Refractory and 17p-deleted chronic lymphocytic leukemia: improving survival with pathway inhibitors and allogeneic stem cell transplantation.

Refractory/early relapsed and 17p deletion/p53 mutation (del(17p)/TP53mut)-positive chronic lymphocytic leukemia (CLL) has been conventionally considered a high-risk disease, potentially eligible for treatment with allogeneic stem cell transplantation (alloSCT). In this multicenter retrospective analysis of 157 patients, we compared the outcomes of patients with high-risk CLL treated with alloSCT, a B-cell receptor pathway inhibitor (BCRi), and both. Seventy-one patients were treated with BCRis, 67 patients underwent reduced-intensity conditioning alloSCT, and 19 received alloSCT with a BCRi before and/or after transplantation. Inverse probability of treatment weighting analyses were performed to compare the alloSCT and no-alloSCT groups; in the 2 groups, 5-year OS, PFS, and cumulative incidence of nonrelapse mortality (NRM) and relapse were 40% versus 60% (P = .096), 34% versus 17% (P = .638), 28% versus 5% (P = .016), and 38% versus 83% (P = .005), respectively. Patients treated with alloSCT plus BCRi had a 3-year OS of 83%. The 3-year OS and NRM by year of alloSCT, including patients treated with BCRi, were 53% and 17% in 2000 to 2007, 55% and 30% in 2008 to 2012, and 72% and 18% in 2013 to 2018. In conclusion, the combination of pathway inhibitors and alloSCT is feasible and may further improve the outcome of high-risk CLL patients.

Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi.

BACKGROUND: Tumor regression after antiviral therapy (AT) is in favor of an etiological role of hepatitis C virus (HCV) in non-Hodgkin's B-cell lymphomas (NHL). PATIENTS AND METHODS: We carried out a cohort study of 704 consecutive HIV-negative, HCV-positive patients with indolent NHL diagnosed and treated from 1993 to 2009 in 39 centers of the Fondazione Italiana Linfomi; 134 patients were managed with AT for lymphoma control. RESULTS: For entire cohort, 5-year overall survival (OS) was 78% [95% confidence interval (CI): 74%-82%] and 5-year progression-free survival (PFS) was 48% (95% CI: 44%-53%). In multivariate analysis, the use of AT during the patients' life had positive impact on OS. Forty-four of the 100 patients treated with first-line AT achieved a complete remission (CR) and 33 a partial response (PR). HCV-RNA clearance was achieved in 80 patients and was related to lymphoma response. At a median follow-up of 3.6 years, 5-year PFS was 63% (95% CI: 50%-73%). CR + PR rate was 85% with AT as second-line treatment. CONCLUSION: AT produces HCV-RNA clearance and consequent tumor regression in most patients with HCV-related indolent NHL. AT used at any time is associated with improved OS. Consequently, AT can be considered an option for patients with indolent lymphomas who do not need immediate cytoreductive treatment.

Multicentre retrospective study on endoscopic ultrasound complications.

BACKGROUND: Endoscopic ultrasonography, both conventional and interventional, has been used increasingly during the past 20 years and is deemed a safe technique. Its complication rate, however, has been studied to only a limited extent. This multicentre investigation sought to establish the complication rate for a large number of endoscopic ultrasonography procedures. METHODS: By means of a questionnaire, we collected data from six centres on the number of endoscopic ultrasonography examinations performed and divided them into conventional and interventional examinations of the upper and lower gastrointestinal tract. Information was obtained on technical modalities such as instruments and sedation and, for interventional endoscopic ultrasonography, indications, pre-procedural exams and technical details (needle calibre, number of passes) had to be specified. Complications were classified as mild, moderate, severe or fatal and their onset as immediate, early or late. Variables that entered into the analysis of complication rate included type of endoscopic ultrasonography instrument used, type and site of lesion biopsied, number of needle passes and operator experience. RESULTS: Eleven thousand five hundred thirty nine endoscopic ultrasonographic procedures were reported, of which 10,731 were conventional and 808 interventional. No deaths occurred; there were 14 (0.12%) complications, 5 (0.046%) of them following conventional endoscopic ultrasonography and 9 (1.11%) after interventional endoscopic ultrasonography. Seven complications were mild, four moderate and three severe. CONCLUSIONS: Both conventional and interventional endoscopic ultrasonography were confirmed to be acceptably safe techniques.

