The use of local allograft irradiation following renal transplantation

Over a 10 year period, 67 recipients of 71 renal allografts received graft irradiation following the diagnosis of rejection. The majority of kidneys were treated with a total dose of 600 rad, 150 rad per fraction, in 4 daily fractions. Fifty-three kidneys were irradiated following the failure of standard systemic immunosuppression and maximally tolerated antirejection measures (pulse high dose steroids, Actinomycin, ATG) to reverse an episode of acute rejection. Seven of these patients (13%) had greater than a 50% improvement in serum creatinine (Cr) 1 week following completion of the irradiation. Twenty-two (42%) of these allografts were noted to have stable (i.e. no deterioration) or improved function 1 month following the treatment with irradiation. Eleven (21%) of these allografts maintained function 1 year following transplantation. There were 10 patients whose allografts were irradiated because of renal dysfunction in a clinical setting which did not permit the administration of further immunosuppression, i.e., infection or hematologic dyscrasias. Three of these patients (30%) had greater than a 50% improvement in serum Cr 1 week following completion of the irradiation. Nine (90%) of these allografts had stable or improved function 1 month following the treatment with irradiation. Biopsies were obtained of 41 allografts. Of the 24 renal allografts with predominantly cellular rejection, 10 (42%) had the process reversed or stabilized at 1 month following irradiation. Five (21%) of these allografts were functioning at 1 year following irradiation. Rejection was reversed or stabilized in 6 of 17 (35%) allografts at 1 month when the histologic features of renal biopsy suggested predominantly vascular rejection. One (6%) of these allografts was functioning at 1 year following transplantation. Local graft irradiation has helped maintain a limited number of allografts in patients whose rejection has failed to respond to systemic immunosuppression. Irradiation may also benefit patients with ongoing rejection in whom further systemic immunosuppression is contra-indicated.     

Graft irradiation in the treatment of acute rejection of renal transplants: A randomized study

A randomized study of graft irradiation in the treatment of acute rejection of renal transplants was conducted from 1978 to 1981. Patients developing clinical signs of an acute graft rejection received customary antirejection treatment in the form of intravenous administration of high-dose (1 gm per day) of methylprednisolone. They were at the same time randomized to either receive therapeutic irradiation (175 rad every other day to a total of 525 rad) or sham irradiation. Neither the patient nor the Transplant Service surgeons knew at any time whether the radiation treatment had been given. Eighty-three rejection episodes occurring in 64 grafts were entered into the study. Acute rejection was reversed in 84.5% of grafts in the control and 75% in the treated group. The incidence of recurrent rejection was higher in the treated group (66 vs. 46% ) and graft survival was lower (22% vs. 54% ). The study failed to demonstrate a beneficial effect of graft irradiation in the treatment of acute renal allograft rejection, when used in conjunction with high dose steroids.     

Prospective randomized study of the efficacy of adjuvant hormone therapy in patients with breast cancer

Tentative results of a randomized controlled evaluation of the effectiveness of adjuvant hormonal therapy of breast cancer are discussed. The data on 118 cases examined in 1981-1984 were considered on the basis of menstrual cycle characteristics and extension of tumor. The results obtained as a result of an average 16.9 month-long examination pointed to a relatively higher recurrence incidence in untreated patients and suggested that such studies should be continued. Tolerance evaluation established a higher incidence of side-effects in cases treated with diethylstilbestrol (33.3%) than with tamoxifen (3.8%).     

Radiotherapy of malignant glioma--prospective randomized clinical study of whole brain vs local irradiation

Prospective randomized clinical study was conducted to evaluate the factor of radiation field in radiotherapy for malignant glioma from 1981 to 1988 at Tokyo Women's Medical College. Radiation methods were randomized to two groups; (I) whole brain (40 Gy) and local irradiation (18 Gy), total dose 58 Gy/29 f/6 weeks (TDF 91), (II) local irradiation, total 56 Gy/28 f/6 weeks (TDF 90). Twenty three cases were registered as group I and 26 cases as group II. Two and four years cumulative survival rate were 43% and 17% in group I and 39% and 27% in group II. There were no significant differences on response, survival, recurrent pattern, late effect and complications between whole brain and local irradiation. This study confirmed that local control was the most important in the treatment of malignant glioma.     

