HLA-haploidentical hematopoietic stem cells transplantation with regulatory and conventional T-cell adoptive immunotherapy in pediatric patients with very high-risk acute leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is still needed for many children with very high-risk acute leukemia. An HLA-haploidentical family donor is a suitable option for those without an HLA-matched donor. Here we present outcomes of a novel HLA-haploidentical HSCT (haplo-HSCT) strategy with adoptive immunotherapy with thymic-derived CD4+CD25+ FoxP3+ regulatory T cells (Tregs) and conventional T cells (Tcons) performed between January 2017 and July 2021 in 20 children with high-risk leukemia. Median age was 14.5 years (range, 4-21), 15 had acute lymphoblastic leukemia, 5 acute myeloid leukemia. The conditioning regimen included total body irradiation (TBI), thiotepa, fludarabine, cyclophosphamide. Grafts contained a megadose of CD34+ cells (mean 12.4 × 106/Kg), Tregs (2 × 106/Kg) and Tcons (0.5-1 × 106/Kg). All patients achieved primary, sustained full-donor engraftment. Only one patient relapsed (5%). The incidence of non-relapse mortality was 15% (3/20 patients). Five/20 patients developed ≥ grade 2 acute Graft versus Host Disease (aGvHD). It resolved in 4 who are alive and disease-free; 1 patient developed chronic GvHD (cGvHD). The probability of GRFS was 60 ± 0.5% (95% CI: 2.1-4.2) (Fig. 6), CRFS was 79 ± 0.9% (95% CI: 3.2-4.9) as 16/20 patients are alive and leukemia-free. The median follow-up was 2.1 years (range 0.5 months-5.1 years). This innovative approach was associated with very promising outcomes of HSCT strategy in pediatric patients.

Radiation therapy of spinal cord compression caused by breast cancer: report of a prospective trial.

Fifty-six breast cancer patients with metastatic spinal cord compression were consecutively treated with radiation therapy alone. All patients received steroids plus chemotherapy and/or hormonal therapy. Emergency radiation therapy was administered using a split-course regimen: 5 Gy for 3 days, stopped for 4 days and, only in responders, a further 3 Gy for 5 days (time dose fractionation 68). Median follow-up was 22 months (range, 4 to 52 months). Response and survival were assessed on the basis of, pretreatment and posttreatment walking capacity, presence of vertebral body collapse or osteolysis, presence of other metastatic sites apart from bone and chemotherapy and/or hormonal therapy. In 89% of patients with back pain the pain disappeared or lessened. Four of 6 cases (67%) with urinary dysfunction responded to radiation therapy. Of 35 cases with motor dysfunction at the time of diagnosis, 21 (60%) regained the ability to walk and another five (14%) who were able to walk with support at diagnosis did not deteriorate. All 21 cases without motor deficits before treatment maintained good motor performance after radiation therapy. Response to therapy was better in pretreatment walking than in nonwalking patients (97% vs 69%; p less than 0.02). Probability of duration of response at 1 year was 59% and 10% for posttreatment walking and nonwalking patients, respectively (p less than 0.0001). One year survival probability was 66% for posttreatment walking and 10% for posttreatment nonwalking patients, respectively (p less than 0.0001). Pretreatment and posttreatment ambulatory status were the most important prognostic factors.

Interstitial pneumonitis after hyperfractionated total body irradiation in HLA-matched T-depleted bone marrow transplantation.

