Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. METHODS: Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. RESULTS: A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. CONCLUSIONS: This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.

Risk factors, preemptive therapy, and antiperistaltic agents for Clostridium difficile infection in cancer patients.

BACKGROUND: Clostridium difficile infection (CDI) is a serious complication of chemotherapy including high-dose regimens with autologous stem cell transplantation (ASCT). Antiperistaltic agents are contraindicated in CDI and preemptive CDI therapy is not recommended. We assessed the incidence, risk factors, and outcomes of CDI in patients with newly diagnosed multiple myeloma (MM) receiving similar antineoplastic therapy and supportive care including antiperistaltic agents and preemptive CDI antibiotics for significant diarrhea. METHODS: A total of 303 consecutive MM patients (2004-2007) were enrolled in a protocol consisting of induction chemotherapy, tandem melphalan (MEL)-ASCT, and consolidation. Patients with grade 2-4 diarrhea were simultaneously tested for CDI, and initiated on antiperistaltic agents (loperamide) and preemptive anti-CDI therapy. Risk factors, including prior CDI and MM immunoglobulin (Ig) isotype, were evaluated. Multinomial logistic regression was used to compute the relative risk ratio (RRR) and 95% confidence intervals (CIs). RESULTS: There were 43 cases of CDI (14.2%) during 1529 chemotherapy courses (536 ASCT). IgA MM protected against CDI (RRR 0.35; 95% CI 0.13-0.93, P = 0.04) whereas CDI during first induction markedly increased the risk of recurrence during second induction (RRR = 10.94; 95% CI 1.90, 62.92, P = 0.01) and following MEL-ASCT (RRR = 6.63; 95% CI 1.51, 29.12, P = 0.01). No CDI-related surgical intervention or death ensued despite use of antiperistaltic agents. CONCLUSIONS: CDI was not uncommon in cancer patients receiving chemotherapy. IgA myeloma appears to be protective. Concurrent antiperistaltic (loperamide) and preemptive CDI therapies were associated with excellent outcomes. Prior CDI history increased the risk for recurrence during successive chemotherapy courses.

Recovery from neutropenia can be predicted by the immature reticulocyte fraction several days before neutrophil recovery in autologous stem cell transplant recipients.

The duration of neutropenia (absolute neutrophil count (ANC) < or = 100/microl) identifies cancer patients at risk for infection. A test that precedes ANC > or = 100/microl would be of clinical value. The immature reticulocyte fraction (IRF) reflects erythroid engraftment and hence a recovering marrow. We evaluated the IRF as predictor of marrow recovery among 90 myeloma patients undergoing their first and second (75 patients) melphalan-based autologous stem cell transplantation (Mel-ASCT). The time to IRF doubling (IRF-D) preceded ANC > or = 100/microl in 99% of patients after the first Mel-ASCT by (mean+/-s.d.) 4.23+/-1.96 days and in 97% of the patients after the second Mel-ASCT by 4.11+/-1.95 days. We validated these findings in a group of 117 myeloma patients and 99 patients with various disorders undergoing ASCT with different conditioning regimens. We also compared the time to hypophosphatemia and to absolute monocyte count > or = 100/microl to the time to ANC > or = 100/microl. These markers were reached prior to this ANC end point in 55 and 25% of patients but were almost always preceded by IRF-D. We conclude that the IRF-D is a simple, inexpensive and widely available test that can predict marrow recovery several days before ANC> or = 100/microl.

Oral mucositis in myeloma patients undergoing melphalan-based autologous stem cell transplantation: incidence, risk factors and a severity predictive model.

Melphalan-based autologous stem cell transplant (Mel-ASCT) is a standard therapy for multiple myeloma, but is associated with severe oral mucositis (OM). To identify predictors for severe OM, we studied 381 consecutive newly diagnosed myeloma patients who received Mel-ASCT. Melphalan was given at 200 mg/m2 body surface area (BSA), reduced to 140 mg/m2 for serum creatinine >3 mg/dl. Potential covariates included demographics, pre-transplant serum albumin and renal and liver function tests, and mg/kg melphalan dose received. The BSA dosing resulted in a wide range of melphalan doses given (2.4-6.2 mg/kg). OM developed in 75% of patients and was severe in 21%. Predictors of severe OM in multiple logistic regression analyses were high serum creatinine (odds ratio (OR)=1.581; 95% confidence interval (CI): 1.080-2.313; P=0.018) and high mg/kg melphalan (OR=1.595; 95% CI: 1.065-2.389; P=0.023). An OM prediction model was developed based on these variables. We concluded that BSA dosing of melphalan results in wide variations in the mg/kg dose, and that patients with renal dysfunction who are scheduled to receive a high mg/kg melphalan dose have the greatest risk for severe OM following Mel-ASCT. Pharmacogenomic and pharmacokinetic studies are needed to better understand interpatient variability of melphalan exposure and toxicity.