Thiotepa-based high-dose therapy for autologous stem cell transplantation in lymphoma: a retrospective study from the EBMT.

Clinical information about thiotepa-based autologous stem cell transplantation (auto-SCT) outside the primary central nervous system lymphoma (PCNSL) field is sparse. In this registry-based retrospective study, we evaluated potential risks and benefits of thiotepa-based preparative regimens compared with BEAM (carmustine, etoposide, cytarabine, melphalan) in auto-SCT for diffuse large B-cell lymphoma (DLBCL, excluding PCNSL), follicular lymphoma (FL) or Hodgkin lymphoma (HL). A total of 14 544 patients (589 thiotepa and 13 955 BEAM) met the eligibility criteria, and 535 thiotepa- and 1031 BEAM-treated patients were matched in a 1:2 ratio for final comparison. No significant differences between thiotepa and BEAM groups for any survival end point were identified in the whole sample or disease entity subsets. For a more detailed analysis, 47 TEAM (thiotepa, etoposide, cytarabine, melphalan)-treated patients were compared with 75 matched BEAM patients with additional collection of toxicity data. Again, there were no significant differences between the two groups for any survival end point. In addition, the frequency of common infectious and non-infectious complications including secondary malignancies was comparable between TEAM and BEAM. These results indicate that thiotepa-based high-dose therapy might be a valuable alternative to BEAM in DLBCL, HL and FL. Further evaluation by prospective clinical trials is warranted.

Oncologic emergencies secondary to advanced colorectal cancer successfully treated with oxaliplatin/5-fluorouracil/leucovorin: report of three cases.

Metastatic/advanced colorectal cancer is considered a resistant disease and oncologic emergencies secondary to advanced disease may be regarded with a nihilistic attitude. The objective of this report is to emphasize the efficacy of the oxaliplatin/5-fluorouracil/leucovorin regimen (FOLFOX-4) in three patients presenting oncologic emergencies secondary to advanced colon cancer. The first case was a 40-year-old man with severe respiratory insufficiency due to massive carcinomatous lymphangitis; subsequently a cecal adenocarcinoma was diagnosed. The patient's conditions became life-threatening and he was admitted to the intensive care unit. The second case was a 41-year-old woman presenting with fever, abdominal mass and pain. Ultrasound and CT-scan revealed two hepatic masses (13 x 15 and 15 x 20 cm), diagnosed as liver metastases from colon cancer. The patient's condition deteriorated with intestinal obstruction secondary to the large left liver mass. The third case was a 58-year-old woman presenting with hepatic mass, fever and weight loss. Ultrasound and CT-scan showed a liver lesion occupying the right lobe (12 x 14 cm). Ultrasonically-guided biopsy and colonoscopy showed liver metastases from cecal cancer. A 5-fluorouracil/leucovorin regimen failed to improve her clinical condition and she had disease progression, inferior vena cava neoplastic thrombosis and right hydronephrosis. All three patients rapidly improved after a few cycles of oxaliplatin-containing chemotherapy. These cases demonstrate that even patients with advanced colorectal cancer presenting with oncologic emergencies and life-threatening conditions can be successfully treated with the FOLFOX-4 regimen.

Abnormal renal responses to calcium entry blockade in normotensive offspring of hypertensive parents.

