A Rare Case of Coexisting Breast Cancer and Refractory Acute Myeloid Leukemia.

The occurrence of acute myeloid leukemia (AML) within six months from a diagnosis of breast cancer (BC) is rarely reported in the literature, and it is associated with a poor prognosis. We report herein the case of a 40-year-old woman referred to our centre affected by BC and simultaneous AML. The patient proved refractory to first line therapy and achieved complete remission (CR) with a clofarabine-based regimen followed by allogeneic stem cell transplantation (ASCT). Both during salvage chemotherapy and after ASCT, the patient presented severe infectious complications ( acute cholecistytis and Nocardia pneumonia, respectively) treated with surgery, and currently she is alive in CR for both diseases after 29 months of follow-up. The case highlights the importance of a diagnostic assessment of any unexplained cytopenia in association with solid neoplasia under treatment, underlining the feasibility and priority of a timely treatment of the haematological neoplasm in order to achieve long-term survival.

Prospective multicentre study on azole resistance in Aspergillus isolates from surveillance cultures in haematological patients in Italy.

OBJECTIVES: This study was conducted to assess the prevalence of azole resistance in Aspergillus isolates from patients with haematological malignancies or who were undergoing haematopoietic stem cell transplantation and to identify the molecular mechanism of resistance. METHODS: In this 28-month prospective study involving 18 Italian centres, Aspergillus isolates from surveillance cultures were collected and screened for azole resistance, and mutations in the cyp51A gene were identified. Resistant isolates were genotyped by microsatellite analysis, and the allelic profiles were compared with those of resistant environmental and clinical isolates from the same geographical area that had been previously genotyped. RESULTS: There were 292 Aspergillus isolates collected from 228 patients. The isolates belonged mainly to the section Fumigati (45.9%), Nigri (20.9%), Flavi (16.8%) and Terrei (4.8%). Three isolates showed itraconazole resistance: Aspergillus fumigatus sensu stricto, Aspergillus lentulus (section Fumigati) and Aspergillus awamori (section Nigri). The itraconazole resistance rates were 1% and 1.48% considering all Aspergillus spp. isolates and the Aspergillus section Fumigati, respectively. The prevalence of azole resistance among all the patients was 1.3%. Among patients harbouring A. fumigatus sensu stricto isolates, the resistance rate was 0.79%. The A. fumigatus isolate, with the TR34/L98H mutation, was genotypically distant from the environmental and clinical strains previously genotyped. CONCLUSIONS: In this study, the Aspergillus azole resistance rate was 1% (3/292). In addition to A. fumigatus sensu stricto, A. lentulus and A. awamori azole-resistant isolates were identified. Therefore, it is important have a correct identification at the species level to address a rapid therapy better, quickly understand the shift towards cryptic species and have an updated knowledge of the local epidemiology.

Speculations on the clinical significance of asymptomatic viral infections.

A detailed understanding of asymptomatic chronic viral infections is critical to analyse their pathogenesis, assess the severity and burden of disease and, where required, optimize public health control measures. Recent studies on herpesviruses showed that the host-virus interactions are modulated by co-infections, emphasizing the relevance of co-infections in determining the clinical expression (from asymptomatic to symptomatic infections) and the severity of herpesvirus-associated diseases (either neoplastic or infectious diseases). To demonstrate causality between viruses (virome) and diseases, Koch's postulates should be adapted adding new knowledge on host-microbe relationship and microbial interactions. In the present review we aim to provide an update on asymptomatic chronic infections and criteria for causality and on the virological, immunological and host-virus interactions in asymptomatic chronic infections in human hosts, focusing on herpetic infections.

Complete remission obtained with azacitidine in a patient with concomitant therapy related myeloid neoplasm and pulmonary mucormycosis.

Mucormycosis is the third cause of invasive mycosis after candidiasis and aspergillosis in AML patients, representing a poor prognostic factor associated with a high rate of fatal outcome. We report a case of a patient with AML and a concomitant pulmonary mucormycosis at diagnosis, who obtained a complete remission both of her AML and of the fungal infection. The incidence of the infection at the onset of leukemia is extremely unusual, and, to our knowledge, the sporadic cases reported in the literature are included in heterogeneous series retrospectively examined. In our case, Liposomal Amphotericin B as single agent appeared incapable of controlling the infection, so anti-infective therapy was intensified with posaconazole and simultaneously antileukemic treatment with 5-azacitidine was started, with the understanding that the only antifungal treatment would not have been able to keep the infection under control for a long time if not associated with a reversal of neutropenia related to the disease. We observed a progressive improvement of the general conditions, a healing of pneumonia and a complete remission of the leukemic disease, suggesting that a careful utilization of the new compounds available today, in terms of both antifungal and antileukemic treatment, may offer a curative chance a patient who would have otherwise been considered unfit for a potentially curative therapeutic strategy.