Iron overload is a major risk factor for severe infection after autologous stem cell transplantation: a study of 367 myeloma patients.

We evaluated the risk factors for infection of 367 consecutive myeloma patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT). Examination of bone marrow iron stores (BMIS) prior to ASCT was used to evaluate body iron stores. Other variables included age, sex, active smoking, myeloma remission status, severity of mucositis and duration of severe neutropenia post-ASCT (<100 absolute neutrophils counts (ANC)/microl). Median age was 56 years; 61% of patients were males. 140 episodes of severe infections occurred in 116 patients, including bacteremia (73), pneumonia (40), severe colitis (25) and bacteremia with septic shock (two). The infection incidence per 1,000 days at risk was 45.2. Pre-ASCT risk factors for severe infection by univariate analysis were increased BMIS (OR=2.686; 95% CI 1.707-4.226; P<0.0001), smoking (OR=1.565; 95% CI 1.005-2.437; P=0.0474) and male gender (OR=1.624; 95% CI 1.019-2.589; P=0.0414). Increased BMIS (OR=2.716; 95% CI 1.720-4.287; P<0.0001) and smoking (OR=1.714; 95% CI 1.081-2.718; P=0.022) remained significant by multivariate analysis. Duration of ANC <100 micro/l (OR=1.129; 95% CI 1.039-1.226; P=0.0069 and OR=1.127; 95% CI 1.038-1.224; P=0.0045 by both univariate and multivariate analysis, respectively) was the only post-ASCT risk factor for infection. Increased pre-transplant BMIS and smoking are significant predictors of severe infection after myeloablative chemotherapy followed by ASCT in myeloma patients.

Treatment of neutropenia-related fungal infections with granulocyte colony-stimulating factor-elicited white blood cell transfusions: a pilot study.

Neutropenia-related fungal infections can be life-threatening despite antifungal therapy. We evaluated the role of recombinant granulocyte colony-stimulating factor (rG-CSF)-elicited white blood cell (WBC) transfusions in patients with neutropenia-related fungal infections. Adult patients with hematologic malignancies, absolute neutrophil counts (ANC) <500/microl and fungal infections refractory to amphotericin B, received daily transfusions of rG-CSF-elicited and irradiated WBC transfusions from related donors. Donors received 5 microg/kg/day of rG-CSF subcutaneously. Donors achieved a mean ANC of 29.4 x 10(3) per microliter. The mean yield of neutrophils per transfusion was 41 x 10(9) (range, 10-116). Fifteen patients received a median of eight transfusions (range, 3-16). Fourteen patients had received rG-CSF for a median of 12 days. The median ANC baseline was 20/microl. Eleven patients had favorable responses and eight of them remained free of infection 3 weeks after therapy. Favorable responses occurred among patients with better Zubrod performance status (median, 3 vs 4) and shorter duration of both profound neutropenia (median, 15 vs 25 days) and active infection (median, 8 vs 17 days). The mean 1- and 24-h post-transfusion ANCs were 594/microl (range, 98-1472/microl) and 396/microl (range, 50-1475/microl), respectively. Adverse reactions were observed in nine of 35 donors and in the recipients of six of 130 transfusions. rG-CSF-elicited WBC transfusions may be a safe and promising approach for treating neutropenia-related fungal infections.

Stenotrophomonas (Xanthomonas) maltophilia urinary tract infection. A disease that is usually severe and complicated.

BACKGROUND: Stenotrophomonas (Xanthomonas) maltophilia has emerged as a causative agent of serious nosocomial infections. However, well-documented cases of urinary tract infection with this organism have rarely been reported. METHODS: review of the medical records of patients admitted to a large cancer center with cultures yielding S maltophilia from urinary sources during a 15-month period. RESULTS: All urinary tract infections were serious: 13 were complicated and two were acute uncomplicated pyelonephritis. The urinary tracts of 13 other patients were colonized with S maltophilia. Most of the colonized and infected patients were hospitalized with genitourinary malignancy, underwent urinary catheterization, and were receiving antibiotics inactive against S maltophilia. Neutropenia and urinary structural abnormalities were significantly associated with infection. The clinical course of infection was usually severe: fever (100%), sepsis disorder (47%), neutrophilia (70% of patients without neutropenia), bacteremia (13%) and death (7%). Still, response to treatment was prompt. CONCLUSIONS: Stenotrophomonas maltophilia urinary tract infection is usually associated with a severe clinical course. Risk factors for urinary colonization by this organism include hospitalization, urinary catheterization, and administration of inactive antibiotics. Risk factors for urinary tract infection include neutropenia and urinary structural abnormalities. In the presence of these risk factors, treatment of S maltophilia should be considered in patients with urinary colonization by the organism or in those with nosocomial urinary tract infection caused by an unknown pathogen and that is unresponsive to therapy with the antibiotics that are used to treat the common uropathogens.

