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Background: Pneumococcal disease is still considered a global problem. With the introduction of pneumococcal conjugate vaccines (PCVs) serotype epidemiology changed, but antimicrobial resistance persists constituting a serious problem. The current study aimed to determine the serotype distribution and the antimicrobial susceptibility of recent Streptococcus pneumoniae isolates, following implementation of the 13-valent conjugate vaccine (PCV13)., Materials and Methods: From January 2017 to December 2022 we evaluated 116 nonduplicate S. pneumoniae isolates collected from adult patients (21 - 98 years) cared for in the University Hospital of Heraklion, Crete, Greece. Pneumococcal isolates were serotyped by the Quellung reaction, and antimicrobial susceptibility testing was performed using E-test. Multidrug resistance (MDR) was defined as non-susceptibility to at least one agent in ≥3 classes of antibiotics., Results: Among the 116 isolates, 31% were recognized as invasive pneumococcal strains, while 69% were non-invasive. The isolates tested belonged to 25 different serotypes. The most prevalent serotypes were 11A (10.3%), and 35B (10.3%), followed by 3 (9.5%), 15A (7.8%), 25F (6.9%), 19A (5.3%), 35F (5.3%), and others (44.6%). The coverage rates of PCV13 and the pneumococcal polysaccharide vaccine (PPSV23) were 26.7% and 57.8%, respectively. PCV13 and PPSV23 serotypes decreased between 2017 - 2019 and 2020 - 2022, with a parallel increase in the non-vaccine types. Resistance rates to erythromycin, clindamycin, trimethoprim/sulfamethoxazole, penicillin, levofloxacin, and ceftriaxone, were 40.5%, 21.6%, 13.8%, 12.1%, 3.4%, and 0%, respectively. All isolates were susceptible to vancomycin, linezolid, and daptomycin. MDR was observed among 36 (31%) S. pneumoniae isolates., Conclusion: The increasing levels of resistance in S. pneumoniae in Crete, Greece, highlight the need for continuous surveillance of antimicrobial resistance and development of strategies for its reduction, including antimicrobial stewardship programs, increased pneumococcal vaccination, and development of next generation PCVs with a wider serotype coverage., Competing Interests: No conflict of interest., (Copyright © 2024 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.)

Skin and soft tissue infections (SSTIs) are associated with significant morbidity and healthcare costs, especially when caused by methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is a preferred antimicrobial therapy for the management of complicated SSTIs (cSSTIs) caused by MRSA, with linezolid and daptomycin regarded as alternative therapeutic options. Due to the increased rates of antimicrobial resistance in MRSA, several new antibiotics with activity against MRSA have been recently introduced in clinical practice, including ceftobiprole, dalbavancin, and tedizolid. We evaluated the in vitro activities of the aforementioned antibiotics against 124 clinical isolates of MRSA obtained from consecutive patients with SSTIs during the study period (2020-2022). Minimum inhibitory concentrations (MICs) for vancomycin, daptomycin, ceftobiprole, dalbavancin, linezolid and tedizolid were evaluated by the MIC Test Strip using Liofilchem strips. We found that when compared to the in vitro activity of vancomycin (MIC 90 = 2 μg/mL), dalbavancin possessed the lowest MIC 90 (MIC 90 = 0.094 μg/mL), followed by tedizolid (MIC 90 = 0.38 μg/mL), linezolid, ceftobiprole, and daptomycin (MIC 90 = 1 μg/mL). Dalbavancin demonstrated significantly lower MIC 50 and MIC 90 values compared to vancomycin (0.064 vs. 1 and 0.094 vs. 2, respectively). Tedizolid exhibited an almost threefold greater level of in vitro activity than linezolid, and also had superior in vitro activity compared to ceftobiprole, daptomycin and vancomycin. Multidrug-resistant (MDR) phenotypes were detected among 71.8% of the isolates. In conclusion, ceftobiprole, dalbavancin and tedizolid exhibited potent activity against MRSA and are promising antimicrobials in the management of SSTIs caused by MRSA.

