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.

Factors influencing survival after hepatectomy for metastases from gastric cancer.

PURPOSE: To investigate clinical factors influencing the prognosis of patients submitted to hepatectomy for metastases from gastric cancer and their clinical role. METHODS: Retrospective multi-center chart review. We evaluated how survival from surgery was influenced by patient-related, gastric cancer-related, metastasis-related and treatment-related candidate prognostic factors. RESULTS: One hundred and five patients submitted to hepatectomy for metastases from gastric cancer, in the synchronous and metachronous setting of the disease. In 89 cases a R0 resection was achieved, while in 16 a R+ hepatic resection was performed. Adjuvant chemotherapy was administered to 29 patients. Surgical mortality was 1% and morbidity 13.3%. Median disease-free survival was 10 months, median overall survival was 14.6 months. Overall 1, 3, and 5-year survival rates were 58.2%, 20.3%, and 13.1%, respectively. Survival was influenced independently by the factor T of the gastric primary (p < 0.001), by the curativity of surgical procedure (p = 0.001), by the timing of hepatic involvement (p < 0.001) and by adjuvant chemotherapy (p < 0.001). T4 gastric cancer, R+ resection, synchronous metastases, and abstention from adjuvant chemotherapy were associated with a worse prognosis; T4 gastric cancer and R+ resections displayed a cumulative effect (p < 0.001). CONCLUSIONS: Our data show that R0 resection must be pursued whenever possible. Furthermore, in the synchronous setting, the coexistence of T4 gastric primaries and R+ resections suggests prudence and probably abstention from hepatectomy. Finally, a multimodal treatment associating surgery and chemotherapy offers the best survival results.

Challenge in differential diagnosis of a liver mass histologically defined as a metastatic lesion from an occult primary intestinal tumour. The importance of clinical findings and the limitations of histology and molecular profiles. A case report.

Differential diagnosis of liver lesion in the absence of proven primary tumor is still a challenge. We experienced a case of an asymptomatic 14 cm lesion of right hemiliver in a 67 year-old man submitted to right hepatectomy in December 2010. One year before the patient underwent to endoscopic removal of a tubular adenoma of the right colon. Preoperative diagnosis was supported by ultrasound, CT scan, PET and liver biopsy. The patient received 6 cycles of preoperative chemotherapy (FOLFOX) with down-staging of the lesion diameter. Immunohistochemistry on the surgical specimen showed positivity for cytokeratins 19 and 20, CEA, MUC-2, negativity for cytokeratin 7 and a-fetoprotein. Moreover, the neoplastic cells showed a focal positivity with lower intensity for MUC-1 and MUC-5AC. The immunohistochemical profile suggested the possibility of a metastatic tumour from the large bowel, without excluding a primitive mucinous cholangiocarcinoma with intestinal phenotype. At 6 months after intervention, the patient was submitted to chemotherapy (FOLFOX). At present he is in good condition, without radiological signs of recurrence. Oncologists must evaluate the possible benefits of further adjuvant treatments based on the differential diagnosis between a primitive or metastatic liver tumour. In conclusion, correct diagnosis of liver masses is mandatory and remains a challenge that can differentiate either follow-up or surgical and adjuvant treatment. Histology and immunohistochemistry must be related to clinical findings as they may not always be sufficient to reach a correct final diagnosis, and can even be confusing. At present, molecular biology cannot be considered a helpful for diagnosis in these cases.

Simultaneous occurrence of primary diffuse large B-cell lymphoma and extranodal marginal zone (MALT) B-cell lymphoma in the gallbladder: a case report.

Primary lymphoma of the gallbladder is extremely rare. We present an asymptomatic case of primary combined DLBCL--MALT lymphoma of the gallbladder in a 78-year-old man in whom definitive diagnosis was made with laparotomic cholecystectomy. Preoperative diagnosis was supported by NMR, CT and PET scans. The pathological report identified a polypoid lesion measuring 3.5 cm in diameter. A non-Hodgkin lymphoma with two different coexisting patterns was identified histologically: large diffuse B-cell lymphoma (DLBCL) associated with focal areas of extranodal marginal zone B-cell lymphoma (MALT-type) of the gallbladder. The postoperative course was uneventful and the patient is currently without clinical or radiological signs of disease. Chemotherapy was not indicated due to cardiopathy. In conclusion, a primary gallbladder lymphoma is a rare entity. Radiological findings may be helpful, but cholecistectomy may be necessary for definitive diagnosis. In this report, we describe the possible association between MALT and DLBCL of the gallbladder.

Coping strategies in intestinal transplantation.