Antimicrobial susceptibility, biochemical and genetic profiles of Staphylococcus haemolyticus strains isolated from the bloodstream of patients hospitalized in critical care units.

Staphylococcus haemolyticus strains (n=20), responsible of blood stream infections, were consecutively isolated from patients hospitalized in two different wards at high risk of infection. Strains displayed high rate of resistance to oxacillin (90%). All strains but two with decreased susceptibility (MIC = 4 microg/mL), were sensitive to vancomycin. Ten strains were resistant to teicoplanin. Among the strains susceptible to glycopeptides, three displayed heteroresistance to vancomycin and seven to teicoplanin, when tested by Etest technique with 2 x McFarland inoculum. Biochemical reactions allowed to assign strains to eight biotypes, with 11 strains clustering under two main biotype A and biotype B. Pulsed-field-gel-electrophoresis (PFGE) identified 11 different PFGE-types. Seven strains grouping under the major PFGE-type 1 and three strains clustering in PFGE-type 2, closely correlated to biotype A and biotype B respectively. Seven teicoplanin-resistant isolates clustered in the PFGE-type 1, two in the PFGE-type 2 and one in PFGE-type 5. Therefore, teicoplanin-resistant strains were biochemically and genetically related and clonally distributed, despite different clones of S. haemolyticus circulated in the units during the study period.

Differences in the proportions of fluoroquinolone-resistant Gram-negative bacteria isolated from bacteraemic children with cancer in two Italian centres.

The proportion of ciprofloxacin-resistant Gram-negative bacteria isolated from the blood of children with cancer (not receiving prophylaxis) was 10% in a paediatric hospital (Genoa) where the use of quinolones was highly restricted, compared with 41% in a department of haematology (Rome) where leukaemic adults, who received fluoroquinolone prophylaxis, were also treated (p < 0.0001). Moreover, simultaneous resistance to ciprofloxacin and ceftazidime, amikacin or imipenem-cilastatin was 11% in Genoa compared with 37% in Rome (p < 0.001). Ciprofloxacin resistance was more frequent in children who shared an environment with adults who were receiving ciprofloxacin prophylaxis.

Neutropenic enterocolitis in acute leukemia: diagnostic and therapeutic dilemma.

The main purpose of this report is to focus on the importance of an accurate etiologic diagnosis of gastrointestinal complications during chemotherapy for acute myeloid leukemia, taking into account that a syndrome characterized by bowel wall thickening associated with diarrhea and abdominal pain may have etiologies different from neutropenic enterocolitis (NE) and in such a case necessitate a different treatment approach. We describe a case of a 46-year-old woman affected by acute myeloid leukemia presenting the onset of a syndrome with clinical features of NE. Supportive therapy for NE was instituted, but during treatment the patient presented a life-threatening gastrointestinal bleeding and was submitted in emergency to hemicolectomy. Following surgery, the patient recovered completely and she is currently alive in complete remission after receiving allogeneic bone marrow transplantation. Histological examination of the surgical specimens showed that the acute abdominal syndrome was related to massive infiltration of the bowel by leukemia cells. A correct baseline evaluation and a prompt diagnosis of the complication may help in making the therapeutic decision, which in our case led necessarily to a surgical procedure, because the bleeding was due to post-chemotherapy necrosis of the leukemic infiltrating tissue. A close collaboration between the hematologist and the surgeon may provide guidelines for behavior in such cases, giving these patients the possibility of survival and the opportunity to carry on the treatment planned for the primary disease.

Methicillin-resistant staphylococcal bacteremia in patients with hematologic malignancies: clinical and microbiological retrospective comparative analysis of S. haemolyticus, S. epidermidis and S. aureus.