Exophiala dermatitidis is a dematiaceous, ubiquitous, dimorphic fungus, which can cause a wide range of invasive diseases in both immunocompromised and immunocompetent hosts. Bloodstream infections due to E. dermatitidis are rarely encountered in clinical practice, especially in pediatric patients. We describe a case of central line-associated bloodstream infection due to E. dermatitidis in a 4.5-year-old boy with Ewing's sarcoma. The fungus was isolated from blood specimens taken from the Hickman line. The isolate was identified by its phenotypic characteristics, by MALDI-TOF and by using molecular methods. The infection was successfully treated with voriconazole and catheter removal. The literature was also reviewed on pediatric infections caused by E. dermatitidis, focusing on clinical manifestations and challenges associated with diagnosis and management., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Vaccination against COVID-19 is among the most effective measures to stop the spread of the disease. However, acceptance of vaccination against COVID-19 among HCWs has not been universal and emergence of new variants with increased transmissibility, reduced neutralization by BNT162b2 vaccine-elicited sera and ability to cause breakthrough infections in vaccinated individuals is concerning. The aim of this study was to compare viral load, clinical presentation at diagnosis and type of exposure among vaccinated (with BNT162b2) and non-vaccinated healthcare workers (HCWs)., Methods: Prospective cohort of HWCs diagnosed with COVID-19 by nasopharyngeal PCR from 4 January to 14 April. Viral loads were expressed by the cycle threshold (Ct) in PCR., Results: During the study period 55 HCWs were found positive for SARS-CoV-2, most of whom (44/55) were identified from March 28 to April 14 during an in-hospital COVID-19 outbreak. Of the 55 HCWs, 21 were fully vaccinated and another three had received one dose. Most cases (54/55) were due to variant B.1.1.7. Vaccinated and unvaccinated HCWs did not differ significantly in regards to age, gender, site of acquisition, presence of symptoms at diagnosis and viral load., Conclusions: This study found a similar viral load in vaccinated and non-vaccinated HCWs infected by SARS-CoV-2 variant B.1.1.7, suggesting potentially reduced efficacy of BNT162b2 in preventing transmission of B.1.1.7.

Background: Although Candida is a commensal of the urogenital tract, intrauterine fungal infections are extremely uncommon in clinical practice., Aims: In the present work we evaluated whether amniotic fluid (AF) possesses direct antifungal activity against clinical isolates of Candidaalbicans and other Candida species., Methods: A total of 23 AF samples from pregnant women with gestational age of 38-41 weeks were obtained under aseptic conditions by the aspiration of the amniotic sac during cesarean section. Different Candida species were inoculated in amniotic fluid and Sabouraud broth, used as control, and were incubated at 37°C for 48h. Quantitative cultures of test samples and controls were performed at 0, 4, 8, 12, 24, and 48h., Results: AF collected from 23 pregnant women had consistent and significant inhibitory activity against all Candida isolates tested. Nonetheless, a complete inhibition of growth by all 23 AF samples tested was observed only against Candida glabrata., Conclusions: It is likely that the antifungal activity of the AF against C. albicans, C. glabrata and Candida parapsilosis observed in vitro also exists in vivo, contributing to protect against intrauterine fungal infections., (Copyright © 2021 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.)

The human organism coexists with its microbiota in a symbiotic relationship. These polymicrobial communities are involved in many crucial functions, such as immunity, protection against pathogens, and metabolism of dietary compounds, thus maintaining homeostasis. The oral cavity and the colon, although distant anatomic regions, are both highly colonized by distinct microbiotas. However, studies indicate that oral bacteria are able to disseminate into the colon. This is mostly evident in conditions such as periodontitis, where specific bacteria, namely Fusobacterium nucrelatum and Porphyromonas gingivalis project a pathogenic profile. In the colon these bacteria can alter the composition of the residual microbiota, in the context of complex biofilms, resulting in intestinal dysbiosis. This orally-driven disruption promotes aberrant immune and inflammatory responses, eventually leading to colorectal cancer (CRC) tumorigenesis. Understanding the exact mechanisms of these interactions will yield future opportunities regarding prevention and treatment of CRC.