Interstitial pneumonia is one of the major causes of morbidity and mortality after bone-marrow transplantation. We here report a series of 58 patients suffering from hematological malignancies who received HLA-matched T-lymphocyte depleted bone-marrow transplants between July 1985 and January 1990. Interstitial pneumonia occurred in 7/58 patients (12%) and was fatal in six. Three different pre-bone-marrow transplantation conditioning regimens were employed. Total body irradiation was delivered according to a hyperfractionated scheme of 12 fractions given three per day 5 hr apart for 4 days. Twenty-three patients received 36 mg/Kg procarbazine, 1275 UL/Kg antithymocite globulin, 14.4 Gy hyperfractionated total body irradiation and 120 mg/Kg cyclophosphamide. Only one patient developed interstitial pneumonia, but two rejected the graft and 10 relapsed. As a consequence, the total hyperfractionated scheme was increased to 15,6 Gy, cyclophosphamide to 200 mg/Kg, antithymocite globulin to 3400 UL/Kg and procarbazine eliminated. There were three cases of interstitial pneumonia, no rejection and four relapses in the 17 patients who received this regimen. In the last 18 patients hyperfractionated total body irradiation was reduced to 15 Gy, cyclophosphamide to 100 mg/Kg, and 10 mg/Kg of the myeloablative agent thiothepa added to enhance the cytoreductive effect without significantly increasing extramedullary toxicity. Three cases of interstitial pneumonia, one relapse but no rejection were recorded. Our results demonstrate that the absence of graft-versus-host disease due to T-cell depletion, and radio-chemotherapy doses and schedules used for the conditioning regimen each contributed to reducing the risk of interstitial pneumonitis. Hyperfractionated total body irradiation therefore, seems to play an important role in lowering the incidence of this complication.

Role of radiotherapy in metastatic spinal cord compression: preliminary results from a prospective trial.

A non-randomized prospective trial in which radiotherapy (RT) alone played the major role in the treatment of metastatic spinal cord compression (MSCC) is reported. Diagnosis was formulated on myelography and/or myelography plus computed thomography (CT). Of 51 cases treated, 48 are evaluable. The therapy consisted of radiation alone (42 cases) or decompressive laminectomy followed by radiotherapy (6 cases). Surgery was performed when the site of the primary tumor was unknown. The group of patients who received radiotherapy alone (42 of 48 evaluable cases) are analysed in this report. Medium to high doses of steroids were administered to all patients depending on the gravity of the case. Patients with chemo- or hormone-responsive primary tumors also received chemotherapy and/or hormone therapy. Pain relief, assessed by comparing use of narcotics and minor analgesics before and after treatment, was achieved in 54% cases (confidence limits, CL = 38-69%). In 36% (CL = 22-51%) of patients back pain diminished to the point when only milder analgesics were necessary (partial remission). Motor performance, based on patients' ability to walk, improved in 48% cases (CL = 31-65%). The 19 patients who were ambulatory before RT, did not deteriorate after treatment. Sphincter function, evaluated by patient's need for indwelling catheter, improved in 3 of 7 automatic dysfunction cases. It was found that early diagnosis was more important than primary tumor type for predicting a good was found that early diagnosis was more important than primary tumor type for predicting a good prognosis. In fact, all ambulating patients responded to treatment independent of the radiosensitivity of the tumor histology.(ABSTRACT TRUNCATED AT 250 WORDS)

Lung damage following bone marrow transplantation after hyperfractionated total body irradiation.

From July 1985 to December 1989, 72 evaluable patients aged between 6 and 51 (median age 27 years) suffering from haematological malignancies received an allogeneic bone marrow transplant (BMT) depleted of T-lymphocytes to reduce the risk of graft-versus-host-disease (GvHD); 57 were matched and 15 mismatched. Three different conditioning regimens were used in an effort to enhance cytoreduction without increase extramedullary toxicity. Mismatched patients were treated with more immunosuppressive regimens. Total body irradiation (TBI) was given in three doses per day, 5 h apart, over 4 days for a total of 12 fractions. The dose to the lungs was 14.4, 15.6 and 9 Gy according to the conditioning regimen. The incidence of interstitial pneumonia (IP) was 12.3% in matched and 46.7% in mismatched patients. Our results seem to indicate that lung toxicity is correlated with the intensity of the conditioning regimen, the stage of disease and, in mismatched patients, with the degree of human leucocyte antigen (HLA) disparity and the poor post-BMT reconstitution, rather than the radiotherapy dose delivered to the lungs. On the contrary, the hyperfractionated scheme adopted, the absence of GvHD and, perhaps, the post-TBI administration of cyclophosphamide all seem to have contributed to the low incidence of IP in our matched patients.