Although Staphylococcus haemolyticus (SH) represents an emerging etiology of methicillin-resistant (MR) coagulase-negative staphylococcal nosocomial bacteremia, little is known of clinical significance of this infection. Thus, we performed case-control retrospective comparative analysis of MRSH bacteremias (MRSHB), methicillin-resistant S. epidermidis bacteremias (MRSEB), and methicillin-resistant S. aureus bacteremias (MRSAB) in patients with hematologic malignancies. Most patients in the three groups were neutropenic and had a central venous catheter (CVC) in place at the onset of bacteremia. However, MRSHB patients had a CVC in place prior to bacteremia for a time significantly more prolonged than MRSEB and MRSAB ones (p<0.05). Severe sepsis or septic shock were more common in patients with MRSAB as compared with MRSHB (p=0.02). Nosocomial attributable mortality rate was very low in the 3 study groups (0 to 5.4%) and only two patients developed metastatic infections. Overall, reduced susceptibility to teicoplanin was observed in 19 (47.5%) MRSH and in 4 (10%) MRSE isolates. Resistance to teicoplanin was observed in 6 isolates, all MRSH. Reduced susceptibility or resistance to vancomycin was observed in 2 isolates, both MRSH. All MRSA isolates were susceptible to the glycopeptides. Comparison between cases of bacteremia in patients with MRSH isolates with reduced susceptibility to teicoplanin and those with susceptible MRSH did not reveal significant differences in the clinical-microbiological response to teicoplanin therapy and outcome. Our results seem to suggest that MRSHB in hematologic patients is associated with low morbidity and mortality rates. MRSH frequently shows a reduced susceptibility to teicoplanin; however these in vitro data do not seem associated with an unfavorable clinical response to teicoplanin therapy for MRSHB in patients with hematologic malignancies.

Infectious complications in patients with acute promyelocytic leukaemia treated with the AIDA regimen.

Infections represent a frequent complication of chemotherapy used for acute myeloid leukaemia (AML) and are associated with important toxicity frequently leading to treatment discontinuation. Acute promyelocytic leukaemia (APL) is a unique AML subset requiring tailored therapy including all-trans retinoic acid and anthracycline-based chemotherapy. We analysed in this study the incidence and type of infections complicating the clinical course of 89 consecutive APL patients receiving the AIDA protocol at a single institution. A total of 179 febrile episodes were registered during induction and consolidation, 52% of which were of unknown origin. Infections were clinically and microbiologically documented in 10.6 and 37.4% of cases, respectively. Coagulase-negative staphylococci represented the major cause of septicaemia (28%) and were more frequently isolated during induction, whereas viridans group streptococci, the second pathogen most frequently isolated from blood (27%), represented the principal pathogen detected during consolidation and were significantly associated with mucositis. Gram-negative bacteria accounted for 33.3% of all blood isolates. Fungal infections were only occasionally observed. Bloodstream infections in APL patients were compared with those documented in 271 consecutive patients affected by other subtypes of AML. The incidence of total septicaemia episodes, of staphylococcal bacteraemias and of fungaemias was significantly higher in patients with other AMLs. Empirical antibiotic therapy with ceftriaxone plus amikacin was effective in 73% of APL cases, most of the remaining cases being successfully managed by the addition of teicoplanin. One single death apparently related to infectious complication was recorded. Overall, infections led to antileukaemic treatment withdrawal in six patients, five of whom currently remain in haematologic remission for 13-106 months. These results indicate that a particular pattern of infections is observed in APL patients receiving ATRA plus anthracycline-based chemotherapy and that these appear to be effectively counteracted by standard management.

A multicenter, double-blind, placebo-controlled trial comparing piperacillin-tazobactam with and without amikacin as empiric therapy for febrile neutropenia.

In a prospective, multicenter, double-blind, randomized clinical trial, we compared the efficacy of piperacillin-tazobactam (4.5 g 3 times daily intravenously) plus placebo versus piperacillin-tazobactam plus amikacin (7.5 mg/kg twice daily intravenously) for the treatment of 760 febrile, adult patients with cancer with chemotherapy-induced profound (<500 neutrophils/mm3) and prolonged (>10 days) neutropenia. A total of 733 patients were assessable for efficacy of the drug regimens, and an overall successful outcome was reported in 49% (179 of 364) of the patients who received monotherapy, compared with 53% (196 of 369) of patients who received combination therapy (P=.2). Response rates were similar with both regimens, as were incidences of bacteremia and clinically documented and possible infections. In our epidemiological setting, the initial empiric combination therapy was not associated with improved outcomes when compared with initial monotherapy.

Neutropenic enterocolitis in patients with acute leukemia: prognostic significance of bowel wall thickening detected by ultrasonography.