The psychological construct of coping has been studied extensively in other medical populations and has more recently been applied in the field of transplant psychology. Coping can be defined as all abilities used by people to face problematical and stressful situations, as the data in literature describe the experience of transplantation. The purpose of this study was to describe the coping styles used by 25 intestinal transplant recipients. To assess the coping strategies, we used the Italian version of Coping Orientation to Problems Experienced (COPE) by Sica, Novara, Dorz, and Sanavio (1997). The authors divided these strategies into three classes: problem-focused, emotion-focused, and potentially disadaptive strategies. This questionnaire is usually used in a medical setting. Even if the long process of psychological-clinical adaptation required by intestinal transplantation put patients in a passive acceptance of their situation and their incapacity to face it, our patients showed high levels of problem-focused strategies, indicators of positive outcomes for this intervention. Anyway, this is a slow and gradual path that goes with the psychological distress and the need for a peculiar psychological support of problem-focused strategies. The result suggested that assessment of coping strategies should be explored in intestinal transplant to encourage the use of action-oriented methods and discourage those with possible negative effects.

Italian experience in adult clinical intestinal and multivisceral transplantation: 6 years later.

PATIENTS AND METHODS: Between December 2000 and November 2006, 28 isolated intestinal transplants and nine multivisceral transplants (five with liver) from cadaveric donors have been performed for short gut syndrome (n = 15), chronic intestinal pseudo-obstruction (n = 10), Gardner's syndrome (n = 9), radiation enteritis (n = 1), intestinal atresia (n = 1), and massive intestinal angiomatosis (n = 1). Indications for transplantations were: loss of venous access, recurrent sepsis due to central line infection, and/or major electrolyte and fluid imbalance. Liver dysfunction was present in 19 cases. All patients were adults of median age at transplant of 34.7 years and mean weight 59.6 kg. All recipients were on total parenteral nutrition for a mean time of 38.8 months. Mean donor/recipient body weight ratio was 1.1. RESULTS: The mean follow-up was 892 +/- 699 days. Twenty-five patients were alive (67.5%) with 3-year patient survivals of 70% for isolated intestinal transplantations and 41% for the multivisceral transplantations (P = .01). The mortality rate was 32.5% with losses due to sepsis (63%) or rejection. Our 3-year graft survival rates were 70% for isolated intestinal transplantations and 41% for multivisceral transplantations (P = .02); graftectomy rate was 16%. These were 88% of grafts working properly with patients on regular diet with no need for parenteral nutrition. DISCUSSION AND CONCLUSIONS: Induction therapy has reduced the doses of postoperative immunosuppressive agents, especially in the first period, lowering the risk of renal failure and sepsis, mucosal surveillance protocol for early detection of rejection dramatically reduced the number of severe acute chronic rejections.

Rejection episodes and 3-year graft survival under sirolimus and tacrolimus treatment after adult intestinal transplantation.

PURPOSE: Mammalian target of rapamycin (mTOR) inhibitors have been recently introduced in clinical practice after intestinal transplantation. We focused on Sirolimus (Rapamycin) to examine effects on rejection and graft survival following intestinal transplantation. PATIENTS AND METHODS: Twenty isolated intestinal recipients and 5 multivisceral patients (2 with liver) in our series were divided into 3 groups: patients started on Sirolimus (because of nephrotoxicity or biopsy-proven rejection), who continued therapy longer than 3 months (n = 11); patients started on Sirolimus (because of nephrotoxicity or biopsy-proven rejection), who received therapy less than 3 months because of side effects (n = 4); and a control group, who never received rapamycin (n = 10). RESULTS: During prolonged treatment combined with Tacrolimus (Prograf), both Sirolimus groups showed a decreased number of acute cellular rejections (P < .01). Cumulative 3-year graft and patient survival rates were 81% in the Sirolimus greater than 3 months group, 100% in the Sirolimus less than 3 months group, and 80% and 90% in the control group, respectively (P = .63 and P = .62). CONCLUSION: In our experience, the use of mTOR-inhibitors in combination with calcineurin-inhibitors seemed to be more effective than monotherapy to reduce the number of rejections. Side effects can limit its use as maintenance therapy.

Artificial neural network is superior to MELD in predicting mortality of patients with end-stage liver disease.