Hyperfractionated total body irradiation for T-depleted HLA identical bone marrow transplants.

Twenty patients suffering from malignant hemopathies (mean age 31.7 years) were given hyperfractionated total body irradiation (TBI) (120 cGy/3 fractions per day: total dose = 1440 cGy/4 days) as conditioning for T-depleted HLA identical allogeneic bone marrow transplantation. At an average of 12 months (range of 4.5-22 months) follow-up there were two cases of early death and two cases (11%) of rejection. There were no cases of acute or chronic graft versus host disease (GVHD) nor cases of interstitial pneumonitis. The average time for durable engraftment was 22 days. Disease-free survival at 12 months was 65%. To improve the results and further reduce the percent of rejection, the authors propose intensifying the immunosuppressive conditioning by increasing the cyclophosphamide dose and that of TBI so that a total dose of 1560 cGy is reached.

Radiation-induced myelopathy in long-term surviving metastatic spinal cord compression patients after hypofractionated radiotherapy: a clinical and magnetic resonance imaging analysis.

BACKGROUND AND PURPOSE: Hypofractionated radiotherapy is often administered in metastatic spinal cord compression (MSCC), but no studies have been published on the incidence of radiation-induced myelopathy (RIM) in long-term surviving patients. Our report addresses this topic. PATIENTS AND METHODS: Of 465 consecutive MSCC patients submitted to radiotherapy between 1988 and 1997, 13 live patients (seven females, six males, median age 69 years, median follow-up 69 months) surviving for 2 years or more were retrospectively reviewed to evaluate RIM. All patients underwent radiotherapy. Eight patients underwent a short-course regimen of 8 Gy, with 7 days rest, and then another 8 Gy. Five patients underwent a split-course regimen of 5 Gy x 3, 4 days rest, and then 3 Gy x 5. Only one patient also underwent laminectomy. Full neurological examination and magnetic resonance imaging (MRI) were performed. RESULTS: Of 12 patients submitted to radiotherapy alone, 11 were ambulant (eight without support and three with support) with good bladder function. In nine of these 11 patients, MRI was negative; in one case MRI evidenced an in-field relapse 30 months after the end of radiotherapy, and in the other, two new MSCC foci outside the irradiated spine. In the remaining patient RIM was suspected at 18 months after radiotherapy when the patient became paraplegic and cystoplegic, and magnetic resonance images evidenced an ischemic injury in the irradiated area. The only patient treated with surgery plus postoperative radiotherapy worsened and remained paraparetic. Magnetic resonance images showed cord atrophy at the surgical level, explained as an ischemic necrosis due to surgery injury. CONCLUSIONS: On the grounds of our data regarding RIM in long-term surviving MSCC patients, we believe that a hypofractionated radiotherapy regimen can be used for the majority of patients. For a minority of patients, more protracted radiation regimens could be considered.

Radiotherapy without steroids in selected metastatic spinal cord compression patients. A phase II trial.

A phase II trial was planned to investigate the feasibility of radiotherapy (RT) without steroids in 20 consecutive patients with metastatic spinal cord compression (MSCC), no neurologic deficits, or only radiculopathy, and no massive invasion of the spine at magnetic resonance imaging (MRI) or computed tomography (CT). Aiming at an early diagnosis, MRI or CT was prescribed for all cancer patients with back pain and osteolysis, even when there were no signs of neurologic spinal compression. All patients were given 30 Gy in 10 fractions over 2 weeks with no steroids. Back pain and motor capacity were the parameters adopted to verify response to RT. Sixteen of 20 patients (80%) were able to walk without support, and 14 (70%) had no radiculopathy. Seventeen of 20 cases (85%) achieved relief from back pain. Regarding motor function, all patients (100%) responded to RT because the 16 patients able to walk without support at diagnosis did not deteriorate and the other 4, who needed support, became ambulatory without motor impairment. Median survival time was 14 months. Eight of 20 (40%) treated patients are still alive (14 to 36 months after end of RT), fully ambulatory, and free from relapse in the treated spine. Acute side effects were documented in only 2 patients (10%) and were managed without steroids. The results of this study suggest that RT without steroids is a feasible regimen for MSCC patients with good motor function. Elimination of steroids from the standard treatment for MSCC avoids cortisone side effects above all in those patients with diabetes, hypertension, peptic ulcer, and other steroid-sensitive medical problems.

