MR-guided vacuum-assisted breast biopsy in the management of incidental enhancing lesions detected by breast MR imaging.

PURPOSE: The objective of this study was to determine the clinical value and accuracy of magnetic resonance (MR)-guided vacuum-assisted breast biopsy (VAB). MATERIALS AND METHODS: We retrospectively analysed 106 incidental breast lesions detected on MR imaging in 98 patients. Patients with nonpalpable suspicious lesions that were only MR visible were referred for MR-VAB performed with a 10-gauge needle. All patients with a VAB diagnosis of infiltrating carcinoma, carcinoma in situ or atypical epithelial hyperplasia were referred for surgery. Histopathology of the surgical specimen was considered the reference standard. RESULTS: MR-guided VAB was attempted in 29/106 lesions (27%); in 2/29 patients, the procedure could not be performed owing to failure to visualise the lesion. Lesions with clearly malignant features and borderline lesions (atypical ductal hyperplasias) were identified in 12 cases (44%) and benign entities in 15 (56%). Seven of 12 (58%) malignant lesions were <10 mm. Among the 27 successful MR-VAB procedures, VAB yielded one false-negative diagnosis (4%) and underestimation (4%). MR-guided VAB sensitivity and specificity were 92% and 100%, respectively, with a positive predictive value of 100% and a negative predictive value of 93%. CONCLUSIONS: The results of this study indicate that MR-guided VAB offers good accuracy in characterising nonpalpable breast lesions visible on MR imaging alone. Small lesion size (<1 cm) did not prove to be a limitation for the success of the procedure.

Inflammatory breast carcinoma and locally advanced breast carcinoma: characterisation with MR imaging.

PURPOSE: This study was done to identify the typical magnetic resonance (MR) imaging findings of inflammatory breast carcinoma (IBC) in comparison with noninflammatory locally advanced breast carcinoma (LABC). MATERIALS AND METHODS: MR images of 30 patients with IBC (T4d) were compared with those of a cohort of 30 patients with LABC (T3/T4a-c). The age distribution was approximately equal in the two groups. MR images were assessed for the following features: skin thickening (>4 mm), skin oedema, architectural distortion, enhancement pattern (mass-like/non-mass-like), time-signal intensity curve (continuous-persistent type/wash-out type), skin enhancement. Fisher's exact text was used to compare MR imaging appearances of IBC and LABC (significant p value <0.05). RESULTS: Skin involvement and enhancement pattern differed between groups: skin thickening was present in 16/30 IBC (53%) vs 8/30 LABC cases (27%, p=0.06), skin oedema was present in 26/30 IBC (87%) vs 8/30 LABC (27%, p < 0.0001), and skin enhancement in 10/30 IBC (33%) vs 2/30 LABC (7%, p=0.02); non-mass-like enhancement was present in 22/30 IBC (73%) vs 12/30 LABC (40%, p=0.02). CONCLUSIONS: IBC is a distinct clinical and pathological entity resulting in typical MR imaging features. Skin changes (thickening, oedema, enhancement) related to neoplastic involvement of the dermal lymphatics are suggestive of IBC and should prompt a skin biopsy to confirm or rule out the diagnosis.

Multifocal, multicentric and contralateral breast cancers: breast MR imaging in the preoperative evaluation of patients with newly diagnosed breast cancer.