Vulvovaginal candidiasis (VVC) is a common infection of the genital tract affecting millions of women worldwide. Data on epidemiological trends of VVC in Greece are scarce. This study was undertaken to evaluate the prevalence of VVC among symptomatic women in Crete, Greece, identify the Candida species involved and determine their susceptibility to antifungals. Over a 6-year period (2012-2017), 10 256 symptomatic women with vaginitis were evaluated. Isolation of yeasts was performed on Sabouraud dextrose agar with chloramphenicol, and the isolates were identified using the API 20 C AUX and/or the Vitek 2 YST card. Susceptibility of the isolates to amphotericin, fluconazole, voriconazole and flucytosine was determined by the Vitek 2 automated system. The results were interpreted according to Clinical and Laboratory Standards criteria. Vaginal swab cultures of 1217 (11.9%) women yielded Candida species. Recurrent VVC was documented in 62 (5.1%) of them. Candida albicans was the most frequently isolated species (75.6%), followed by Candida glabrata (13.6%). Overall, resistance rates to amphotericin B, fluconazole, voriconazole and flucytosine were 0.2%, 6.6%, 1.4% and 2.1%, respectively. Fluconazole resistance of C. albicans significantly increased in the second period of the study (2015-2017) (P = 0.031). This study demonstrated that VVC is a common infection among women in our region, with C. albicans being the predominant species involved. Although resistance to antifungals was infrequent, resistance to fluconazole among C. albicans isolates was found to significantly increase with time. Continued surveillance of changes in species distribution and susceptibility to antifungals are necessary to guide treatment., (© 2019 Blackwell Verlag GmbH.)

Background: Pneumococcal disease is a major cause of morbidity and mortality worldwide, especially in patients with comorbidities and advanced age. This study evaluated trends in epidemiology of adult pneumococcal disease in Crete, Greece, by identifying serotype distribution and antimicrobial resistance of consecutive Streptococcus pneumoniae strains isolated from adults during an 8-year time period (2009-2016) and the indirect effect of the infant pneumococcal higher-valent conjugate vaccines 10-valent pneumococcal conjugate vaccine (PCV10) and 13-valent pneumococcal conjugate vaccine (PCV13)., Materials and Methods: Antimicrobial susceptibility was performed by E-test and serotyping by Quellung reaction. Multidrug resistance (MDR) was defined as non-susceptibility to penicillin (PNSP) combined with resistance to ≥2 non-β-lactam antimicrobials., Results: A total of 135 S. pneumoniae strains were isolated from adults during the study period. Twenty-one serotypes were identified with 17F, 15A, 3, 19A, and 11A, being the most common. The coverage rates of PCV10, and PCV13 were 17.8% and 37.8%, respectively. PCV13 serotypes decreased significantly from 68.4% in 2009 to 8.3% in 2016 ( P = 0.002). The most important emerging non-PCV13 serotypes were 17F, 15A, and 11A, with 15A being strongly associated with antimicrobial resistance and MDR. Among all study isolates, penicillin-resistant and MDR strains represented 7.4% and 14.1%, respectively. Predominant PNSP serotypes were 19A (21.7%), 11A (17.4%), and 15A (17.4%). Erythromycin, clindamycin, tetracycline, trimethoprim-sulfamethoxazole, and levofloxacin resistant rates were 30.4%, 15.6%, 16.3%, 16.3%, and 1.5%, respectively., Conclusion: Although pneumococcal disease continues to be a health burden in adults in Crete, our study reveals a herd protection effect of the infant pneumococcal higher-valent conjugate vaccination. Surveillance of changes in serotype distribution and antimicrobial resistance among pneumococcal isolates are necessary to guide optimal prevention and treatment strategies., Competing Interests: No conflicts of interest., (Copyright © 2018 by The Korean Society of Infectious Diseases and Korean Society for Chemotherapy.)