PURPOSE: Neutropenic enterocolitis (NE) is a severe complication of intensive chemotherapy and is barely identifiable by clinical signs alone. Ultrasonography (US) supports the diagnosis of NE by showing pathologic thickening of the bowel wall. The aim of this study was to evaluate the prognostic value of the degree of mural thickening evaluated by US in patients with clinically suspected NE. PATIENTS AND METHODS: Neutropenic patients with fever, diarrhea, and abdominal pain after intensive chemotherapy for hematologic malignancies were studied with abdominal US. We evaluated the degree of bowel wall thickening detected by US and its correlation with the duration of the clinical syndrome as well as NE-related mortality. RESULTS: Eighty-eight (6%) of 1,450 consecutive patients treated for leukemia had clinical signs of NE. In 44 (50%) of 88 patients, US revealed pathologic wall thickening (mean +/- SD, 10.2 +/- 2.9 mm; range, 6 to 18). The mean duration of symptoms was significantly longer in this group (7.9 days) than among patients without mural thickening (3.8 days, P <.0001), and the NE-related mortality rate was higher (29.5% v 0%, P <.001). Patients with bowel wall thickness of more than 10 mm had a significantly higher mortality rate (60%) than did those with bowel wall thickness < or = 10 mm (4.2%, P <.001). CONCLUSION: Symptomatic patients with sonographically detected bowel wall thickening have a poor prognosis compared with patients without this finding. In addition, mural thickness of more than 10 mm is associated with poorer outcome among patients with NE.

High-dose idarubicine, busulphan and melphalan as conditioning for autologous blood stem cell transplantation in multiple myeloma. A feasibility study.

Extensive studies have tested the clinical impact of double and triple sequential transplants as front-line therapy in MM, following the suggestion that dose escalation can overcome the marked drug resistance characteristic of this disease, but the superiority of such approaches vs one single transplant has still to be demonstrated. The aim of our study was to evaluate the feasibility and efficacy of high-dose idarubicine intensification of a standard busulphan-melphalan conditioning regimen in MM. Twenty-eight patients (median age 55 years) with sensitive disease received PBSCT after high-dose idarubicine combined with busulphan and melphalan and followed by s.c. rhG-CSF until PMN recovery. The most severe toxicity was represented by oral mucositis which resolved with hemopoietic reconstitution. Overall response and CR rate were 52% and 40%, respectively. Currently, 36 patients are alive and 19 are progression-free a median of 20 months (12-36) from transplant. The 3-year projected probability of progression-free survival for patients transplanted after first-line treatment is 60%. The combination of Ida/Bu/Melph appears a promising alternative regimen for PBSCT in myeloma, with low transplant-related toxicity and fast hematological recovery. Long-term follow-up and a prospective randomized study, now ongoing, will probably clarify whether an idarubicine-intensified regimen will result in superior outcomes to conventional conditioning and even be comparable to a double consecutive transplant program.

Bacteremia due to Stenotrophomonas maltophilia in patients with hematologic malignancies.

Predisposing factors, clinical characteristics, and antimicrobial treatment of 37 hematology patients with Stenotrophomonas maltophilia bacteremia who were seen at the department of hematology of the University La Sapienza (Rome) from 1987 to 1996 were evaluated. The results were compared with a control group of patients with Pseudomonas aeruginosa bacteremia. Profound neutropenia was more prolonged in the S. maltophilia group (P=.025), severe cellulitis occurred only in S. maltophilia-infected patients (11 [30%]; P=.0002), and the bacteremia presented as breakthrough infection in 56% of the cases due to S. maltophilia (vs. only 24% of those due to P. aeruginosa; P=.002). Acute mortality rates associated with S. maltophilia and P. aeruginosa bacteremia were 24% and 21%, respectively. In both groups, profound neutropenia and hypotension at the onset of bacteremia, duration of profound neutropenia during bacteremia, severity-of-illness score > or =4, and inappropriate antibacterial treatment were factors significantly associated with death. Most S. maltophilia isolates were resistant to aminoglycosides, beta-lactams, and ciprofloxacin. Cotrimoxazole and ticarcillin-clavulanic acid showed borderline activity. Prompt administration of in vitro-active antibiotics may improve the prognosis of S. maltophilia bacteremia, especially for immunocompromised patients, and novel drug combinations are needed for the treatment of severe infections.

Domiciliary treatment of febrile episodes in cancer patients: a prospective randomized trial comparing oral versus parenteral empirical antibiotic treatment.