Regional node failure in patients with four or more positive lymph nodes submitted to conservative surgery followed by radiotherapy to the breast.

A retrospective analysis was conducted to evaluate the incidence of nodal failure in a subgroup of patients who had T1-T2 breast cancer and four or more positive nodes. Sixty-four 5 patients ranging in age from 29 to 73 years (median, 51) received conservative surgery followed by radiotherapy to the breast between November 1980 and May 1995. Adjuvant chemotherapy was administered to 56 patients, 27 of whom were also treated with tamoxifen, which was used alone in 5 patients. Three patients received no adjuvant treatment. Sixty-two patients are evaluable for regional node failure. There were 10 nodal failures, 4 in the axillary and 6 in the supraclavicular regions, in 9 patients, at a median of 56.5 and 27 months, respectively. There was no internal mammary node failure. Median follow-up was 72.6 months. The 10-year probability of developing axillary and supraclavicular failure is 13.9 +/- 7.7% and 10.5 +/- 4.1%, respectively. Prognosis was better for patients with axillary and breast recurrence and worse when relapse was in the supraclavicular region. On the basis of our results and data already published in premenopausal patients, we believe that radiotherapy to the supraclavicular region should be considered in patients with four or more positive axillary nodes, after a complete dissection.

[Endocavitary curietherapy of tumors of the rhinopharynx after external radiotherapy]. / La curieterapia endocavitaria dei tumori della rinofaringe dopo radioterapia esterna.

We report our experience in the treatment of nasopharyngeal carcinoma with intracavitary curietherapy to cure small recurring carcinomas or residual local disease 2-6 weeks after completing external radiotherapy. Since 1984, 10 patients have received intracavitary radiotherapy with customized molds charged with Ir 192. Six of them received a boost dose because of residual disease and for local recurrence. The technique we employed to shape the molds is described, together with the mode of use and the doses to target volume. Due to both the small number of treated cases and the short follow-up, no significant conclusions could be drawn relative to survival time. However, it must be stressed that this therapeutic approach gives a high local control rate with no severe side-effects or sequelae.

[Quadrant excision and radiotherapy in the treatment of early cancer of the breast]. / Quadrantectomia e radioterapia nel trattamento del cancro iniziale della mammella.

One hundred twenty nine patients with T1 N0 M0 breast cancer were selectively treated with QUART. Mean age was 50 years. Ninety-eight patients (76%) were N- and 31 (24%) were N+. N+ cases received chemotherapy or Tamoxifen if R+. Patients evaluated are 95/129 in a 3 years average follow-up (range 2-7 years). Overall actuarial survival rate at 5 years is 88.9%. Three patients died; local relapses were 3/95 and metastases 3/95. Overall treatment tolerance was satisfactory and esthetic results were good.

[Surgical and radiotherapeutic treatment in stage I endometrial adenocarcinoma. Retrospective analysis of 218 patients]. / Trattamento chirurgico e radioterapico dell'adenocarcinoma endometriale I stadio. Analisi retrospettiva su 218 pazienti.

