days plus 20 mg/m2 intramuscular (im) administered thiotepa on d 1 and 8 every 28 d adjuvant chemotherapy. Eleven patients were premenopausal and 19 were postmenopausal, with a median age of 53 yr. The total number of cycles delivered was 259 (median: 10 cycles per patient). Toxicity was low and usually consisted of leukopenia WHO grade I-II (14%) and neutropenia grade I-II (6%). Gastrointestinal toxicity was minimal. The 5-yr disease-free survival and overall survival were 55% and 84%, respectively. Relapse occurred as bone metastases (50%), local recurrence (25%), and liver (17%) and brain (8%) metastases. Our preliminary data showed that oral ftorafur and im thiotepa is a well-tolerated regimen and could be a useful alternative to the intravenous parenteral route as adjuvant treatment for early breast cancer. Randomized trials are needed to assess the possible advantage of this regimen over intravenous schedules.

Effect of PGI2 infusion during long term extracorporeal circulation with membrane lung in sheep.

PGI2 plus very low dose of heparin was infused in 6 lambs connected for long term extracorporeal circulation with a membrane lung. Hemodynamic and hemostasis parameters were compared to those of a control group treated only with standard doses of heparin. PGI2 efficacy in inhibiting platelet aggregation and platelet fall was confirmed. A small platelet release, measured as antiheparin activity, was observed during all the by-pass, but did not influence platelet capacity of recovering when PGI2 effect dissolved. Heparin needed resulted less than a quarter of the quantity used for the control group. In our experimental conditions the hemodynamic changes were mainly limited to a decrease in diastolic blood pressure.

[Acute hepatic failure and renal damage. Experimental and clinical studies]. / Insufficienza epatica acuta e danno renale. Rilievi sperimentali e clinici.

Renal damage in acute hepatic failure induced in the pig by means of an hepatic state, temporary or permanent devascularisation Amanita phalloides poisoning or orthotopic liver transplant proved of slight degree, particularly in animals treated with replacement therapy. In the cases of animals that died in acute hepatic coma, on the other hand, renal cortex ischaemia and marked medullary congestion were constant. Histologically, the damage consisted of slight tubular nephrosis; this was more apparent in the proximal tubules. Evaluation of renal damage in 38 patients with acute hepatic failure was more complicated owing to the variety of clinical conditions (level of coma, hypovolaemia, intensive care and hepatic assistance). Nevertheless, a clear relation was established between the degree of liver damage and blood creatinine and creatinine clearance values. All patients who died presented liver cell necrosis of over 75%, blood creatinine values of more than 2 mg/100 ml, and less than 50 ml/min clearance. Tubular nephrosis was the predominant lesion. It appeared that renal damage was primarily pre-renal. No signs of a true hepatorenal syndrome could be made out.

Veno-venous bypass without heparin in orthotopic liver allotransplantation in the pig.

It is now widely accepted that a veno-venous bypass is required to minimize the problems of the anhepatic phase in orthotopic liver transplantation. A technique that does not require systemic anticoagulation is needed to prevent damage by heparinization in hepatic patients. The use of heparin-bonded cannulas offers low risks of thromboembolic complication. Fourteen orthotopic liver transplantation were performed in pigs, including 7 with a roller pump and 7 with a centrifugal pump, without systemic anticoagulation and with heparin-bonded circuits except for the portal cannula, connectors, centrifugal pump head and the tract of the circuit on which the roller moves. All the circuits were previously utilized in clinical liver transplantation and repeatedly washed in saline solution and sterilized for each experiment. The haemodynamic control of the anhepatic state was excellent without hypotension and venous engorgement. In only one case a thromboembolic complication was noted. Arterial pressure, heart rate, urine flow, creatinine, arterial pH and thromboelastographic data did not change significantly while on bypass. No difference was found in the use of either a roller or a centrifugal pump even when the blood flow fell to less than 1000 ml/min to 500 ml/min.

Heterotopic liver allograft in acute hepatic failure in pigs.

Seven heterotopic liver allotransplantations were performed in pigs with total, acute hepatic necrosis, induced by arterial and portal vein devascularization. Six pigs survived for 4, 6, 7, 7, 23 and 90 days respectively. Good results can be obtained only with intensive perenteral postoperative support lasting the first three days. The viability of the graft is shown by the biochemical indices and the survival of the animals. These results confirm that a heterotopic liver transplantation provides a viable substitute when the host liver is affected by acute irreversible hepatic necrosis.