PURPOSE: This study was done to verify the usefulness of preoperative breast magnetic resonance (MR) imaging in patients with newly diagnosed breast cancer. MATERIALS AND METHODS: A retrospective analysis of 291 patients with invasive breast cancer newly diagnosed with conventional breast imaging (mammography and ultrasound) was performed. All patients underwent MR imaging prior to surgery. The MR imaging detection rate of additional malignant cancers occult to mammography and ultrasound was calculated. Data were analysed with Fisher's exact test (p<0.05) according to the following parameters: histopathological features of the index tumour (histological type and size) and mammographic density [according to the Breast Imaging Reporting and Data System (BI-RADS) classification from 1 fatty to 4 dense). The gold standard was the histological examination on the surgical specimen. RESULTS: MR imaging identified 40 mammographically and sonographically occult malignant lesions other than the index cancer in 27/291 patients (9%). These additional cancers were located in the same quadrant as the index cancer in 13 women (4%), in a different quadrant in 12 (4%) and in the contralateral breast in the remaining two (1%). The cancer detection rate in the subgroup of index cancers with lobular histological type was 25%, significantly higher (p=0.03) than the detection rate of 11% recorded in the subgroup of ductal cancers. The cancer detection rate in the subgroup of index cancers >2 cm was 27%, significantly higher (p=0.001) than the rate of 8% found in the subgroup of index cancers <2 cm. Mammographic density was not correlated (p=0.48) with MR detection of additional cancer, with 14% of additional malignancies being detected in both dense and fatty breasts. CONCLUSIONS: In patients with newly diagnosed invasive breast cancer, preoperative MR imaging is useful for detecting additional synchronous malignancies that are not detected on conventional breast imaging. The cancer detection rate is 9%. The use of preoperative MR imaging as an adjunct to conventional breast imaging in women with an infiltrating lobular index cancer and an index cancer >2 cm is especially beneficial.

B3 breast lesions determined by vacuum-assisted biopsy: how to reduce the frequency of benign excision biopsies.

PURPOSE: The aim of this study was to identify parameters allowing differentiation among the diverse group of B3 lesion at stereotactic vacuum-assisted biopsy (VAB) to identify patients with a low risk of cancer and who can therefore be referred for follow-up rather than surgery and thus reduce the number of unnecessary surgical procedures. MATERIALS AND METHODS: Among 608 VAB procedures performed for nonpalpable ultrasound (US)-occult mammographic abnormality, 102 cases of B3 were included in this study. Mammographic lesion type, lesion size, Breast Imaging Reporting and Data System (BIRADS) category, number of specimens per lesion and presence of atypia were retrospectively analysed. Results were compared with histological findings at surgery (53 cases) or mammographic findings during follow-up (49 cases). Statistical analysis was performed with univariate analysis (chi-square test), and statistical significance was set at p<0.05. RESULTS: The majority of cases were depicted as isolated microcalcifications (82.3%), were smaller than 10 mm (80.4%), had a low level of radiological suspicion (64.7%) and had 11 or more cores sampled (94.1%). Atypia at VAB was reported in 60 of 102 cases (58.8%). Carcinoma was found at excision in 5/60 (8%) B3 lesions with atypia and in no B3 lesions without atypia (p=0.146). Cancer at surgery was more frequent among cases of isolated microcalcifications (p=0.645), cases with high radiological suspicion (p=0.040) and those with a smaller number of cores sampled (borderline significant p=0.064). CONCLUSIONS: On the basis of our experience, the presence or absence of atypia in our series proved to be the reliable criterion to prompt or avoid surgery in cases with a VAB finding of B3 lesion. This criterion may therefore be adopted in practice to more accurately select patients for surgery.

Fischer's score criteria correlating with histopathological prognostic factors in invasive breast cancer.