From April 1977 through April 1985, 218 stage I endometrial carcinomas were treated with radiosurgery or radiotherapy alone. Postoperative irradiation was external (60Co) in 131 and curietherapy in 27 patients. Twenty patients underwent preoperative curietherapy and 40 patients radiotherapy alone. Median follow-up was 5.6 years (range 3-11). The overall 5-year actuarial survival (Kaplan-Meier method) was 86.1% +/- 2.5. The 5-year D.F. actuarial survival was 95% +/- 4.9, 93.1% +/- 4.7, 88.4% +/- 2.9, respectively, for preoperative radiotherapy, postoperative curietherapy and postoperative external irradiation groups. The 5-year actuarial survival was 69.8% +/- 7.7 in the radiotherapy alone group. There was difference in survival among patients treated with radiotherapy alone as compared to those radiosurgically treated (P less than 0.001). Local and general recurrence rate was 8.2%; vaginal recurrences 2/218 (0.9%); pelvic recurrences 7/218 (3.3%); distant metastases 9/218 (4.1%). Overall side effects were observed in 20/218 patients (9.1%): grade I and II in 8.6% of cases, grade III in 0.9% of cases. The authors conclude that good results can be achieved with adjuvant radiotherapy both in high risk cases and in low risk cases, with minimal side effects.

[Testicular seminoma in stages I and II non-bulky. 16 years' experience]. / Il seminoma del testicolo negli stadi I e II non-bulky. Sedici anni di esperienza.

From June 1977 through June 1993, ninety-five patients with testicular seminoma were treated in our center. This paper reports on 67 assessable patients--52 with stage I and 15 with non-bulky stage II disease. Median follow-up is 8 years (range: 4-16 years). Postorchiectomy radiotherapy consisted in 30 Gy (1.5 Gy/day) precautionary treatment to ipsilateral hemipelvis and paraaortic nodes (stage I) or 40-45 Gy to the same area plus 25.5-30 Gy prophylactic irradiation to mediastinum and supraclavicular fossae (stage II). Ten-year actuarial survival is 100%-96.8% +/- 2.2 considering deaths from other diseases. Ten-year disease-free survival is 95.3% +/- 2.6. The 3 relapsed patients were rescued with chemotherapy or radiotherapy (1 and 2 cases, respectively). Acute side-effects were nausea (30% of cases) and vomiting (18%) which disappeared after oral antiemetics. Late toxicity-asymptomatic osteolysis of the ipsilateral pubic region--was observed in 1 patient only (1.5%) who received cobalt therapy to inguinal canal and hemiscrotum (40.5 Gy in 27 fractions). The current diagnostic and therapeutic approaches to testicular seminoma are discussed. In stage I the conventional treatment is low-dose (20-25 Gy) subdiaphragmatic radiotherapy and a policy of surveillance is justified only for clinical trials. In non-bulky stage II disease lumboaortic and hemipelvic irradiation (36-40 Gy) is the treatment of choice whereas precautionary irradiation should not be given to the mediastinum. If abdominal CT scans show nodal metastases, chest CT is necessary for staging instead of chest X-ray films. When abdominal CT findings are negative or questionable, bi-pedal lymphography must be performed. Residual testis US should be the routine examination for the early diagnosis of metachronous contralateral seminoma. The semen should be tested for further storage and sexual functions should be accurately analyzed to distinguish between organic and psychologic causes. Although limited, our experience demonstrates the good prognosis of this condition and the optimal tolerance in testicular seminoma patients even with a radiotherapy regimen which is now considered suboptimal, though it was the standard about 10 years ago.

[Pre- and postoperative radiotherapy of operable carcinoma of the rectum]. / Radioterapia pre- e postoperatoria del carcinoma del retto operabile.

This was a non-randomized prospective study on the "sandwich" radiosurgical treatment of resectable rectal and rectosigmoid carcinomas. From December 1984 to December 1989, 100 patients were treated 86 of them are now evaluable. Mean follow-up was 38 months (range: 9-69). Surgery was abdomino-perineal resection in 33 cases and anterior resection in 53 cases. Radiotherapy was preoperative pelvic irradiation, with a single 500-Gy fraction, the day before surgery. To stages B2, C1 and C2 patients (Astler and Coller) postoperative radiotherapy was administered for a total dose of 4500 Gy (180 Gy/fraction, 5 fractions/week), with box technique, from a Co 60 unit or Linear Accelerator (photon 18 MV). Preliminary results indicate 8% (7/86) local recurrences and 9.3% (8/86) distant metastases. Five-year actuarial disease-free survival is 63.2% +/- 8 for stage B1, 55.6% +/- 19 for stage B2, and 40.2% +/- 13 for stages C1 + C2. Overall 5-year actuarial disease-free survival is 53% +/- 10. No lethal or severe complications were observed following treatment.