Single lung transplantation for emphysema. Lessons learned on the field. The Lung Transplant Group of the Ospedale Maggiore of Milan.

Emphysematous patients that were once treated with double lung transplantation can now also be treated with single lung transplantation. However, single lung transplantation in emphysematous patients presents problems in lung size matching, choice of side to transplant and post-operative assistance. Analysing their own experience of three single lung transplants performed on emphysematous patients, the Authors evaluate the effectiveness of the operation, the results and the difficulties encountered. Single lung transplantation is a good therapeutic option for end-stage emphysematous patients. In these patients right lung transplantation is preferable and the donor organ should be oversized. Positive and expiratory pressure in the native emphysematous lung should be applied with extreme caution.

Left lung allotransplantation in pig feasibility and transplanted lung function. Experimental Lung Transplant Group of Ospedale Maggiore of Milan.

Changing attitudes to animals in research and practical considerations prompted the authors to evaluate whether the pig might be a suitable substitute for dog and baboons for single left lung transplants. Twenty-nine paired pigs were used. The first transplants on 13 pairs (group 1) were done to adapt the lung transplant technique to pigs; later transplants on 16 pig pairs (group 2) were done to evaluate operative survival, and function and histological modifications of the transplanted lung in the absence of immunosuppressive treatment. Surgical and anesthetic techniques for both donor and recipient are described in detail. The survival rate in group 2 was 68%. Hemodynamic and blood gas changes were assessed during operation. PaO2 did not drop significantly after occluding the right pulmonary artery by an inflatable cuff placed around it; this suggests that the function of the transplanted lung was preserved. The pigs were put down on the third postoperative day. Vascular and bronchial anastomoses were patent and intact, but the transplanted lung was macroscopically and microscopically altered. Lung transplants can be performed in pigs and the transplanted lung seems to be capable of functioning immediately after the operation. Alteration in the lung after 3 days is probably due to rejection.

[Evaluation of plasma carnitine levels after orthotopic transplantation of the liver]. / Valutazione dei livelli plasmatici di carnitina dopo trapianto ortotopico di fegato.

Variations in plasma levels of total carnitine (TC), free carnitine (FC), and acyl-carnitine (AC) were studied in 10 patients undergoing orthotopic liver transplantation. The postoperative values were higher than the preoperative ones and positively related to time flow. As exogenous carnitine was not supplied during the study, these data suggested a better biosynthetic activity in the transplanted liver, in spite of standard blood tests results. No positive correlation between carnitine levels and variations in serum transaminases, bilirubin, cholestasis related enzymes, pre-albumin and albumin supply was found. Carnitine plasma levels were not influenced either by nutritional caloric input or by methionine and lysine inputs. Our results show that variations in carnitine plasma levels are a specific and responsive index of functional recovery in the transplanted liver.

WE-E-BRB-05: A Novel Detector Dose Calculation Model for in Vivo Delivery Verification of IMRT Treatments.

PURPOSE: Exit 2D detectors are widely used in clinics as a tool for pre- treatment field verification. It is desired to have accurate modeling of the detector dose for each IMRT plan with patient geometry for in-vivo delivery verification. We propose a novel hybrid of model and measurement based methods to estimate the detector dose using the information from TPS and plan/verification CT. METHODS: Our approach is based on the generalized equivalent field size (GEFS) method. It requires two commissioning tables for various square fields (l×l, 2×2, …40×40): the percent depth dose (PDD) table and the detector correction factor (DDCF) table. PDDs are retrieved from the treatment planning system (TPS), and DDCFs are reconstructed from measurement with various field sizes and air gaps (from 5 cm to 50 cm). GEFS models the detector point dose as the superposition of annular contribution of the fluence map, which is retrieved from the TPS. Correction on the radiological path length is calculated through ray-tracing the patient CT. Corrections on the air gap between the couch and detector and detector response are applied via table lookup on PDD and DDCF. RESULTS: We validated the proposed method using TPS with extended geometry and direct clinic measurements for both regular and IMRT fields, various phantom and patient geometry. For all calculations, more than 98% of pixels pass the gamma index with criteria of 3%, 3mm. Each calculation took only a few seconds on a single PC. CONCLUSIONS: We proposed a novel detector dose calculation method that can be applied for arbitrary IMRT field and arbitrary patient geometry. The calculation is simple and fast and when compared with detector measurement during IMRT treatment, makes in- vivo delivery verification and dose reconstruction feasible.