PURPOSE: This study aimed to evaluate whether the Fischer score criteria on contrast-enhanced magnetic resonance (CE-MR) imaging could correlate with histopathological prognostic factors in invasive breast cancer. MATERIALS AND METHODS: Seventy-two women with histologically proven invasive breast cancer underwent preoperative CE-MR imaging. Images were assessed for the following parameters, according to the scoring system described by Fischer in 1999: tumour shape, margins, internal enhancement, signal intensity increase, signal intensity course and overall Fischer score. Evaluated histopathological prognostic factors included histological type, associated extensive intraductal component, diameter, lymph node metastasis, tumour grade, and oestrogen receptor (ER), progesterone receptor (PgR), Ki67 proliferation, oncogene c-erbB-2 (HER2/neu) expression. Fisher's exact test was used to correlate the CE-MR imaging parameters and histopathological findings (with significance set a p < 0.05). RESULTS: Fischer's score was 0-4 in 14/72 (19%) cases, >4 in 58/72 (81%) and 3 in 5/72 (7%; false negative), with a sensitivity of 93%. A significant correlation (p=0.02) was found between stellate-dendritic shape and the presence of an associated extensive intraductal component (EIC), which was found in 78% of stellate tumours vs. 49% of round-oval tumours. A significant correlation (p=0.039) was found between Ki67 expression and signal intensity course (Ki67 overexpression was present in 81% of tumours with washout course vs. 21% with plateau course). CONCLUSIONS: The CE-MR imaging findings that correlate with prognostic factors are shape and signal intensity curve. Fischer's multifactorial analysis was helpful in the interpretation of CE-MR images, showing a sensitivity of 93% for invasive breast cancer.

Utility of second-look ultrasound in the management of incidental enhancing lesions detected by breast MR imaging.

PURPOSE: To assess the utility of second-look ultrasound (US) for identifying and characterising incidental enhancing lesions detected by breast magnetic resonance imaging (MRI). MATERIALS AND METHODS: From among 655 consecutive breast MRI studies, 62 lesions (MRI visible, nonpalpable, occult at first-look US and mammography) were recommended for second-look US. MRI enhancement of lesions was mass-like in 59 cases (95%) and non-mass-like in three (5%). Forty-two lesions (68%) were ≤10 mm; only three lesions (5%) were >20 mm. Of all lesions, the Breast Imaging Reporting and Data System (BI-RADS) MRI category was highly suggestive of malignancy in six cases (10%), suspicious abnormality in 33 (53%) and probably benign in 23 (37%). The correlation between MRI lesion appearance, lesion size, histopathology findings and detection rate at second-look US were analysed. The reference standard was histopathology and/or follow-up (range 18-24 months). Statistical analysis was performed with the Fisher exact test. RESULTS: Second-look US identified 44 out of 62 (71%) lesions depicted at MRI. The detection rate at second-look US was higher for mass-like MRI lesions (75%) than non-mass-like lesions (0%), for lesion size >10mm (90%) and for BI-RADS 4 lesions (88%). Second-look US-guided biopsy detected 12 out of 17 (71%) malignant lesions. There was no correlation between the likelihood of carcinoma and the presence of a sonographic correlate. CONCLUSIONS: Second-look US is a reliable problem-solving tool in identifying and characterising most incidental MRI findings. It contributes to accurately selecting the cases in which MRI-guided biopsy is required.

Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas.

