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.

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.

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.

In vivo detection of somatostatin receptors in patients with functionless pituitary adenomas by means of a radioiodinated analog of somatostatin ([123I]SDZ 204-090).

The recent availability of a Tyr3-substituted octreotide (SDZ 204-090) for radioiodination has allowed somatostatin (SRIH) receptor binding to be studied in vivo, and receptor-positive tumors of different origins to be visualized with a gamma-camera. This prompted us to investigate whether this compound could be used for external imaging of functionless pituitary adenomas displaying SRIH receptors. Eight patients with functionless pituitary adenomas, three patients with acromegaly, and three with macroprolactinoma were injected iv with 123I-labeled Tyr3-octreotide and then scanned with a gamma-camera. Positive scans were obtained in the three acromegalics and in two of the eight patients with functionless pituitary tumors. The patients with macroprolactinoma had negative scans. The diagnosis of functionless pituitary adenomas was confirmed by light and electron microscopic examination as well as immunocytochemical studies. In vitro binding of [125I]Tyr11-SRIH to cell membranes was evaluated in four functionless and three GH-secreting adenomas removed from seven of the patients. All of the GH-secreting as well as one of the four functionless adenomas had high affinity SRIH-binding sites, without differences in number or affinity, whereas SRIH-binding sites were not detected in the others. Positive scans were observed only in patients bearing tumors with high affinity SRIH-binding sites. In conclusion, [123I]Tyr3-octreotide appears to be a promising tool for singling out, in vivo, patients with functionless pituitary tumors displaying SRIH receptors who might potentially benefit from octreotide treatment.

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.

Heparin transfer across the rabbit peritoneal membrane.

Variable quantities of heparin have been proposed to avoid intraperitoneal clotting during peritoneal dialysis without the risk of systemic effects, because heparin is presumed to be incapable of passing through the peritoneal membrane. This study set out to verify this assumption by using labeled heparin in experimental dialysis in 7 New Zealand white rabbits. Heparin was labeled with 99mTc. Labeling quality, assessed by two chromatographic checks, showed less than 5% of free pertechnetate. Chromatographic determinations showed more than 95 and 80% of labeled heparin in inflow and outflow dialysates and in blood samples respectively. Following sodium thiopental anesthesia, animals underwent three protocols: a single 15 min cycle of time diffusion with heparin 500 U/l (A), 6 successive 15 min cycles with heparin 500 U/l (B), and a single 3 h cycle with heparin 2,500 U/l (C). Labeled heparin was found in blood organs and urine in variable percentages. The total amount of recovered radioactivity ranged from 1.5% (A) to 20% (C) of that introduced. It may be concluded that heparin passes through the peritoneum according to some law dependent on the amount used and the diffusion time.

99mTc-aprotinin: comparison with 99mTc-DMSA in normal and diseased kidneys.

Aprotinin (A) and DMSA labelled with 99mTc were compared in patients with normal (NK, n = 12) and diseased kidneys (CRF, n = 13) by means of quantitative serial scans and measurements of blood clearance and urinary excretion. Serial scans only were obtained in additional 13 patients. Scan quality in the NK patients was essentially equal: faster blood clearances, reduced urinary excretions and higher fixations of A in the target compensated for the increased liver uptake. On the other hand, the scan quality in the CRF patients was definitely superior with A, allowing detection of residual functioning parenchyma also in severe kidney failure. Correlation between the net kidney uptake 6 hrs p.i. and the separate hippuran clearance rate was better with A than with DMSA, indicating the feasibility of A in evaluating relative renal function.

[Diagnostic, clinical and therapeutic aspects of primary transitional cell carcinoma of the prostate]. / Aspetti diagnostici, clinici e terapeutici del carcinoma primitivo a cellule di transizione della prostata.

Transitional cell carcinoma is a rare neoplasm with an reported incidence of 2%. It is biologically different from adenocarcinoma in that it is not hormonally responsive and it is not associated with an elevated serum acid phosphatase. It is marked by local invasiveness and distant metastases. Transitional cell carcinoma has its origin at the level of the periurethral ducts in the area of the junction of the cylindrical and transitional epithelium. Transitional cell carcinoma can be distinguished from adenocarcinoma and carcinoma endometriode exclusively for its histological aspect. Various therapies have been used to treat transitional cell carcinoma but with poor results. Surgical treatment is still today the most efficient with a surviving average of 2 years. The Authors report 3 new cases, discussing diagnostic, clinical and therapeutical aspects of this rare neoplasm.

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.

[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.

[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.

[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.

[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.

[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.