BACKGROUND: Despite its accuracy, the model for end-stage liver disease (MELD), currently adopted to determine the prognosis of patients with liver cirrhosis, guide referral to transplant programmes and prioritise the allocation of donor organs, fails to predict mortality in a considerable proportion of patients. AIMS: To evaluate the possibility to better predict 3-month liver disease-related mortality of patients awaiting liver transplantation using an artificial neural network (ANN). PATIENTS AND METHODS: The ANN was constructed using data from 251 consecutive people with cirrhosis listed for liver transplantation at the Liver Transplant Unit, Bologna, Italy. The ANN was trained to predict 3-month survival on 188 patients, tested on the remaining 63 (internal validation group) unknown by the system and finally on 137 patients listed for liver transplantation at the King's College Hospital, London, UK (external cohort). Predictions of survival obtained with ANN and MELD on the same datasets were compared using areas under receiver-operating characteristic (ROC) curves (AUC). RESULTS: The ANN performed significantly better than MELD both in the internal validation group (AUC = 0.95 v 0.85; p = 0.032) and in the external cohort (AUC = 0.96 v 0.86; p = 0.044). CONCLUSIONS: The ANN measured the mortality risk of patients with cirrhosis more accurately than MELD and could better prioritise liver transplant candidates, thus reducing mortality in the waiting list.

Analysis of risk factors for early hepatic artery thrombosis after liver transplantation. Possible contribution of reperfusion in the early morning.

BACKGROUND: Since the incidence of myocardial infarction and other cardiovascular ischaemic events is highest in early morning, on account of a relative hypercoagulable state occurring in this time period, an attempt was made to test whether reperfusion of the hepatic artery at this time of the day, at liver transplantation, produces an increased risk of early thrombosis. METHODS: The records of 255 consecutive patients receiving a first transplant for chronic liver disease were retrospectively analysed. As possible risk factors, for early post-operative thrombosis (<30 days from transplantation), several medical and surgical parameters were taken into consideration. Arterial reperfusion was considered to have taken place at a time of high coagulability when occurred between 6.00 a.m. and 10.00 a.m. on the basis of previous reports. RESULTS: Logistic regression identified donor age (OR for age >60: P=0.017), bench reconstruction of the artery (OR: 5.06, P=0.013) and time of high coagulability at reperfusion (OR 2.93, P=0.087), as independently associated with early hepatic artery thrombosis. CONCLUSIONS: The present findings identified three independent predictors of early hepatic thrombosis, warranting stricter post-surgical follow-up of patients presenting such conditions. Interestingly, these factors are consistent with arterial reperfusion in the early morning being associated with an increased risk of early hepatic artery thrombosis, suggesting relative coagulative imbalances to provide a contribution in the pathogenesis of this severe complication of liver transplantation.

Surgical approach to complicated intestinal failure for benign disease in adult patients: transplantation or surgical rehabilitation?

Surgical approaches to complicated benign intestinal failure are gaining acceptance, especially in the pediatric population. Less international experience has been obtained in adult patients, who are usually treated with total parenteral nutrition (TPN). An intestinal rehabilitation program was started in our institution with comprehensive medical rehabilitation, surgical bowel rescue, and transplantation. Among 38 adult patients referred by our gastroenterologists for bowel rehabilitation and surgically treated in our institution, 92.2% received TPN on admission. After careful evaluation, 71% underwent transplantation. Five patients died, but 18 recipients were completely weaned off TPN at follow-up. Eleven patients underwent surgical resection of the affected bowel and a subsequent program of intestinal rehabilitation: they were all alive and weaned off TPN at discharge. At a 2-year mean follow-up, deaths occurred only in the transplant population. Therefore, intestinal surgical rescue, if successful, is optimal in adult patients.

Preliminary results of immunosuppression with thymoglobuline pretreatment and hepatitis C virus recurrence in liver transplantation.

Induction with thymoglobulin, a potent anti-thymocyte polyclonal antibody, has been recently reported to allow minimization of postoperative immunosuppression in organ transplantation. The relationship with recurrence of hepatitis C virus (HCV) after liver transplantation (LT) has never been investigated. We report herein on the outcome of 22 HCV+ patients receiving thymoglobulin pretreatment and minimal immunosuppression after liver transplantation. Patient survival and acute rejection rates were good, with remarkably low dosages and levels of immunosuppression achieved with thymoglobulin, and without exposing patients to an elevated risk of rejection. A progressive weaning of the primary immunosuppressant was also possible in the majority of patients without complications. The HCV recurrence rate was similar to that reported in the literature, although lower HCV RNA viral loads were obtained with thymoglobulin and a mild histologic course. Although our results need to be validated in large cohort studies, our experience shows that minimization of immunosuppression with thymoglobulin is effective to protect against rejection and demonstrated a positive impact on HCV recurrence that deserves further investigation.