Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study.

TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.

Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors.

Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.

Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy.

BACKGROUND: Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer. We report results of the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer. METHODS: Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3-T4) or hypopharynx (T2-T4), with regional lymph nodes in the neck staged as N0-N2 and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arm. In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles (60 Gy total). All nonresponders underwent salvage surgery and postoperative radiotherapy. The Kaplan-Meier method was used to obtain time-to-event data. RESULTS: The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68 to 1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm. CONCLUSIONS: Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

Bone marrow mammaglobin expression as a marker of graft-versus-tumor effect after reduced-intensity allografting for advanced breast cancer.

We assessed mammaglobin (MMG) gene expression in bone marrow (BM) aspirates from patients with advanced breast cancer who had received a reduced-intensity conditioning and stem cell allografting, in order to detect a graft-versus-tumor effect on micrometastatic disease. Nine patients received a reduced-intensity conditioning with fludarabine, cyclophosphamide, and thiotepa, followed by peripheral blood allografting from HLA-identical sibling donors. Nested RT-PCR analysis with sequence-specific primers for MMG was carried out on a monthly basis on BM samples. Three patients had MMG-positive BM, four patients had MMG-negative BM before allografting, and two were undetermined. In two patients, a clinical response after allografting (partial remission) occurred concurrently with the clearance of MMG expression, at a median of 6 months after allografting, following immune manipulation. In two patients, a prolonged stable disease and negative MMG expression occurred after day +360 from allografting. In two patients, progression of the disease was associated with MMG RT-PCR changing from negative to positive. In one case, a disease response occurring after donor lymphocyte infusion and grade II acute GVHD was heralded by negativization of MMG expression. Although preliminary, these data suggest that a graft-versus-breast cancer effect is detectable on micrometastatic BM disease.

Two familial cases of perianal streptococcal dermatitis.

Two cases of perianal streptococcal dermatitis (PSD) occurred in a brother and sister, aged 4 and 6 years, respectively. The diagnosis was confirmed by the detection of group A beta-hemolytic streptococci in the perineal area and pharynx of both patients. We emphasize the importance of a quick and accurate diagnosis of the infection because PSD is frequently confused with other perianal diseases of infancy.

Uninephrectomy increases kidney beta2-microglobulin: can it play a role in the progression of kidney damage?

Beta2-microglobulin (beta2M) is highly accumulated by the kidneys of normal rats. The aim of this study was to verify if uninephrectomy can modify the renal uptake of labeled beta2M. For this purpose the radioactivity of plasma and those of the remaining kidney, liver and urine have been measured in uninephrectomized rats (NX) and in controls (C) at different times after the injection as i.v. bolus of 131I-beta2M. The experiments were performed in 114 Sprague-Dawley male rats. Fifty seven animals underwent right nephrectomy, the other animals being the C. NX and their C were divided in 3 groups, studied 2, 4 and 6 weeks after nephrectomy, respectively. Part of the animals were sacrificed 12 min after the injection of labeled beta2M (peak-time, i.e. time of highest kidney accumulation of 131I-beta2M in the normal rat) and part 10 min later. The results demonstrate that: - uninephrectomy increases plasma retention of 131I-beta2M - kidney uptake (total and per gram) is always higher in NX - liver uptake (much lower than that of kidney) is not influenced by uninephrectomy - urine excretion of radioactivity is minimal in both NX and C. The behavior of beta2M is similar to that we previously observed with alpha1-microglobulin and lysozyme. The higher kidney content of some low mw proteins after uninephrectomy could play a role in the progressive reduction of renal function determined by the reduction of renal mass.

Treatment of early-stage Hodgkin's disease with four cycles of ABVD followed by adjuvant radio-therapy: analysis of efficacy and long-term toxicity.