Acute leukaemia following renal transplantation

Four renal transplant patients on immunosuppressive therapy who presented with acute myeloid leukaemia are described. In two cases, azathioprine may have played an important role as a cofactor in leukaemogenesis. In a third case, the alkylating agent cyclophosphamide may have contributed. All patients were treated for leukaemia with full doses of cytotoxic chemotherapy and, in each case, a functioning renal allograft was preserved throughout the treatment despite attenuation of immunosuppressive therapy. Three patients achieved complete remission. Of the three, one is surviving at 2 years and two expired during the pancytopenic phase of their treatment with no active leukaemia present, and with intact renal function. As increasing expertise in the field of organ transplantation allows patients to survive longer, such patients’ exposure to immunosuppressive and potentially leukaemogenic drugs is prolonged. The risk of secondary neoplasia has been previously documented in this population. Two of the four cases reported here suffered from polycystic kidney disease as their underlying condition. While this report suggests that the leukaemias are related to renal transplantation, we cannot rule out an association with the underlying disease which led to the transplant. This report further suggests that the leukaemia that develops in such patients may respond to standard therapy, and that such treatment does not compromise the transplanted kidney.     

肾移植术后恶性肿瘤

目的 总结我们中心肾移植病人恶性肿瘤的发病情况,探讨预防及治疗措施。方法 回顾分析我们中心从1979年12月-2001年5月1037例临床资料。结果 在1037例肾移植病人中发现15例恶性肿瘤,发病率为1.4％。其中最多的是肝癌(6/15),其次是卡帕氏肉瘤(4/15),再其次是肺癌(2/15)。结论 肾移植术后病人恶性肿瘤的发病率较一般人群高;治疗的效果取决于早期发现肿瘤并及早施行手术;同时,用最小的免疫抑制剂维持移植肾的正常功能。     

A randomized study of adjuvant chemotherapy for cancer of the upper aerodigestive tract

A prospective, randomized trial of induction chemotherapy in advanced squamous cell carcinomas of the upper aerodigestive tract (UAD) was conducted between July 1979 and September 1982. Eighty-three patients with locally advanced Stage III-IV tumors received standard treatment (STD RX; defined as preoperative irradiation and radical excision or irradiation alone), or induction chemotherapy (CTX) followed by STD RX. Chemotherapy consisted of two cycles of bleomycin (30 units/day by continuous infusions Days 1-4), cyclophosphamide (200 mg/m2 IV Days 1-5), methotrexate (30 mg/m2 Days 1 + 5), and 5-fluorouracil (400 mg/m2 IV Days 1-5). Response to CTX was complete in 2 and partial (greater than 50% reduction) in 27; the overall response rate was 68%. Tumor clearance was documented in 30/40 STD RX patients at completion of irradiation and/or surgery and in 24/43 CTX patients (17/29 responders, 7/14 non-responders). Freedom from local-regional disease was noted at 2 years in 53% STD RX and 35% CTX patients (p less than .06). CTX patients had a higher proportion of local-regional persistence and recurrence. The difference was apparent only in the subset of patients treated with primary irradiation; local-regional control following irradiation and surgery was equal in STD RX and CTX groups. Survival at 2 years was 43% STD RX and 31% CTX. Disease-free survival in those with clearance was 64% STD RX and 59% CTX. Induction chemotherapy did not improve tumor clearance or survival in this series. Caution regarding local-regional control with CTX and primary irradiation is noted.     

Polycythemia following renal transplantation unrelated to the allograft

A case of polycythemia following renal transplantation is described. The polycythemia, which was associated with high erythropoietin levels, reverted to normal after bilateral nephrectomy of the patient's own glomerulonephritic kidneys. It is concluded that polycythemia following renal transplantation is not always due to the allograft.     