Objective: Recent studies have shown that in carefully selected patients, conservative treatment alone can be an option in the management of spinal epidural abscess (SEA). The aim of this study was to identify prognostic factors of outcome in patients with spontaneous SEA treated conservatively., Patients and Methods: A retrospective cohort study of all patients with spontaneous SEA treated with antibiotics alone from January 2012 to December 2015 was conducted in a 1200-bed tertiary referral center. Demographic, clinical, microbiological, and radiological characteristics were analyzed. Failure of medical treatment was defined as the need for delayed surgical intervention, no neurological improvement or deterioration, death due to the infection, or relapse after hospital discharge., Results: We identified 21 patients diagnosed with spontaneous SEA treated conservatively. Median age was 72 years and 10 patients were male. Eleven patients presented with radicular weakness and/or radicular sensory deficit, or incomplete cord injury. Inflammatory markers were markedly elevated in all patients. Thirteen patients were successfully treated with conservative treatment, while among 8 patients with treatment failure, 1 died due to the infection. Presence of serious neurological deficits and infection due to methicillin-resistant S. aureus (MRSA) were associated with failure of conservative treatment. Notably, neither the extension nor the location of the abscess on magnetic resonance imaging (MRI) was associated with failed medical management., Conclusions: A significant proportion of patients with spontaneous SEA can respond to antibiotic treatment alone. However, in patients with infection due to MRSA or with severe neurological impairment, conservative management has an increased risk of failure., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Colonization of the gastrointestinal (GI) tract by Candida species is a principal pathogenetic event for development of invasive candidiasis. Importantly, the effect of echinocandins, the preferred antifungal agents for treatment of invasive candidiasis, on GI tract colonization by Candida spp. is currently unknown. Herein, we used an established model of persistent murine GI tract colonization by Candida albicans to test the ability of different echinocandins to eradicate the yeast from murine gut. Adult male Crl:CD1 (ICR) BR mice were fed with chow containing C. albicans and subsequently treated with different echinocandins or normal saline via daily intraperitoneal injections for 10 days. Quantitative stool cultures were performed immediately before (week one), and weekly for three months after discontinuation of treatment. Notably, treatment with all three echinocandins used (caspofungin, anidulafungin, and micafungin) resulted in eradication of Candida albicans from the stools, as evidenced by the significant reduction of yeast cells from a mean of 4.2 log10 CFU/g of stool before treatment (week one of colonization) to undetectable (<2 log10 CFU/g of stool) levels (week 12, P < 0.0001). In contrast, there was no significant reduction of Candida yeast cells in the stools of control mice. Collectively, the ability of echinocandins to eradicate C. albicans from the stools could have important implications in prophylaxis of high-risk patients for development of invasive candidiasis originating from the GI tract., (© The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Candida parapsilosis isolates occasionally display resistance in vitro to echinocandins and cause breakthrough infections to echinocandins. The degree of the in vivo cross-resistance among echinocandins and the fitness loss associated with caspofungin (CAS) resistance of C. parapsilosis are not well studied. We compared the activities of CAS and anidulafungin (ANF), each given at 2 dosing schedules (high dose or low dose) in a nonneutropenic mouse model of invasive candidiasis (IC) caused by ANF-susceptible isolates of C. parapsilosis with different degrees of susceptibility to CAS (CAS resistant [CAS-R], MIC, >16 mg/liter; CAS intermediate [CAS-I], MIC, 4 mg/liter; and CAS susceptible [CAS-S], MIC, 2 mg/liter). We analyzed tissue fungal burden, histopathology, and weight loss patterns. Increasing CAS resistance was associated with reduced virulence of C. parapsilosis isolates (mortality rates for CAS-S versus CAS-I versus CAS-R, 100% versus 11.1% versus 0%, respectively; P < 0.001). High doses of either echinocandin were active against infection with the CAS-I isolate when assessed by fungal burden reduction and weight gain. In contrast to CAS-S and CAS-I isolates, there was no reduction in fungal burden in mice infected with the CAS-R isolate following treatment with either echinocandin, each given at a high or low dose. Nevertheless, mice infected with the CAS-R isolate had reduced disease severity following echinocandin treatment, suggesting that echinocandins have activity in vivo, even against echinocandin-resistant strains. A complex interplay of residual echinocandin activity, decreased virulence, and/or fitness of isolates with altered cell wall and possible immunomodulatory effects can be encountered in vivo during infection with CAS-resistant C. parapsilosis isolates.