The microphthalmia transcription factor/transcription factor E (TFE)-family translocation renal cell carcinomas bear specific translocations that result in overexpression of TFE3 or TFEB. TFE3 fusion gene product overexpression occurs as consequence of different translocations involving chromosome Xp11.2, whereas TFEB overexpression is the result of the specific translocation t(6;11)(p21;q12), which fuses the Alpha gene to TFEB. Both TFE3 and TFEB are closely related members of the microphthalmia transcription factor/TFE-family, which also includes TFEC and microphthalmia transcription factor. These transcription factors have overlapping transcriptional targets. Overexpression of microphthalmia transcription factor has been shown to mediate the expression of cathepsin-K in osteoclasts. We hypothesize that the overexpression of the related TFE3 fusion proteins and TFEB in translocation renal cell carcinomas may have the same effect. We studied cathepsin-K in 17 cytogenetically confirmed microphthalmia transcription factor/TFE-family translocation renal cell carcinomas. Seven cases showed a t(6;11)(p21;q12), ten cases showed translocations involving Xp11.2; five cases t(X;1)(p11;q21) resulting in a PRCC-TFE3 gene fusion; three cases t(X;1)(p11;p34) resulting in a PSF-TFE3 gene fusion, one t(X;17)(p11;q25) resulting in an ASPL-TFE3 gene fusion, and one t(X;3)(p11;q23) with an unknown TFE3 gene fusion. As control we analyzed cathepsin-K in 210 clear cell, 40 papillary, 25 chromophobe renal cell carcinomas and 30 oncocytomas. All seven TFEB translocation renal cell carcinomas were labeled for cathepsin-K. Among the cytogenetically confirmed TFE3 translocation renal cell carcinomas, 6 out of 10 were positive. None of the other renal neoplasms expressed cathepsin-K. We conclude the following: (1) cathepsin-K is consistently and strongly expressed in TFEB translocation renal cell carcinomas and in 6 of 10 TFE3 translocation renal cell carcinomas. (2) Cathepsin-K immunolabeling in both TFE3 and TFEB translocation renal cell carcinomas distinguishes these neoplasms from the more common adult renal cell carcinomas, and may be a specific marker of these neoplasms. (3) These results further support the concept that the overexpression of TFE3 or TFEB in these neoplasms activates the expression of genes normally regulated by microphthalmia transcription factor in other cell types.

Multiple input control strategies for robust and adaptive climate engineering in a low-order 3-box model.

A low-order 3-box energy balance model for the climate system is employed with a multivariable control scheme for the evaluation of new robust and adaptive climate engineering strategies using solar radiation management. The climate engineering measures are deployed in three boxes thus representing northern, southern and central bands. It is shown that, through heat transport between the boxes, it is possible to effect a degree of latitudinal control through the reduction of insolation. The approach employed consists of a closed-loop system with an adaptive controller, where the required control intervention is estimated under the RCP4.5 radiative scenario. Through the online estimation of the controller parameters, adaptive control can overcome key issues related to uncertainties of the climate model, the external radiative forcing and the dynamics of the actuator used. In fact, the use of adaptive control offers a robust means of dealing with unforeseeable abrupt perturbations, as well as the parametrization of the model considered, to counteract the RCP4.5 scenario, while still providing bounds on stability and control performance. Moreover, applying multivariable control theory also allows the formal controllability and observability of the system to be investigated in order to identify all feasible control strategies.

Rehabilitation of chronic graft versus host disease in children. A clinical series.

The study was aimed at evaluating clinical and functional assessment and results obtained following rehabilitative treatment in children affected by chronic graft versus host disease (cGVHD) after allogeneic transplantation of hemopoietic stem cells (HSCT). From 1999 to 2003 we evaluated 6 children with cGVHD after HSCT presenting severe complications and disabilities. Clinical and functional assessment was performed prior to rehabilitative treatment (T1), at follow-up at 6 (T6) and 12 (T12) months after treatment. Each child received a personalized rehabilitative treatment program based on the use of neuromotor re-education techniques, massotherapy, chest rehabilitation and occupational therapy. Six children presented sclerodermoid skin lesions, joint contractures, anchylosis, respiratory insufficiency, postural and walking alterations which led to reduction in motor performance and autonomy in daily living activity. After 1 year of rehabilitation treatment, 3 patients showed improvement in motor performance, 2 remained stable and 1 patient worsened. Rehabilitative treatment associated with pharmacological therapy has proven to be useful in patients affected by cGVHD. We believe that cGVHD is a pathology which must be seen by a physiatrist as early as possible at onset of first cutaneous signs of cGVHD to limit its invalidating evolution.

Pathological complete response in a patient affected by multiple synchronous, breast and lung primary malignancies: a case report and review of the literature.