BACKGROUND AND OBJECTIVES: The use of combined modality therapy in early-stage Hodgkin's disease can spare staging laparotomy and reduces the risk of relapse compared to radiation alone. This paper reports on the efficacy and long-term events of a combined modality approach consisting of a brief course of chemotherapy followed by adjuvant radiotherapy, without laparotomy, in early-stage Hodgkin's disease. DESIGN AND METHODS: This study included 78 patients with Hodgkin's disease (20 in stage I and 58 in stage II); 60% had mediastinal enlargement (12% had bulky disease) and 5% had subdiaphragmatic disease. Their median age was 33 years (range: 15-64) and median follow-up 60 months. The treatment program consisted of four cycles of ABVD followed by adjuvant radiation to involved sites (43 patients) or involved and contiguous sites of disease (35 patients); radiation doses ranged from 30 to 36 Gy to uninvolved and involved sites, respectively; bulky disease received up to 44 Gy. Gonadal function in women was assessed by hormonal tests and evaluation of menses; young men were given the opportunity to have their semen cryopreserved. RESULTS: The treatment program was completed in a median of 6.2 months (range: 5-10). The complete remission rate was 88% after 4 courses of ABVD and 98.7% after adjunctive RT. The 5-year relapse-free survival was 97% and overall survival 98%; three patients died, one of disease progression and two of small cell lung carcinoma. Long-term events included three cases of pulmonary fibrosis with symptomatic interstitial disease, one case of dilated cardiomyopathy with cardiac failure (all had received mediastinal radiation) and four cases of dysthyroidism. Fertility was preserved in young women, with three subsequent normal pregnancies. Second neoplasms included two small cell lung carcinomas and one breast carcinoma. INTERPRETATION AND CONCLUSIONS: In early-stage Hodgkin's disease, four cycles of ABVD followed by adjuvant radiotherapy produced a 5-year overall survival of 98%. Prolonged monitoring for therapy-related long term complications is mandatory in these potentially curable patients.

Rituximab (IDEC-C2B8): validation of a sensitive enzyme-linked immunoassay applied to a clinical pharmacokinetic study.

Rituximab is a chimeric monoclonal antibody (MAb) directed against the B-cell CD20 antigen that has been approved for therapy of relapsed and resistant follicular non-Hodgkin's lymphoma (NHL). This study describes the development and validation of a highly sensitive, rapid, accurate, precise enzyme-linked immunosorbent assay (ELISA) to measure Rituximab serum concentrations. This study also describes the application of the ELISA method to a pharmacokinetic study in a homogeneous group of patients with follicular lymphoma who received 4 weekly doses of MAb at the standard dose of 375 mg/m2 as consolidation of chemotherapy. In the patients in this study, the median Rituximab serum concentrations increased during therapy, and showed a slow decline during the posttreatment period. The Rituximab elimination half-life of approximately 20 days accounts for the demonstrated accumulation of MAb in serum samples. Because previous pharmacokinetic studies showed a correlation between Rituximab serum levels and tumor response, the ELISA method used in this study, which allows a precise control of serum concentrations, could be useful for predicting the final response to the MAb and for selecting patients able to benefit from higher dosage or repeated drug administration.

The risk of acute leukemia in patients treated for Hodgkin's disease is significantly higher aft [see bined modality programs than after chemotherapy alone and is correlated with the extent of radiotherapy and type and duration of chemotherapy: a case-control study.

BACKGROUND AND OBJECTIVE: Patients treated for Hodgkin's disease have an increased risk of developing subsequent acute leukemia. This co-operative study was conducted to assess the relative risk associated with several candidate factors including age, splenectomy, combined modality therapy and cumulative drug dose including alkylating agents and nitrosurea derivatives. DESIGN AND METHODS: This study evaluated the risk of acute leukemia according to pretreatment variables and therapy modalities among 1659 patients treated for Hodgkin's disease and followed for a median time of 10 years. Both case-control and actuarial risk studies were performed. Median age was 34 years (range: 12-83); 53% of patients were splenectomized. As to the overall therapy, 348 patients (21%) were given radiotherapy (RT) alone, 375 (23%) chemotherapy (CT) alone (including MOPP, MOPP + ABVD or MOPP + ABVD + lomustine); 936 (56%) received both CT and RT, either as primary or salvage treatment. RESULTS: The overall 15-year actuarial risk of leukemia was 4.2%; the hazard function curve showed two peaks of risk at the 3th and the 8th year from the initiation of therapy and no leukemia beyond the 12th year of follow-up. Risk of leukemia was 0.3% after RT alone, 2.8% after CT alone (2.2% after MOPP; 4.4% after MOPP + ABVD + lomustine), and 5.4% in patients given combined modality therapy (10.2% for RT + MOPP; 15.6% for RT + MOPP + lomustine). No leukemia occurred after ABVD alone and the risk was low (0.6%) when neither mechlorethamine nor lomustine were utilized. Patients who had received extended radiotherapy including abdomen and pelvis in addition to MOPP showed a significantly higher risk of leukemia compared to those given limited RT + MOPP (P = 0.01). Case-control analysis indicated advanced stage, type and duration (> 8 months) of CT and extension of RT as significant risk factors for leukemia. Compared to RT alone, the odds ratio was 5.9 after MOPP + extended RT, and 8 when a lomustine-containing regimen was used, as well. Neither age nor splenectomy were independent risk factors for leukemia; splenectomy was influential only when patients had been given MOPP chemotherapy, as well. INTERPRETATIONS AND CONCLUSIONS: Both case-control and actuarial analyses indicated that: a) combined modality therapy with MOPP and extensive RT (including abdomen and pelvis), and the use of lomustine added to the leukemogenic risk of MOPP alone; b) programs without mechlorethamine, procarbazine and lomustine were almost devoid of leukemogenic risk.