Airborne opportunistic fungi, including Aspergillus and other less common saprophytic molds, have recently emerged as important causes of mortality in immunocompromised individuals. Understanding the molecular mechanisms of host-fungal interplay in robust experimental pathosystems is becoming a research priority for development of novel therapeutics to combat these devastating infections. Over the past decade, invertebrate hosts with evolutionarily conserved innate immune signaling pathways and powerful genetics, such as Drosophila melanogaster, have been employed as a means to overcome logistic restrains associated with the use mammalian models of fungal infections. Recent studies in Drosophila models of filamentous fungi demonstrated that several genes implicated in fungal virulence in mammals also play a similarly important pathogenic role in fruit flies, and important host-related aspects in fungal pathogenesis are evolutionarily conserved. In view of recent advances in Drosophila genetics, fruit flies will become an invaluable surrogate model to study immunopathogenesis of fungal diseases.

Mucormycosis (formerly zygomycosis) is a life-threatening opportunistic mycosis that infects a broad range of hosts with qualitative or quantitative defects in innate immunity, including patients with severe neutropenia, recipients of corticosteroids or other immunosuppressive medications, poorly controlled diabetes mellitus, and those with iron overload states. Mucormycosis has recently emerged as breakthrough sinopulmonary infection in hematologic patients and recipients of transplantation being on antifungal prophylaxis with Aspergillus-active antifungals that lack activity against Mucorales. Unlike pulmonary aspergillosis, the prognosis and outcome of pulmonary mucormycosis have not improved significantly over the last decade, mainly because of difficulties in early diagnosis and the limited activity of current antifungal agents against Mucorales. Recent evidence suggests a critical role for iron metabolism and fungal-endothelial cell interactions in pathogenesis of mucormycosis, and holds promise for development of novel therapeutic strategies. Currently, prompt initiation of antifungal therapy with a lipid amphotericin B-based regimen, reversal of underlying host factors, and aggressive surgical approach offers the best chances for survival of patients infected with this devastating mycosis., (© Thieme Medical Publishers.)

Background: Ovarian germ cell tumors (OGCT) are highly curable when treated with cytoreductive surgery and platinum-based chemotherapy. We evaluated the safety and activity of a 3-day modified bleomycin, etoposide, and cisplatinum (mBEP) regimen in patients with OGCT., Patients and Methods: Patients with FIGO stages I-IV OGCT were treated with three (stages I-III complete resection) or four cycles (incomplete resection or stage IV) of bleomycin 15 mg iv, etoposide 120 mg/m(2) iv, and cisplatin 40 mg/m(2) iv for 3 days every 3 weeks., Results: Forty-eight patients (14 with dysgerminoma and 34 with non-dysgerminomatous tumors) were included in our study. Most patients had stage I disease (65%) and complete resection of their tumor (67%). Twenty percent of patients developed grade 3 or 4 neutropenia with 4 episodes of neutropenic fever. During follow-up (median: 5 years), two patients developed progressive disease including one patient who died. All patients with stage I or II disease and all patients with dysgerminoma remain free of disease. However, 20% of patients with non-dysgerminomatous tumors stage III or IV experienced progressive disease., Conclusion: The modified 3-day BEP regimen was safe and effective in patients with OGCT. Further improvements are needed for patients with advanced, suboptimally debulked non-dysgerminomatous tumors.

We evaluated the predictive value of several parameters, including the International Staging System (ISS) for myeloma, in patients with advanced disease treated with thalidomide-based regimens (TBR). We analyzed 119 patients, from 3 phase II studies. Patients with pretreatment beta2 microglobulin<3.5 mg/l and albumin 3.5 g/dl were scored ISS stage 1, patients with beta2 microglobulin<3.5 mg/l and albumin<3.5 g/dl or beta2 microglobulin 3.5-5.5 mg/l regardless of albumin levels were scored ISS stage 2, patients with beta2 microglobulin>5.5 mg/l ISS stage 3. ISS stage was 1, 2 and 3 in 45, 32 and 23% of patients respectively. Seventy-four patients (62%) achieved at least partial response. Median progression-free and overall survival were 8 months and 19.5 months respectively. ISS stage, serum LDH and performance status were independent predictive factors for survival. Based on these 3 variables a scoring system was developed with survival times of 38.1, 28.8 and 5.8 months for scores 0, 1 and 2 respectively. The ISS staging system was highly predictive for overall survival of patients with advanced myeloma treated with TBR. With the addition of performance status and serum LDH, a simple scoring system was developed which may help select patients likely to benefit from TBR.