In nine young normotensive subjects with no family history of hypertension and nine age-matched normotensive subjects with one parent with essential hypertension, effective renal plasma flow (p-aminohippuric acid clearance), glomerular filtration rate (inulin clearance), and excretion of sodium and exogenously administered lithium were measured for 90 minutes before and after administration of a single 20-mg oral dose of the calcium entry blocker nifedipine. Segmental tubular handling of fluid and sodium was estimated using lithium clearance as a marker of proximal tubular reabsorption. Nifedipine did not cause any change in subjects with no family history of hypertension, but in those with one hypertensive parent there was a marked increase in effective renal plasma flow (from 644 +/- 39 to 847 +/- 42 [SEM] ml/min x 1.73 m2; p less than 0.001) and a decrease in filtration fraction (from 17.6 +/- 1.0 to 12.6 +/- 0.4%; p less than 0.001), while the glomerular filtration rate was unchanged, thus suggesting a prevailing efferent vasodilation. Sodium excretion rate (p less than 0.02) and fractional sodium excretion (p less than 0.025) increased slightly but significantly in subjects with one hypertensive parent, but not in normotensive subjects with no family history of hypertension. Lithium clearance also rose (from 29.0 +/- 2.0 to 32.8 +/- 1.9 ml/min, p less than 0.001), and the derived value of fractional proximal reabsorption diminished (from 75.8 +/- 1.0 to 71.3 +/- 1.2%, p less than 0.001). Estimated distal delivery of sodium and absolute distal sodium reabsorption both increased significantly (p less than 0.005), while fractional distal sodium reabsorption was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical efficacy of ultrasound guided percutaneous drainage of abscesses in patients with leukaemia and lymphoma.

Ultrasound guided percutaneous drainage (US-PD), a minimally invasive technique, has been reported as highly effective for the treatment of deeply located abscesses, particularly in immunocompromised patients. Therefore, we retrospectively studied its therapeutic efficacy and safety in a series of 14 patients with leukaemia and lymphoma. We collected the clinical and sonographic data of 14 patients with various types of leukaemia and lymphoma. These patients were consecutively observed in four clinical centres with long-term experience with ultrasound guided therapeutic techniques. The cases were analysed according to underlying disease, clinical features, location of the abscess, drainage technique, microbiological data and both short- and long-term outcome. In our series, 11 patients were treated with repeated ultrasound guided needle aspirations (US-NA) and 3 underwent catheter drainage (US-PCD). In 12/14 cases the procedure was successful (86%): the mortality rate was 14%. 5 patients died during the follow-up period because of the underlying disease, without abscess recurrence. No complications were reported. Our data suggest that ultrasound guided percutaneous drainage should be considered the first choice, minimally invasive procedure for the treatment of deeply located abscesses in patients with leukaemia and lymphoma.

Focal liver lesions in non-Hodgkin's lymphoma: investigation of their prevalence, clinical significance and the role of Hepatitis C virus infection.

Imaging techniques like ultrasonography (US) or computed tomography (CT) allow full liver scanning and the accurate detection of focal lesions of the liver parenchyma. The occurrence of such lesions in concomitance with non-Hodgkin's lymphoma (NHL), both at the onset of the disease and during follow-up, is of great significance, because it affects staging, prognosis and therapeutic choices. Moreover, the occurrence of focal liver lesions in the setting of a lymphoma is generally considered to be a marker of liver involvement. Nonetheless, data on the prevalence and clinical significance of focal liver lesions occurring in these clinical conditions are limited. Therefore, we retrospectively evaluated the prevalence, nature and clinical significance of focal liver lesions diagnosed by imaging techniques (US and CT) in 414 consecutive NHL patients. The nature of the lesions was established either by US-guided biopsy or by evaluation of the response to chemotherapy for the underlying disease and confirmed by clinical and US follow-up. Subtype of NHL (aggressive or indolent) and Hepatitis C virus (HCV) status were also considered. We detected 129 focal liver lesions (76 at onset and 53 during the follow-up). Hepatic involvement by NHL was found in 69 cases (53%). We observed 7 cases of Hepatocellular Carcinoma (HCC) and 3 cases of metastasis. At onset, only 39% of the detected lesions were due to lymphoma and 58% were benign. Conversely, 74% of the liver lesions detected during the follow-up were due to NHL while 15% to a malignancy other than NHL. All HCC cases occurred in HCV-positive patients with chronic liver disease. We concluded that the focal liver lesions detected at onset in NHL patients are frequently benign and unrelated to the underlying disease. Conversely, most focal liver lesions detected during the follow-up period are malignant and the possibility of HCC occurrence in HCV-positive patients should always be considered. Therefore, these lesions should undergo a full diagnostic work-up, including US-guided biopsy.