A pathological complete response in a patient affected by multiple synchronous, breast and lung primary malignancies is reported. A 63-year-old woman presented with an invasive ductal carcinoma of the breast and a lung adenocarcinoma. After multidisciplinary discussion, the patient underwent pulmonary left lower lobectomy followed by radio-chemotherapy with cisplatin and vinorelbine and started hormone therapy with letrozole. Ten months later, a left mastectomy with axillary lymph nodes dissection was performed. Histologically, a pathological complete response (pCR) was documented. With a review of the Literature, we discuss the issue of multiple primary malignancies, with its diagnostic and therapeutic implications. In cases of multiple synchronous malignancies it has been highlighted the importance of the choice of the best therapeutic approach for both the malignancies, reducing collateral individual effects.

Extra-nodal extension of sentinel lymph node metastasis is a marker of poor prognosis in breast cancer patients: A systematic review and an exploratory meta-analysis.

Invasive breast cancer is the most common malignancy in women. Its most common site of metastasis is represented by the lymph nodes of axilla, and the sentinel lymph node (SLN) is the first station of nodal metastasis. Axillary SLN biopsy accurately predicts axillary lymph node status and has been accepted as standard of care for nodal staging in breast cancer. To date, the morphologic aspects of SLN metastasis have not been considered by the oncologic staging system. Extranodal extension (ENE) of nodal metastasis, defined as extension of neoplastic cells through the nodal capsule into the peri-nodal adipose tissue, has recently emerged as an important prognostic factor in several types of malignancies. It has also been considered as a possible predictor of non-sentinel node tumor burden in SLN-positive breast cancer patients. We sought out to clarify the prognostic role of ENE in SLN-positive breast cancer patients in terms of overall and disease-free survival by conducting a systematic review and meta-analysis. Among 172 screened articles, 5 were eligible for the meta-analysis; they globally include 624 patients (163 ENE+ and 461 ENE-) with a median follow-up of 58 months. ENE was associated with a higher risk of both mortality (RR = 2.51; 95% CI: 1.66-3.79, p < 0.0001, I(2) = 0%) and recurrence of disease (RR = 2.07, 95% CI: 1.38-3.10, p < 0.0001, I(2) = 0%). These findings recommend the consideration of ENE from the gross sampling to the histopathological evaluation, in perspectives to be validated and included in the oncologic staging.

Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings.

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA-identical siblings can be used to treat children with acute lymphoblastic leukemia (ALL). However, a significant proportion of patients with ALL who undergo HSCT relapse. For this reason, we prospectively evaluated a preparative regimen that included total body irradiation (TBI), thiotepa (TT), and cyclophosphamide (CY) in patients with high-risk ALL in first complete remission (CR) and in children with ALL in second CR. PATIENTS AND METHODS: Forty children (median age, 9 years; range, 1 to 18 years) with ALL in first or second CR who underwent allogeneic HSCT from HLA-identical siblings were conditioned with a combination of fractionated TBI, TT (10 mg/kg), and CY (120 mg/kg over 2 days). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine administered intravenously at a dose of 1 to 3 mg/kg/d for the first 21 days and subsequently orally at a dose of 6 mg/kg/d. RESULTS: All assessable patients were engrafted, with a median time of 11 and 24 days for neutrophil and platelet recovery, respectively. The preparative regimen was well tolerated. Only one patient died as a result of regimen-related causes. Eight patients relapsed at a median time of 8 months after transplantation (range, 3 to 9 months), and this determined a cumulative probability of relapse of 23%. Twenty-six of 40 patients (65%) are alive and in complete hematologic remission, with a median observation time of 36 months (range, 14 to 57 months), which results in a disease-free survival (DFS) at 3 years of 65%. The 13 patients who underwent transplantation in first CR had a DFS of 85%, whereas the 27 patients who underwent HSCT in second CR had a DFS of 56%. CONCLUSION: These data suggest that TT is an effective cytotoxic drug that can be safely added to the classical TBI-CY regimen. Because of its cell cycle-independent action, good CNS diffusion, and limited extramedullary toxicity, TT may contribute to increasing the percentage of children with ALL who are successfully cured with allogeneic BMT.