[Gastric pull-up in pharyngo-esophageal reconstruction: a personal experience]. / Il pull-up gastrico nella ricostruzione faringo-esofagea: esperienza personale.

During the five-year period from 1992 to 1997 a total of 62 patients with advanced hypopharyngeal carcinoma extended to the cervical esophagus came to our attention. Of these 42 (67.7%) were deemed operable and of these 31 (23 males, 8 females; age range 48 to 74 years; mean age 58.5 years) underwent total pharyngolaryngoesophagectomy and gastric pull-up reconstruction. Post-operative mortality was seen in 3 cases (9.7%). In addition, the following complications were encountered: dehiscence of the anastomosis (3 cases), neck hemorrhage (2 cases), pyloric stenosis (1 case). Two patients required intraoperative splenectomy to stop the hemorrhage caused by gastric mobilization and one required thoracic drainage, again because of hemorrhage. The average period of hospitalization was 36 days (range: 20 to 63 days). Per os feeding was restored from 20 to 63 days after surgery (average 20 days). Three patients (9.6%) showed functional failure--that is the inability to feed without the nasogastric probe. To date 10 patients (32.2%) are alive and disease free at an average 18.8 months after surgery (min. 1 month, max. 66 months); 7 patients (22.5%) are alive but not disease free; 11 (35.5%) passed away (in addition to the 3 post-operative cases) and 10 (32.2%) of these deaths were due to recurrence while 1 patient was still disease free at the time of autopsy. In conclusion the authors feel that total pharyngolaryngoesophagectomy with gastric pull-up is a safe treatment; i.e. with an acceptable mortality rate. Post-operative morbidity is high but the final functional outcome is good and, in most cases, can certainly improve the quality of the patients' remaining life. Even though prognosis is quite severe, with average survival of around one year, some of our patients are still alive and disease free 4-5 years after treatment.

[Primary carcinoma of the thyroglossal duct. 2 case reports]. / Il carcinoma primitivo del dotto tireoglosso. Due casi clinici.

AA. present two cases of carcinoma arising on thyroglossal duct's cystic. Those carcinomas are a rare event and will be suspected in the patients that present an irregular tumefaction of medial neck's district. Etiology is unknown; is possible that a preceding irradiation on the neck will represent a factor risk. AA. retained that in case of medial neck's district tumefactions is necessary executed a total examination of neck's and head's district, an echography, a thyroid scintigraphy, a thoracic radiography, a panendoscopy and a FNAB. When we found a squamous carcinoma on residual thyroglossal duct the therapy is chirurgical in function of dimension of T and N with following radiotherapy in function of stage (possible lymph node metastasis). When we found a different adenoma is necessary chirurgical removal of tumefactions with hyoid bone's a body resection (Sistrunk's operation) with total thyroidectomy and following Pochin's test for seeking eventual residual with radiometabolic and suppressive therapy.

[The randomized double-blind study of postoperative tonsillectomy pain control by muscle relaxants]. / Studio randomizzato a doppio cieco per il controllo del dolore postoperatorio nell'intervento di tonsillectomia per dissezione con miorilassanti.

Tonsillectomy is accompanied by 7 to 14 days of pain. We entered 36 patients into a double blind placebo controlled study with dantrolene sodium, lioresal to evaluate modification of tonsillectomy pain and analgesic requirements after tonsillectomy. Patients were randomly assigned either dantrolene or lioresal or placebo orally four times a day for 5 days postoperatively. On a standardized questionnaire the patients recorded pain, activity level, analgesic requirements and side effects. We conclude that there is no significant differences in subjective pain or analgesic requirements between 3 groups. The muscle spasm is not the only factor of tonsillectomy pain. There is the association of other factors: nerve endings, individual sensitivity, local products of inflammation. In conclusion to control tonsillectomy pain we must use drugs with different action.

Epirubicin, methotrexate and bleomycin in the management of recurrent squamous cell head and neck cancer. A GSTTC randomised phase II study.