Biochemical disease-free survival following adjuvant and salvage irradiation after radical prostatectomy

PURPOSE: To present the biochemical cure rates (biochemically no evidence of disease) after external irradiation (RT) in patients with high-risk prostate cancer after radical prostatectomy. METHODS AND MATERIALS: Seventy-six patients who underwent radical prostatectomy and subsequent RT were included in this analysis. No patient received hormonal therapy. Adjuvant RT was administered in 35 patients (46%), and 41 patients (54%) underwent salvage RT. After prostatectomy, the Gleason score was <7 in 87%, and 24% had seminal vesicle invasion. The median RT dose in the adjuvant RT and salvage RT groups was 60 Gy and 65 Gy, respectively. The biochemical cure rate was defined as a serum prostate-specific antigen of < or =0.2 ng/mL. RESULTS: The overall 5-year Kaplan-Meier biochemical control rate from the end of RT was 70%. The 5-year biochemical cure rate for adjuvant RT was significantly superior to that after salvage RT (86% vs. 57%). The significant predictors of biochemical failure were seminal vesicle invasion in the adjuvant RT group and the presence of Gleason grade 4 or 5 in the salvage RT group. The clinical local control rate in the prostate bed was 100%. CONCLUSION: This report demonstrates the efficacy of RT in achieving high biochemical cure rates after radical prostatectomy. Additional clinical studies are required to determine the optimal treatment of patients at high risk of biochemical failure after postprostatectomy RT.     

Seminiferous epithelial function in the pubertal rat following local testicular irradiation

The dose- and time-related responses of the irradiated seminiferous epithelium in the pubertal rat have been investigated. The threshold dose for Sertoli cell dysfunction, as assessed by serum androgen binding protein (ABP) concentrations, was estimated to be 5 Gy. A significant reduction (to less than 50% of control levels) in serum ABP was observed at 8 weeks post-irradiation, with further reductions at later times (24 and 36 weeks). Serum follicle-stimulating hormone (FSH) was elevated to between 130 and 175% of control at only 2 weeks post-irradiation, but recovered with time. Normal FSH levels seemed to be related to recovery of spermatogenesis, as assessed by counts of regenerating tubule cross-sections. The results indicate that the clonogenic spermatogonia and Sertoli cells of the pubertal rat testis are less sensitive to radiation than those of the adult.     

Leydig cell function in the pubertal rat following local testicular irradiation

Dose- and time-response relationships were measured after irradiation of the pubertal rat testis with between 1 and 20 Gy of 300 kVp X-rays. The threshold dose for Leydig cell dysfunction was about 5 Gy. Dysfunction after higher doses was observed by 2 weeks post-irradiation as a dose-dependent decrease in serum testosterone (T) concentrations, and the levels were undetectable after 15 or 20 Gy. Despite the recovery of serum T by 24 and 36 weeks, dysfunction of the Leydig cell population was still observed as an increase in luteinizing hormone (LH) secretion (1.5 to 2-fold increase after 15 or 20 Gy at 24 weeks; 2 to 3-fold increase after 10 or 20 Gy at 36 weeks). The endocrine changes were probably due to the observed loss of Leydig cells following irradiation. These results indicate that the Leydig cells of pubertal rats are more radioresponsive than those of the adult.     

A randomized control study of the antiemetic efficacy of betamethasone versus methylprednisolone

A randomized control study of the antiemetic activity of betamethasone (B) vs. methylprednisolone (MP) was carried out. Fifty-six patients receiving CDDP (60 mg/m2-80 mg/m2) were entered. B (8 mg/body on day 1, 4 mg/body on days 2 and 3) was administered intravenously in 18 patients, and MP (1,000 mg/body on day 1, 500 mg/body on days 2 and 3) was administered intravenously in 19 patients. Severe vomiting occurred in 5 of the 19 (26.3%) with MP, 10 of the 18 (55.6%) with B, and 11 of 19 (57.9%) controls. Severe nausea occurred in 3 of the 19 (15.8%) with MP, 6 of the 18 (33.3%) with B, and 5 of the 19 (26.3%) controls. Methylprednisolone was thus considered effective (P less than 0.05) for CDDP-induced emesis.     