Total-body irradiation and melphalan is a safe and effective conditioning regimen for autologous bone marrow transplantation in children with acute myeloid leukemia in first remission. The Italian Association for Pediatric Hematology and Oncology-Bone Marrow Transplantation Group.

PURPOSE: To evaluate the safety and efficacy of a preparative regimen consisting of fractionated total-body radiation (9.9 to 12 Gy) and melphalan (140 mg/m(2) in a single dose) in children with acute myeloid leukemia in first complete remission (CR) given autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Fifty-three children (30 males and 23 females; age range, 1.5 to 18 years) were enrolled onto the study. The median time from first CR to ABMT was 3.5 months (range, 1.4 to 13 months), with 45 patients (85%) undergoing transplantation within 6 months from the diagnosis. Forty-five patients received in vitro marrow purging with standard-dose mafosfamide (100 microg/mL), seven patients were treated with interleukin-2 before marrow collection, and in the remaining child, the marrow was unmanipulated. The median infused cell dose was 1.8 x 10(8)/kg (range, 0.4 to 5.8 x 10(8)/kg). RESULTS: All patients but one achieved hematopoietic engraftment, with a median time to neutrophil recovery of 24 days (range,11 to 66 days). Treatment-related toxicity was moderate and consisted mainly of mucositis. One patient died from cytomegalovirus interstitial pneumonia, and one died from pulmonary hemorrhage. Fourteen patients (26%) relapsed at a median time of 6 months after ABMT (range, 2 to 17 months), with a cumulative relapse probability of 29% (95% confidence interval, 16% to 42%). The 5-year Kaplan-Meier estimate of survival for all 53 patients was 78% (range, 65% to 90%), whereas the overall 5-year disease-free survival was 68% (range, 55% to 81%), with a median follow-up duration of 40 months (range, 7 to 130 months). CONCLUSIONS: These data suggest that, in our cohort of patients, the combination of total-body irradiation and melphalan is safe and associated with good antileukemia activity, making ABMT an appealing alternative for postremission therapy in children with acute myeloid leukemia in first CR.

Transdermal nitroglycerin reduces the frequency of anginal attacks but fails to prevent silent ischemia.

OBJECTIVES: The aim of this study was to objectively evaluate the effects of intermittent administration of transdermal nitroglycerin on effort tolerance, frequency of anginal attacks and presence of silent ischemic events that occur during normal daily activities. BACKGROUND: Previous studies have shown that transdermal nitroglycerin patches reduce the incidence of anginal attacks and improve exercise capacity when given intermittently. However, no carefully controlled studies are available on the effects of these preparations (and their dosing schedule) on the occurrence of "silent" ischemic events during unrestricted daily activities. METHODS: Twelve men with chronic stable angina, a positive exercise test result and significant coronary artery disease completed a randomized, double-blind, placebo-controlled trial in which patches were worn either continuously or with overnight (8 h) removal. The effects of treatment were objectively assessed by both treadmill exercise testing and 24-h ambulatory electrocardiographic monitoring. RESULTS: Only the intermittent dosing schedule afforded a small but significant improvement in exercise tolerance and prolonged exercise duration and time to ST segment depression. The frequency of anginal attacks was also reduced by both the continuous and intermittent treatment, but the effects on symptoms were not paralleled by a concomitant reduction in ischemic episodes recorded during ambulatory monitoring. CONCLUSIONS: The results indicate that when used as monotherapy, intermittent transdermal nitroglycerin preparations lessen symptoms but are ineffective for the long-term prophylaxis of silent myocardial ischemia.

Assessment of residual tissue viability by exercise testing in recent myocardial infarction: comparison of the electrocardiogram and myocardial perfusion scintigraphy.