Association between hepatitis C virus and non-Hodgkin's lymphoma, and effects of viral infection on histologic subtype and clinical course.

PURPOSE: Because an etiologic role for hepatitis C virus in non-Hodgkin's B-cell lymphoma has been suggested by several reports, we assessed the prevalence of hepatitis C virus infection in patients with non-Hodgkin's B lymphoma and in controls, and evaluated the influence of viral infection on histologic and clinical features of the lymphoma patients. PATIENTS AND METHODS: We prospectively investigated 175 consecutive patients with non-Hodgkin's lymphoma and 350 controls for serologic and molecular markers of hepatitis C virus infection. Controls were selected from inpatients (n = 175) and outpatients (n = 175) cared for at our hospital. Patients with lymphoma who had hepatitis C virus infection were tested for mixed cryoglobulinemia. Aminotransferase levels were measured in all lymphoma patients at baseline and during and after chemotherapy. RESULTS: Hepatitis C virus prevalence in patients with non-Hodgkin's lymphoma was significantly greater than in control subjects (37% vs 9%, P = 0.0001). Among patients with lymphoma, viral infection was associated with older mean (+/-standard deviation) age (67 +/- 14 vs 61 +/- 8 years, P = 0.001), and women (41 of 87, 47%) were more likely than men (24 of 88, 27%) to have evidence of hepatitis C infection (P = 0.006). Thirteen of the 20 cases of immunocytoma were associated with hepatitis C virus infection, which was also more common in patients with orbital and conjunctival localization of lymphoma. Patients with mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach were less likely to have evidence of hepatitis C infection. Mixed cryoglobulinemia was much more common in patients with hepatitis C virus infection (14 of 65 vs 1 of 110, P = 0.0001); it was not associated with the histologic type of lymphoma. Patients with and without hepatitis C virus infection underwent similar chemotherapy regimens and had no differences in response to chemotherapy or in overall and disease-free survival. Hepatic toxicity from chemotherapy was seen only in patients with hepatitis C virus infection, although all but one of these patients were able to complete their planned treatment. CONCLUSION: These findings suggest that the hepatitis C virus may have a role as an etiologic agent in non-Hodgkin's B-cell lymphoma. Some clinical and pathologic features of the disease are associated with hepatitis C virus infection, but the virus does not seem to affect prognosis.

Dopaminergic modulation of acute renal effects of nicardipine.

In order to investigate whether dopamine receptors are involved in the acute natriuretic effects of calcium channel blockade, experiments were carried out in humans with uncomplicated essential hypertension. In 8 hypertensives 5 mg intravenous nicardipine produced a large decrease in blood pressure and renal vascular resistance, a slight but significant increase in glomerular filtration rate (GFR) and marked natriuresis. When a second identical experiment was performed in the same subjects with the addition of 10 mg metoclopramide as dopamine blocker, changes in sodium excretion and vascular resistance were the same, but GFR did not increase during nicardipine. In a second set of experiments (n = 5) the same design was used, but nicardipine was infused at a dose of 0.01 mg/kg, ie, seven times less than in previous experiments. Under these conditions, blood pressure, renal vascular resistance and GFR did not change, but significant natriuresis occurred. Natriuresis was almost completely prevented by metoclopramide. In 5 additional hypertensives, metoclopramide alone was infused and 0.01 mg/kg nicardipine was added to the infusion. No change in any parameter was observed. Our findings suggest that the dopaminergic system participates in maintaining or increasing GFR during blood pressure reduction by calcium antagonists, although renal vasodilation and natriuresis are largely independent of dopamine receptor activity. In addition, when low doses of calcium antagonists produce natriuresis in the absence of renal or systemic hemodynamic changes (direct tubular effect), dopamine blockade is able to blunt this effect. This indicates a modulation by dopaminergic receptors of the direct tubular action of calcium antagonists.

ProMECE-CytaBOM vs MACOP-B in advanced aggressive non-Hodgkin's lymphoma: long term results of a multicenter study of the Italian Lymphoma Study Group (GISL).