Early detection of damage following bilateral renal irradiation in the mouse

The rate and early pattern of development of radiation-induced renal damage has been determined in the mouse by measuring reductions in both haematocrit and excretion of 51Cr-EDTA, and increases in both urination frequency and urine volume. Kidneys of CBA mice were irradiated bilaterally with 2 fractions of X-rays, one week apart. Renal function was determined immediately prior to irradiation and at 3-4 weekly intervals to 22 weeks post-irradiation. Onset of damage was detected as early as 3-6 weeks using the urination frequency assay. This was confirmed by estimating the volume of urine excreted. A significant fall in haematocrit was not detected until 6-9 weeks post-treatment and a fall in isotope clearance was not detected significantly until 12 weeks. This early detection of damage was consistent with reports using both mouse and other species. The time at which damage was detected first was independent of radiation dose for the frequency and haematocrit assays. For 51Cr-EDTA clearance, there was the suggestion of earlier functional loss for the higher doses. Following the onset of damage, a steady, dose-dependent decline in renal function was measured by all assays. The latency period is defined as the time required to reach a given level of functional damage. This time decreased with increasing radiation dose, to a minimum value set by the time of onset of damage, which varied from 3 to 12 weeks, depending on the assay used. The differences in response measured prior to 12 weeks post-irradiation represent the first occasion on which a dissociation between these 3 assays has been detected.(ABSTRACT TRUNCATED AT 250 WORDS)     

A randomized study of efficacy of regimes of large-fraction irradiation for metastatic lesions to the skeleton. (I) Single factor analysis

A randomized study included 167 patients with metastases to the bone (breast cancer--73%). 117 patients received distance radiotherapy on an area-by-area basis: 2 areas--30, and 3 or more areas--20. Radiotherapy was not used until chemo-hormonal proved useless. The following four regimes were used (1) 4 fractions of 6.5 Gy each (overall dosage--26 Gy) (2 fractions per week); (2) 5 fractions of 6.5 Gy each (overall dosage--32.5 Gy) (2 fractions per week); (3) 4 daily fractions of 6.5 Gy each (overall dosage--26 Gy), and (4) 23 fractions (overall dosage--46 Gy) (5 weekly fractions). Overall efficacy was 96.7% (complete response--66.7%; pain syndrome in the exposed area--4.2%). No differences between large-fraction irradiation regimes were reported. Late-onset radiation-induced lesions (soft-tissue fibrosis stage II-III) were significantly more frequent after standard low-dosage fractionated irradiation (28.6+/-17.0%).     

Cardiac effects following adjuvant chemotherapy and breast irradiation in operable breast cancer

AIM: To assess the frequency and type of cardiac effects in womentreated with adjuvant chemotherapy with or without breast irradiationfor operable breast cancer. PATIENTS AND METHODS: Retrospective analysis of a series of 825 women taking partin prospectively randomized trials on adjuvant chemotherapywith or without adriamycin (doxorubicin; Farmitalia-Carlo Erba,Milan, Italy) for operable breast cancer at high risk of newdisease manifestations. A total of 360 patients (44%) also receivedbreast irradiation because of conservative surgery. Median follow-upin first clinical complete remission from end of all adjuvanttreatments was 80 months. According to the protocol requirements,electrocardiograms were obtained before breast cancer surgery,before starting therapy with adriamycin and at the end of alladjuvant treatments. During the followup observation, electrocardiogramswere systematically obtained at least once a year. In the presenceof suspicious findings as well as of clinical symptoms and signsof cardiovascular disease, additional cardiac investigationswere undertaken. However, percutaneous endomyocardial biopsieswere never performed. RESULTS: Congestive heart failure occurred in a total of 4 women (0.5%of all patients; 0.8% following adriamycin-containing chemotherapy;2.6% after both adriamycin and irradiation to the left breast),in two of whom it was fatal. ST-segment and T-wave abnormalitiesin the absence of other symptoms and signs were detected in3.4% of the case series. Other cardiac events were documentedin 6.8% of all patients. Overall, cardiac effects were morefrequently detected in women who received irradiation to theleft breast. In addition, age greater than 55 years at surgeryand history of risk factors were important risk modifiers inthe occurrence of cardiac events. CONCLUSIONS: The addition of full-dose adriamycin to alkylating-containingadjuvant chemotherapy, as given in our studies, failed per seto increase the frequency of cardiac effects. Thus anthracyclines,which have the potential to improve current treatment results,deserve a proper place in the design of future adjuvant studies. adjuvant chemotherapy, breast irradiation, doxorubicin, cardiac effects     