[Radiotherapy of testicular seminoma. Stages I and II A, B]. / Radioterapia del seminoma testicolare. Stadio I e II A, B.

From June 1977 through June 1987, 46 patients (36 evaluable) affected by stage I and II non-bulky testicular seminoma were treated with postoperative telecobaltotherapy (TCT). In stage I seminomas, radiotherapy was extended to the omolateral iliac and the para-aortic areas (total dose: 30 Gy over 4 weeks). In stage II seminomas, the subdiaphragmatic lymph nodes were irradiated with 40-45 Gy over 5-6 weeks; after an interval of one month the subdiaphragmatic lymph nodes were irradiated again with a total dose of 25 Gy over 3.5 weeks. Minimal follow-up lasted two years and maximum ten years (average: 5.5). Two (5.5%) recurrences occurred, but salvage radiotherapy and salvage chemotherapy respectively allowed a complete permanent remission. One patient died from a different neoplasia with no evidence of testicular involvement. The 5-year actuarial survival is 96.6 +/- 3.4. In 20% of the patients the side effects were nausea and/or vomiting, easily controlled. No late complications were observed.

[Treatment of stage I and II cervix carcinoma with radiotherapy alone or with combined radiation-surgery]. / Il trattamento del cervico-carcinoma I e II stadio con radioterapia esclusiva o associazione radiochirurgica.

From 1975 to 1982, among 138 patients affected by stage IB and IIA-B cervical carcinoma, 93 were treated with radiotherapy and surgery, while 45 were treated with radiotherapy alone. 137Cs applied with individual "moulages" was used for uterine-vaginal brachycurietherapy, while telecobalt therapy was used in external beam radiotherapy. Surgery consisted of either a classical Wertheim-Meigs procedure or a hysterosalpingo-oophorectomy with pelvic lymphadenectomy. Dosage methods for remote-loading curietherapy with 137Cs are discussed. Actuarial survival at 5 years in the 56 patients in stage IB was 90.2% +/- 3; in the 37 patients in stage IIA was 75% +/- 5; and in the 45 patients in stage IIB was 46.2% +/- 7.5. Average follow-up was 6.5 years, with a minimum of 3 years. Survival results in patients undergoing radiotherapy alone were not substantially different. Causes for therapeutic failure were pelvic relapse in 9.4% of the cases, distant metastases in 3.6% and relapse plus metastases in 8.6% of the cases. Severe complications were seen in 2.8% of the cases; mild complications in 8.6% of the cases.

[Combined chemotherapeutic and radiotherapeutic treatment of limited pulmonary microcytoma]. / Il trattamento integrato chemioterapico e radioterapico del microcitoma polmonare a malattia limitata.

Between 1978 and 1983, 34 patients (32 evaluable) suffering from limited small cell lung carcinoma (SCLC-L) were treated following the protocol polychemotherapy (CAV) plus thoracic cobalt teletherapy and "precautionary" cranial irradiation (30 Gy in 2 weeks). Minimum follow-up was 30 months. After induction chemotherapy there was complete remission (CR) in 20% of cases whereas at the end of induction chemo-radiotherapy there was complete remission (CR) in 44% (p less than 0.05) of cases. Median duration of the responds was 12 months. Total median survival is 15 months, median NED survival 32 months (6-90 months). Seven out of 14 CR patients received consolidated thoracic radiotherapy (Rt); 6 of these survived disease-free for over 2 years. No salvage therapy carried out has proved useful. Only in one patient (3%) brain metastasis occurred. Iatrogenic toxicity was also kept within limits of brain level. The role Rt plays in increasing the CR percentage, in drastically diminishing the incidence of brain metastasis, in improving the quality of life by increasing the disease-free interval must be emphasized. Finally it should be noted that only CR patients have the possibility to become "long survivors".