A randomized trial was designed in order to compare the efficacy and feasibility of ProMECE-CytaBOM (P-C) and MACOP-B (M-B) in patients with advanced, aggressive non Hodgkin's lymphoma (NHL). P-C and M-B were chosen due to their association with a very high complete remission rate when compared to other published protocols. The study was conducted on 210 patients with intermediate or high-grade NHL in stage I bulky, or stages II-IV, randomized to receive either 6 courses of P-C delivered every 28 days (106 patients), or 12 weeks of M-B chemotherapy (104 patients). In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin (i.e. 30 mg/m2 of the analog). At the end of induction therapy patients could receive additional radiotherapy to residual masses or to sites of previous bulky disease. The two groups of patients were compared for response rates, number and severity of therapy related side effects, overall survival, disease-free survival, and time to treatment failure. Sixty-five patients (62%) treated with P-C and 69 patients (67%) treated with M-B achieved a complete remission, with no significant differences between the two treatment arms (P = 0.13). The overall objective response rate (complete + partial remission) was 74% for patients treated with P-C, and 81% for patients treated with M-B, respectively. The 4-year relapse-free survival rate was 59% for P-C and 69% for M-B, respectively (P = 0.11).(ABSTRACT TRUNCATED AT 250 WORDS)

Extramedullary plasmacytoma in a patient with AIDS: report of a case and review of the literature.

Human immunodeficiency virus (HIV) is likely to play a role in the onset of plasma cell tumors (PCT). In fact, HIV could be involved in plasmacytomagenesis in several ways: it has the ability to lessen the immunosurveillance to such a degree as to impair the immune response against tumor cell growth. This decreased immunosurveillance could further facilitate the transforming malignant role of possible Epstein-Barr virus (EBV) infection occurring in this setting. Lastly, a murine retrovirus has been shown to be able to accelerate plasmacytomagenesis in mice, thus indicating that these viruses may be directly involved in the onset of PCT. According to cases previously reported in the literature, the clinical features of this case of HIV-associated PCT were more aggressive and the survival was shorter than expected for PCT cases in the general population. Further, the pattern of alteration of gammaglobulinemia differed in this setting. These alterations strongly suggest a direct role of HIV in PCT. Further in-depth investigations are therefore warranted to elucidate this issue.

Acute myelocytic leukemia and chronic myelomonocytic leukemia simultaneously with resectable breast cancer: a report of two cases.

This report describes 2 patients who developed acute myelocytic leukemia (AML) type M2 and chronic myelomonocytic leukemia (CMML) of the FAB classification, respectively 2 months and 2 weeks after diagnosis of operable breast cancer. The patient with AML showed pancytopenia 2 months before the diagnosis of AML, had a normal karyotype, and showed a good response to chemotherapy. The patient with CMML had a normal karyotype, and she was treated with hydroxyurea and supportive therapy. The 2 patients had no previous exposure to irradiation or cytotoxic therapy. These cases show that breast cancer and either leukemia or myelodysplastic syndrome may be associated even without previous irradiation or combination chemotherapy.

Meningeal involvement in multiple myeloma: report of a case with cytologic and immunocytochemical diagnosis.

BACKGROUND: Multiple myeloma (MM) with meningeal involvement is a very rare phenomenon. Only 37 cases of plasma cell neoplasia (MM and plasma cell leukemia) with meningeal involvement have been reported. CASE: A 60-year-old male with stage IIIA light lambda chain MM returned nine months after the diagnosis with back pain, lower right extremity paresthesias and gait disturbance. A lumbar puncture revealed atypical plasma cells in the cerebrospinal fluid (CSF), and immunocytochemical studies showed a cytoplasmic monoclonal light lambda chain. A diagnosis of myelomatous meningitis was made, and the patient received intrathecal chemotherapy and craniospinal irradiation. He died six months after the diagnosis of meningeal disease. CONCLUSION: The present case and a review of the literature show that clinical manifestations of meningeal myeloma are non-specific. MM with meningeal involvement is accompanied frequently by circulating atypical plasma cells or plasma cell leukemia. Atypical plasma cells in the CSF are an important finding for the diagnosis of meningeal myeloma, and their neoplastic nature can be best identified by immunocytochemical analyses. Patients with meningeal myelomatosis can have a good response to treatment initially, but their prognosis is poor.