The assessment of residual myocardial viability in infarcted areas is relevant for subsequent management and prognosis but requires expensive technology. To evaluate the possibility that simple, easily obtainable clinical markers may detect the presence of within-infarct viable tissue, the significance of exercise-induced ST elevation occurring in leads exploring the area of a recent Q wave myocardial infarction was assessed. Twenty-five patients with recent (less than 6 months) myocardial infarction were studied. All had angiographically documented coronary artery disease, diagnostic Q waves (n = 24) or negative T waves (n = 25) on the rest 12-lead electrocardiogram and exhibited during exercise greater than or equal to 1.5 mm ST segment elevation (n = 17) or isolated T wave pseudonormalization (n = 8) in the infarct-related leads. ST-T wave changes were reproduced in all patients during thallium-201 exercise myocardial scintigraphy. A fixed perfusion defect was observed in 24 of the 25 patients. A reversible defect was seen in 16 (94%) of 17 patients who exhibited transient ST elevation during exercise but in only 4 (50%) of the 8 patients who had only T wave pseudonormalization. In conclusion, in patients with recent myocardial infarction, analysis of simple ST segment variables obtained during exercise testing may allow a first-line discrimination of those who may potentially benefit from a revascularization procedure.

Exercise-induced ischemic arrhythmias in patients with previous myocardial infarction: role of perfusion and tissue viability.

OBJECTIVES: This study sought to investigate whether residual viability of infarcted myocardium may play a role in the pathogenesis of exercise-induced ventricular arrhythmias. BACKGROUND: We previously showed that transient ischemia within partially infarcted areas often precipitates ventricular arrhythmias during exercise that are consistently obliterated by intravenous nitrates. METHODS: We studied 60 patients with chronic stable angina and a previous myocardial infarction. All underwent at least two consecutive exercise stress tests, coronary angiography and stress/rest myocardial perfusion tomography by Tc-99m 2-methoxy isobutyl isonitrile (MIBI). In the last 26 consecutive patients, residual viability was assessed by single-photon emission computed tomography (SPECT) using fluorine (F)-18 fluorodeoxyglucose. Perfusion and metabolic data were evaluated qualitatively by three independent observers in blinded manner. RESULTS: With exercise, 30 patients (group A) consistently developed ventricular arrhythmias (> 10 ventricular ectopic beats/min, couplets, nonsustained ventricular tachycardia); the remaining 30 patients (group B) did not. The severity of coronary artery disease (Gensini score) was similar in the two groups. Postexercise SPECT showed partial reperfusion of an infarcted area in 28 of 30 patients of group A but in only 9 of 30 of group B (p < 0.0001). Uptake of F-18 fluorodeoxyglucose was observed within the infarcted zone in 10 of 13 and 1 of 13 patients in groups A and B, respectively (p = 0.0003). CONCLUSIONS: In patients with myocardial infarction, exercise-induced ventricular arrhythmias appear to be triggered by transient ischemia occurring within a partially necrotic area containing large amounts of viable myocardium. Therefore, occurrence of arrhythmias during exercise may represent a clue to the presence of residual viability within a previously infarcted area.

Busulfan, cyclophosphamide and melphalan as conditioning regimen for bone marrow transplantation in children with myelodysplastic syndromes.