A phase II trial of adjuvant low-dose total body irradiation in non-Hodgkin's lymphoma patients following standard CHOP

Because survival results achieved in aggressive NHL with the standard CHOP are not very satisfactory, we investigated adding adjuvant low-dose total body irradiation (LTBI) to standard CHOP in a phase II trial. Thirty-six patients were included between September 1999 and September 2001. All patients were in documented complete remission (CR) after the end of their standard CHOP. LTBI started 4-6 weeks following the last CHOP course and was given in two courses, each with 4 daily fractions of 0.2 Gy, separated by 2 weeks of rest. Patients with bulky disease received involved-field radiotherapy on initial bulky sites starting 4-6 weeks after the last LTBI fraction. Primary end points were disease-free survival (DFS) and overall survival (OS) and the secondary end point was toxicity. The toxicities of LTBI were temporary thrombocytopenia and leucopenia (requiring no transfusions or treatment with growth factors). The 3-year DFS was 61%±9% and the overall survival was 87±6%. Univariate analysis showed time to achieve CR, and whether the patient got LTBI-induced haematological toxicity to be 2 significant prognostic factors affecting DFS. The use of adjuvant LTBI in patients with aggressive NHL in CR after standard chemotherapy is a feasible, non-toxic treatment that is worthy of testing in a future phase III trial.     

A randomized controlled study of adjuvant immunotherapy with N-CWS for head and neck malignancies

The nonspecific adjuvant immunotherapeutic effectiveness of the cell wall skeleton of Nocardia rubra (N-CWS) was studied in patients with head-and-neck malignancies. This study involved 390 patients seen from March 1980 to July 1982. The patients qualifying for statistical analysis were limited to 276 with squamous cell carcinoma without a vestige of tumor after four months of radical therapy. They were divided into two background-factors matched groups of 132 immunotherapy and 144 control patients. The overall two-year nonrecurrence rate was 70.4% for the immunotherapy group and 67.1% for the control. This difference, however, was amplified, when the patients' stages were limited to III and IV: 66.6% for the immunotherapy group and 55.3% for the control.     

Chronic granulocytic leukemia following successful renal transplantation.

The use of immunosuppressive therapy has markedly increased over the past several years, and concomitant with its use has been an increased frequency of associated neoplasia. The patient presented is a 22-year-old white male who, following two renal transplants and prolonged immunosuppressive therapy with azathioprine and methylprednisolone, developed chronic granulocytic leukemia. Chromosome karyotyping demonstrated the somewhat unusual development of a Philadelphia chromosome with translocation to the No. 7 of the C group. A review of transplantation centers revealed that five cases of chronic granulocytic leukemia have occurred in a population of 25,000 renal transplant patients, a 5-fold increased incidence over the general population. Possible etiologies that may be responsible for the development of chronic granulocytic leukemia in patients on immunosuppressive therapy are discussed. It is our hope that by the introduction of these reports of chronic granulocytic leukemia into the medical literature, the need for caution in the use of immunosuppressive drugs in nonmalignant disease will again be emphasized.