Unlabelled: Thalidomide-based regimens (TBR) are now widely used for the treatment of refractory multiple myeloma and have shown significant activity in newly diagnosed patients. In some patients with secretory disease, we observed discrepancies between the reduction of the monoclonal protein levels and the plasma cell infiltration in the bone marrow and/or extramedullary sites of relapse after treatment with TBR. The purpose of this study was to assess the incidence and analysis of this phenomenon in all myeloma patients treated with TBR in our Institution., Patients and Methods: We studied all patients who received TBRs and had a follow up time of at least 6 months. Partial response (PR) was defined as at least 50% reduction of serum myeloma protein and soft tissue plasmacytomas and/or > 90% reduction of Bence Jones protein excretion and minor response as a > 25% reduction of the serum myeloma protein or > 50% reduction of the Bence Jones myeloma protein., Results: Between July 1999 and July 2002 we treated 94 patients with advanced myeloma and 9 patients with newly diagnosed disease with TBR. Sixty-seven patients (66%) achieved either partial or minor response. In 4 patients (3 with advanced and 1 with newly diagnosed myeloma) the bone marrow was heavily infiltrated by plasma cells, despite a decrease of the paraprotein levels ranging from 38% to 68%. This discordance between monoclonal protein levels and bone marrow plasmacytosis was noted in 6% of patients rated as responders and in 11% of responding patients who actually had a repeat bone marrow assessment. Furthermore 6 responding patients, after achieving a PR which lasted between 5 and 9 months, relapsed with bone marrow (all cases), and extramedullary (2 cases) plasmacytosis, without increase of serum and/or urine monoclonal protein. This hyposecretory conversion was noted in 12.5% of relapsing patients., Conclusion: Our data indicate that after treatment with TBR some patients with myeloma show discordant responses of the monoclonal protein levels and the bone marrow or extramedullary plasmacytosis. If our data are confirmed, they may have practical implications for assessment of response and follow up of patients treated with TBR.

Introduction: Thalidomide is an oral agent with significant activity in one-third of patients with refractory myeloma. However, long-term continuous administration of thalidomide can be associated with significant side effects such as deep-vein thrombosis and peripheral neuropathy. Furthermore, it is not clear whether continuous administration of thalidomide is necessary for its antimyeloma effect. We performed a phase II study with a combination that was based on the intermittent administration of thalidomide., Materials and Methods: A total of 53 patients with previously treated myeloma received cyclophosphamide 150 mg/m(2) p.o. every 12 h before meals on days 1-5, thalidomide 400 mg p.o. in the evening on days 1-5 and 14-18 and dexamethasone 20 mg/m(2) in the morning after breakfast on days 1-5 and 14-18 (CTD). The CTD combination was repeated every 28 days for three courses. Subsequently, responding patients were scheduled to receive maintenance treatment with monthly courses of CTD administered only for the first five days of each month., Results: On an intention-to-treat basis, 32 patients (60%) achieved a partial response with a median time to response of 1.5 months. Among the 43 thalidomide-naïve patients, 67% responded. Toxicities were mild or moderate and the cumulative incidence of deep-vein thrombosis and peripheral neuropathy was 4 and 2%, respectively. The median time to progression for responding patients was 12 months and the median overall survival for all patients was 17.5 months., Conclusion: The oral, outpatient pulsed CTD regimen is associated with significant activity in patients with previously treated multiple myeloma. The incidence of deep-vein thrombosis and peripheral neuropathy appears to be lower than expected when thalidomide is being administered on a continuous basis.