As typical disorders of the elderly, myelodysplastic syndromes (MDSs) are relatively unusual in childhood. Nevertheless, up to 17% of cases of pediatric acute myeloid leukemia may have a preleukemic phase. In young patients, the goal of treatment is eradication of the preleukemic malignant clone and reconstitution of normal hematopoiesis. Allogeneic bone marrow transplantation (BMT) has proved to be capable of this, but the optimal conditioning treatment to achieve eradication remains to be defined. Between May 1989 and June 1993, eight consecutive pediatric patients with MDS received a marrow transplant from an HLA-identical, mixed lymphocyte culture (MLC) non-reactive sibling. Diagnosis at time of presentation was refractory anemia with excess of blasts (RAEB) in two patients, RAEB in transformation (RAEB-t) in three, and juvenile chronic myelogenous leukemia (JCML, the pediatric counterpart of adult chronic myelomonocytic leukemia) in the remaining three children. Conditioning regimen consisted of busulfan, cyclophosphamide and melphalan, three alkylating agents potentially capable of killing also dormant preleukemic stem cells. The preparative regimen was very well tolerated, and all patients engrafted promptly. Six out of eight patients (75%) are alive and well with a median observation time of 20 months (range 8-34 months). Serial karyotype monitoring and molecular analyses have demonstrated a full chimerism of donor cells and the complete disappearance of trisomy 8 detected before transplant in three cases. All surviving patients have a Karnofsky score of 100%. One boy, affected by RAEB-t with monosomy 7 resistant to treatment with low-dose ara-C, relapsed 11 months after BMT, evolved in AML and died from progressive leukemia. Another patient with RAEB died on day +95 after BMT due to interstitial pneumonia of unclear etiology. This study confirms that allogeneic BMT is the treatment of choice in pediatric patients with MDS, and suggests that the employed conditioning regimen is a safe and effective means for eradicating the preleukemic malignant clone. Particularly noteworthy is that the three children with JCML obtained a complete remission and one of them is now a long-term survivor.

Autologous bone marrow transplantation for acute myeloid leukaemia in children using total body irradiation and melphalan as conditioning regimen.

We conducted a phase II study on 19 children with AML in first (10 patients) or second (nine patients) complete remission (CR) treated with ABMT, evaluating the combination of total body irradiation (TBI, 12 Gy in six divided fractions) and high-dose melphalan (140 mg/m2 in single dose) in an attempt to improve antitumour efficacy of conditioning regimen. All patients received cryopreserved and in vitro purged (mafosfamide at a dose of 100 micrograms/ml) bone marrow. The median time from first CR to ABMT was 5 months compared with a median time of 3 months for patients in second remission. One of the 19 patients, transplanted in second CR, died of transplant-related complication 10 days after transplant and another second CR patient relapsed on day +28, before engraftment. Three further patients in second CR relapsed at 6, 6 and 18 months after marrow transplant, respectively, and this determined a relapse rate of 43% in children given ABMT in second CR and 0% for patients transplanted in first remission (P < 0.05). Seventy-two per cent of all patients are projected to be alive and disease-free at 6 years, whereas the event-free survival of patients in first and in second CR is 100 and 44%, respectively (P < 0.05). Although the number of patients does not allow us to draw any firm conclusion, our results are encouraging and suggest that the association of TBI and high-dose melphalan appears to be safe and valuable.

Improvement over time in outcome for children with acute lymphoblastic leukemia in second remission given hematopoietic stem cell transplantation from unrelated donors.

Aims of this study were to verify whether reduction in transplant-related mortality (TRM) of children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) given allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated volunteers has occurred over time and to investigate the role of other variables on the probabilities of relapse, TRM and event-free survival (EFS). We compared results obtained in 26 children given HSCT before January 1998 with those of 37 patients transplanted beyond that date. In all donor-recipient pairs, histocompatibility was determined by serology for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 antigen. High-resolution molecular typing of HLA class I antigens was employed in 20 of the 37 children transplanted more recently. Probability of both acute and chronic GVHD was comparable in the two groups of patients. In multivariate analysis, children transplanted before January 1998, those with T-lineage ALL and those experiencing grade II-IV acute GVHD had a higher relative risk of TRM at 6 months after transplantation. Relapse rate was unfavorably affected by a time interval between diagnosis and relapse <30 months. The 2-year probability of EFS for children transplanted before and after 1 January 1998 was 27% (10-44) and 58% (42-75), respectively (P = 0.02), this difference remaining significant in multivariate analysis. EFS of unrelated donor HSCT in children with ALL in second CR has improved in the last few years, mainly due to a decreased TRM. This information is of value for counseling of patients with relapsed ALL.