53 patients with squamous cell carcinoma of the head and neck recurrent after initial treatment were entered into a phase II trial of the epirubicin, methotrexate and bleomycin (EMB) combination. The primary objective of the study was to evaluate the activity of this combination. Compliance to EMB and the possible non-cross-resistance to previous cisplatin-containing chemotherapy were secondary objectives. In order to avoid patient selection bias, the study involved randomisation between EMB and a cisplatin-methotrexate-bleomycin (DMB) combination (with EMB: DMB = 2:1). 23 out of 53 (43% +/- 13) EMB patients showed an objective response, lasting a median of 12 (range 4-39) weeks; interestingly, 5 out of 14 (36% +/- 25) patients pretreated with cisplatin plus 5-fluorouracil responded to EMB. The treatment compliance was good and a median of three courses was delivered. No patient refused the treatment after the initial cycle. Leukopenia (47%) and oral mucositis (42%) were the main side effects. DMB produced a response rate of 33% +/- 18 with a median duration of 5 (4-13) weeks. None of the patients previously treated with cisplatin plus 5-fluorouracil responded. 5 patients refused the treatment after the first cycle and a median of two cycles (0-5) was delivered. In conclusion, EMB produced results similar to cisplatin-containing regimens, with a mild to moderate toxicity and a good compliance; the possible non cross-resistance with cisplatin plus 5-fluorouracil deserves further evaluation.

[Hormonal changes during surgical stress. Comparison of isoflurane anesthesia, neuroleptanalgesia, propofol]. / Modificazioni ormonali in corso di stress chirurgico. Confronto fra anestesia isofluranica, NLA, propofol.

Our purpose is to verify if different techniques of general anaesthesia can modify the patient's hormonal response to surgical stress. For this extent 35 patients, undergoing Cottle's septoplasty, were randomly divided into three groups, treated using different anaesthesiological techniques (forane, NLA and propofol). No variation was noted between the three groups regarding cortisol increments, while the patients, in whom forane was used for anaesthesia maintenance, manifested less significant variations in prolactin levels. This may be indicative of good forane protection for surgical stress.

[Mycosis of the paranasal sinuses: a report of 4 cases]. / Micosi dei seni paranasali: report su 4 casi.

With recent advances in medicine, fungal diseases are not only being better under stood, but are also becoming increasingly important in the management of patients with paranasal sinus disease. Fungal sinus diseases range from allergic fungal sinusitis to invasive and fulminant fungal sinusitis. Although patients often have some predisposing factor, such as local tissue hypoxia or massive fungal ++exposure, most patients are not immuno-compromised. Invasive fungal sinusitis may be treated with the traditional Caldwell-Luc surgical technique or with newer endoscopic procedures. Fulminant fungal sinusitis generally occurs in immuno-suppressed patients and requires aggressive surgical excision and debridement as well as systemic chemotherapy, usually amphotericin B. In this article we review fungal diseases of the paranasal sinuses and present four cases of paranasal fungal sinusitis.

[Gardner's syndrome: a case report]. / Sindrome di Gardner: a case report.

The Gardner syndrome (GS) is a dysplasia in which neoformations in the intestines, soft tissue and osseous tissue are associated. Since extra-intestinal manifestations, in particularly osteomas, appear promptly even in infants, and above all in the light of the possibility of malignant degeneration, the presence of mandibular osteomas indicates the necessity of carrying out investigations in order to ascertain the eventual existence of an intestinal polyposis typical of GS. This study describes a typical case of GS diagnosed merely upon suspicion of the existence of the syndrome in a patient who came to our Department with a mandibular osteoma. The study underlines the importance not only of carrying out investigations in order to ascertain the presence of GS (rectocolonoscopy), but also that of studying the relatives of the patient in light of the fact that this particular dysplasia is transmitted genetically.

[Renal accumulation of radioiodinated alpha-1-microglobulin increases in the mononephrectomised rat]. / L'accumulation rénale de alpha-1-microglobuline radioiodée augmente chez le rat mononéphrectomisé.

Alpha-1-microglobulin (alpha 1M) is highly accumulated by the kidneys of normal rats. Aim of this study has been to verify if uninephrectomy can modify this behaviour. For this purpose the radioactivity of the remaining kidney and those of plasma and urine have been measured in uninephrectomized rats after IV injection of radioiodinated alpha 1M. The experiments have been performed in 100 Sprague-Dawley male rats. Fifty animals underwent right nephrectomy, the others being the controls. Uninephrectomized rats and their controls have been divided in 3 groups, studied 4, 14 and 28 days after surgery, respectively. All the animals were injected with human alpha 1M labelled with iodine-131. They were sacrificed in part 18 minutes after the injection of labelled alpha 1M (time of highest kidney accumulation in the normal rat), and in part 28 minutes after the injection. Uninephrectomy increased plasma retention of labelled alpha 1M. Kidney uptake (total and per gram) was always higher in uninephrectomized animals. Similarly, urine radioactivity was higher in uninephrectomized rats. These results demonstrate that uninephrectomy remarkably increases the accumulation of alpha 1M in the remaining kidney.