Objective: We conducted a phase II trial to evaluate the activity of oral letrozole in women with relapsed or recurrent epithelial ovarian cancer., Methods: Twenty-seven patients were treated with letrozole at a dose of 2.5 mg once a day. Patients with measurable or evaluable disease (n = 21) and those with only increasing CA 125 serum levels (n = 6) were eligible. Paraffin-fixed histological sections from tumor specimens resected at the initial laparotomy were assessed for the presence of estrogen, and progesterone receptors., Results: Among the 21 patients with measurable or evaluable disease who were evaluated for response by WHO criteria, we observed one complete and two partial responses for an objective response rate of 15%. Using criteria for CA 125 response we obtained a marker response in 4 of 27 patients (15%), and the marker remained stable in 5 additional patients (18%). Letrozole treatment was generally well tolerated. No correlation was observed between tumor marker response or stabilization and either estrogen or progesterone receptor expression., Conclusion: The results of our study suggest that the aromatase inhibitor letrozole is an agent with some activity and limited toxicity for relapsed ovarian cancer. As we could not find any association between response and hormonal receptor expression, the underlying mechanisms of letrozole action have to be elucidated., (Copyright 2004 S. Karger AG, Basel)

Fludarabine is an active agent for the treatment of Waldenstrom's macroglobulinemia (WM) and its combination with cyclophosphamide has been effective in many patients with low-grade lymphoma and chronic lymphocytic leukemia. Based on these data, we administered the combination of fludarabine (25 mg/m2 i.v. day 1-3) and cyclophosphamide (250 mg/m2 i.v. day 1-3,) to 11 patients with WM. Most patients had features indicating poor prognosis including median age of 73 years (range 60-84 years), hemoglobin <100 g/l in 73%, B2-microglobulin >3 mg/l in 64%, symptomatic hyperviscosity in 55% of patients. Only 2 patients were previously untreated, 7 were primary refractory and 2 were relapsing on treatment. The fludarabine-cyclophosphamide combination (FC) was administered every 4 weeks for a total of four courses. Partial response, defined by at least 50% reduction of serum monoclonal protein and of tumor infiltrate at all involved sites was documented in 6 patients (55%) (The median time to response was 4 months). Responding patients demonstrated resolution of disease-related symptoms and correction of anemia. Median time to progression for all patients was 24 months. With a mean follow-up of 28 months, two of six responding patients have progressed so far. The probability of 2-year survival is 70%. This regimen was relatively well tolerated. Complications included neutropenia grade 3 or 4 in 3 patients and thrombocytopenia grade 3 or 4 in 2 patients. There were five infectious episodes including two episodes of neutropenic fever. We conclude that the FC combination appears to be active in patients with WM most of whom were resistant to treatment and had poor prognostic factors. The addition of rituximab to FC requires further investigation.

Rituximab, a chimeric monoclonal antibody, produces response rates of up to 73% in patients with previously untreated indolent non-Hodgkin's lymphoma (NHL), and has high activity when combined with chemotherapy. The purpose of this phase II study was to determine the efficacy and safety of rituximab plus cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) chemotherapy in patients with indolent NHL. In all, 42 patients (median age 67 years) with previously untreated follicular, marginal zone or small lymphocytic/lymphoplasmacytic NHL received six infusions of rituximab (375 mg/m(2)) in combination with six cycles of CNOP. The overall response rate was 90% comprising 30 complete (71%) and eight partial (19%) responses. Although patients with marginal zone lymphoma or International Prognostic Index (IPI) score 3 had lower complete response rates, no significant difference in overall response rate was observed between the histological groups (P=0.24) or between patients stratified according to IPI score (P>0.05). Median overall survival, time-to-progression and response duration had not been reached after a median 19.5-month follow-up. In all, 31 patients (74%) are currently free from progression and 38 (90%) remain alive. Treatment was well tolerated. One patient (2%) experienced grade 3/4 infusion-related toxicity; 13 (31%) grade 3/4 leukopenia and 18 (43%) grade 3/4 neutropenia. Infection was observed in nine patients: eight (19%) grade 1/2 and one (2.4%) grade 3. This study demonstrates that combining rituximab with CNOP achieves high remission rates without significant additional toxicity in patients with previously untreated indolent NHL. Further follow-up will determine response duration and survival.