Simultaneous relapse of liver cell carcinoma and non-Hodgkin's lymphoma in the liver. Report of a case with diagnosis by ultrasonically guided fine needle aspiration biopsy.

A 50-year-old man was diagnosed with non-Hodgkin's lymphoma (NHL) in 1980; he was treated with chemotherapy and achieved complete remission. Six years later he reported upper abdominal pain. Ultrasound (US) showed a 3-cm mass in the right lobe of the liver. Needle aspiration showed hepatocellular carcinoma (HCC). The patient was treated with radical resection of the tumor. Three years later (June 1989), abdominal US showed two lesions in the right lobe of the liver. Needle aspiration and tissue core biopsy showed NHL in one lesion and HCC in the other. The lymphomatous lesion resolved after chemotherapy. The patient died 30 months later (January 1992) from a gastrointestinal hemorrhage; the NHL was in complete remission. This case of the simultaneous presence of HCC and hepatic lymphoma is, to our knowledge, the first diagnosed in vivo.

Primary adrenal non-Hodgkin's lymphoma associated with autoimmune hemolytic anemia: a case diagnosed by ultrasound-guided fine needle biopsy.

Primary localized adrenal non-Hodgkin's lymphomas are extremely rare. Only 28 observations have been reported so far, all with a very poor prognosis: a median survival of 12.5 weeks. The authors report the case of a 78-year-old male with primary non-Hodgkin's lymphoma of the right adrenal gland. Disease onset was characterized by severe autoimmune hemolytic anemia, and diagnosis was made by echo-guided biopsy. The patient was admitted to our Department with severe autoimmune hemolytic anemia; the hemoglobin value was 6.5 g/dL and both indirect and direct Coombs' tests were positive. Steroid treatment with methylprednisolone 2 mg/kg/day did not improve the hemolytic process. Abdominal ultrasound examination disclosed a right hypoechogenic suprarenal mass of 10 x 9 cm; imaging techniques such as computed tomography and magnetic resonance imaging were not useful in the etiologic diagnosis of the right suprarenal mass; fine needle aspiration and tissue-core biopsy revealed low-grade non-Hodgkin's lymphoma. Staging procedures, including clinical examination, total body computed tomography scan, bone-marrow biopsy, gallium scan, abdominal magnetic resonance imaging, did not disclose other sites of involvement and strongly supported a diagnosis of primary non-Hodgkin's lymphoma of the right adrenal gland. Hormone assays were within normal limits. The patient was treated with chemotherapy, cyclophosphamide-vincristine-prednisone regimen, with good regression of the adrenal mass after 6 courses, and normalization of hemoglobin level and negativity of Coombs' tests. The importance of this case lies in the very rare occurrence of this disease, its association with autoimmune hemolytic anemia, the diagnosis made by ultrasound-guided biopsy, and good response to treatment with respect to cases reported in the literature. The patient remains in clinical remission 12 months after onset of the disease.

Clinical experiences with emergency ultrasound guided diagnostic and therapeutic procedures in a department of internal medicine.

In some particular clinical emergencies, it is mandatory to obtain a pathological diagnosis as soon as possible and to start therapy quickly. This can be often done by means of ultrasound guided fine needle biopsy. The cases of emergency ultrasound guided fine needle biopsies and drainages performed in our Ultrasound Laboratory over the past 5 years represent 1.6% of all procedures performed on deeply located lesions. Diagnostic accuracy of emergency ultrasound guided fine needle biopsies was comparable to that obtained in routine situations. In 11/12 patients, this diagnostic procedure allowed the immediate start of proper therapy. Emergency ultrasound guided percutaneous drainage was performed in 6 patients and all of them had a successful outcome. We conclude that emergency ultrasound guided diagnostic and therapeutic procedures, although rarely necessary, can be very useful in some clinical situations. The high efficacy of these techniques is not impaired in an emergency.