Hospitalization and empirical broad-spectrum, intravenous antibiotics are the standard treatment for febrile cancer patients. Recent evidence supports the suggestion that febrile episodes in a low-risk population can be managed successfully in an outpatient setting, but the optimal drug regimen is unknown. In a prospective randomized clinical trial we compared ciprofloxacin 750 mg p.o. twice a day with ceftriaxone 2 g i.v. as a single daily dose for the empiric domiciliary treatment of febrile episodes in low-risk neutropenic and nonneutropenic cancer patients. A total of 173 patients, accounting for 183 febrile episodes, were enrolled in the study. Overall, successful outcomes were recorded for 76 of 93 (82%) febrile episodes in patients who were randomized to the oral regimen and for 68 of 90 (75%) febrile episodes in patients randomized to the i.v. regimen: this difference was not statistically significant. The success rate was similar in all subgroups of patients: neutropenic and nonneutropenic, with documented infection and with fever of unknown origin. There were 3 deaths in the group of patients treated with the parenteral regimen, and two of these were related to treatment failure. Both treatments were well tolerated, and the cost of the oral regimen was lower. This prospective study suggests that domiciliary antibiotic empiric monotherapy is feasible in febrile nonneutropenic or low-risk neutropenic outpatients in whom a bacterial infection is suspected, and that either an oral or a parenteral regimen can be used. A number of factors may influence the choice between an orally and an i.v.-administered antibiotic, but owing to the easier administration and lower cost, the oral regimen seems to be preferable.

Detection of Candida mannoproteinemia in patients with neutropenic enterocolitis.

To assess the role of Candida spp. in the etiology of neutropenic enterocolitis complicating aggressive cytotoxic chemotherapy, a dot immunobinding assay for an immunodominant Candida mannoprotein antigen was employed in 20 patients with hematologic malignancies. Candida antigen was detected in at least one serum sample from 12 (60%) patients. Eleven (92%) patients were cured when an antifungal agent was added to the antibacterial treatment. In eight patients a selective anticandidal therapy with fluconazole was administered on the basis of positive Candida mannoproteinemia, and treatment was successful in all cases but one. Detection of Candida mannoproteinemia seems to be a useful diagnostic tool in patients with neutropenic enterocolitis and represents an additional tool for selecting a less empiric, low toxic antifungal treatment with fluconazole.

Itraconazole oral solution as prophylaxis for fungal infections in neutropenic patients with hematologic malignancies: a randomized, placebo-controlled, double-blind, multicenter trial. GIMEMA Infection Program. Gruppo Italiano Malattie Ematologiche dell' Adulto.

To evaluate the efficacy and safety of itraconazole oral solution for preventing fungal infections, a randomized, placebo-controlled, double-blind, multicenter trial was conducted: 405 neutropenic patients with hematologic malignancies were randomly assigned to receive either itraconazole, 2.5 mg/kg every 12 hours (201 patients), or placebo (204 patients). Proven and suspected deep fungal infection occurred in 24% of itraconazole recipients and in 33% of placebo recipients, a difference of 9 percentage points (95% confidence interval [CI], 0.6% to 22.5%; P = .035). Fungemia due to Candida species was documented in 0.5% of itraconazole recipients and in 4% of placebo recipients, a difference of 3.5 percentage points (95% CI, 0.5% to 6%; P = .01). Deaths due to candidemia occurred in none of the itraconazole recipients compared with 4 placebo recipients, a difference of 2 percentage points (95% CI, 0.05% to 4%; P = .06). Aspergillus infection was documented in four itraconazole recipients (one death) and one placebo recipient (one death). Side effects causing drug interruption occurred in 18% of itraconazole recipients and 13% of placebo recipients. Itraconazole oral solution was well-tolerated and effectively prevented proven and suspected deep fungal infection as well as systemic infection and death due to Candida species.

BAVC regimen and autograft for acute myelogenous leukemia in second complete remission.

Since 1984 we have autografted a total of 60 patients with AML in second complete remission (CR) utilizing the BAVC (BCNU, amsacrine, vepesid, cytosine-arabinoside) conditioning regimen and unpurged marrow. Projected disease-free survival (DFS) probability in 42% at 10 years. Autografting was performed at a median interval of 2 months (range 1-13) from second CR. The median duration of first CR was 14 months (range 1-43) and lasted < or = 12 months in 27/60 patients. Three early deaths (5%) occurred, 30 patients relapsed after a median of 6 months from transplant (range 2-28) and, of the remaining 27 patients, 26 are in continuous CR (CCR) after a median follow up of 60 months (range 6-122), while the last patient committed suicide 7 years after ABMT when she was still in CCR. A first CR duration > 12 months is correlated with a significantly better overall survival probability (61 vs 25%, P = 0.02), while no factors influence DFS. Outcome of patients who relapsed after autografting has been analyzed separately; a longer overall survival after relapse is correlated with a longer duration of the second CR (62% at 34 months for patients who relapsed after > 12 months from the autograft vs 5% for the others, P = 0.001). These results confirm that AML patients autografted in second CR with BAVC regimen and unpurged marrow have the possibility of becoming long-term DFS and can therefore be cured.