A comparison of imipenem to ceftazidime with or without amikacin as empiric therapy in febrile neutropenic patients.

BACKGROUND: Neutropenic patients with cancer are traditionally treated with empiric antibiotic combinations when they become febrile. The availability of broad-spectrum antibiotics such as ceftazidime and imipenem has made it possible to initiate therapy with a single agent (monotherapy). The objectives of this trial were to compare ceftazidime and imipenem as single agents for the therapy of febrile episodes in neutropenic patients and to ascertain whether the addition of an aminoglycoside (amikacin) to either of these agents would provide an advantage. METHODS: A prospective clinical trial was conducted in which eligible neutropenic patients with cancer were randomized to one of four treatment arms: ceftazidime alone; imipenem alone; ceftazidime plus amikacin; and imipenem plus amikacin. Efficacy analysis was done for 750 assessable episodes. A multivariate logistic-regression analysis was also performed to examine the unique contribution of various prognostic factors. RESULTS: The overall response rates were 76% with imipenem plus amikacin, 72% with imipenem, 71% with ceftazidime plus amikacin, and 59% with ceftazidime alone. Single-organism gram-positive infections occurred in 101 of 750 episodes. Without a change in antibiotics, the response rates were 50% with imipenem, 40% with imipenem plus amikacin, 39% with ceftazidime plus amikacin, and 38% with ceftazidime. Most responded to vancomycin or other antibiotics, and the mortality associated with gram-positive infections was only 5%. Regardless of the antibiotic regimen, the majority of uncomplicated gram-negative infections responded to therapy and the majority of complicated gram-negative infections failed to respond. Multivariate logistic-regression analysis showed that recovery of the neutrophil count was the most favorable prognostic factor in a patient's response to infection, whereas the presence of gram-positive infection, acute leukemia, pulmonary or enteric infection, and therapy with ceftazidime were unfavorable factors. CONCLUSIONS: Single-agent therapy with imipenem is as effective as more conventional combination antibiotic therapy for the empirical treatment of febrile episodes in neutropenic patients with cancer.

Fusariosis associated with pathogenic fusarium species colonization of a hospital water system: a new paradigm for the epidemiology of opportunistic mold infections.

We sought the reservoir of Fusarium species in a hospital with cases of known fusarial infections. Cultures of samples from patients and the environment were performed and evaluated for relatedness by use of molecular methods. Fusarium species was recovered from 162 (57%) of 283 water system samples. Of 92 sink drains tested, 72 (88%) yielded Fusarium solani; 12 (16%) of 71 sink faucet aerators and 2 (8%) of 26 shower heads yielded Fusarium oxysporum. Fusarium solani was isolated from the hospital water tank. Aerosolization of Fusarium species was documented after running the showers. Molecular biotyping revealed multiple distinct genotypes among the isolates from the environment and patients. Eight of 20 patients with F. solani infections had isolates with a molecular match with either an environmental isolate (n=2) or another patient isolate (n=6). The time interval between the 2 matched patient-environment isolates pairs was 5 and 11 months, and 2, 4, and 5.5 years for the 3 patient-patient isolate pairs. The water distribution system of a hospital was identified as a reservoir of Fusarium species.

Predictors of adverse outcome in cancer patients with candidemia.

BACKGROUND: Many factors, including severity of illness, neutropenia, intravenous catheter management, and drug therapy may affect the outcome of candidemia in cancer patients. METHODS: The records of all patients at M. D. Anderson Cancer Center who developed one or more positive blood cultures for Candida spp between January 1, 1988, and December 31, 1992, were retrospectively reviewed. Four hundred ninety-one episodes of candidemia were identified, for which 476 had complete medical records, which were reviewed in detail. RESULTS: By 3-month follow-up, 52% of the patients had died. Neutropenia, higher APACHE III score, and visceral dissemination were associated with poor prognosis. Cure rates, adjusted for severity of illness, were similar for fluconazole and amphotericin B treatment. Exchange of central venous catheters was associated with a modest improvement in prognosis. CONCLUSION: Several factors that influence the outcome of candidemia in cancer patients have been identified. These factors may be relevant for the clinical management of cancer patients with candidemia, and for the design of therapeutic trials.

Randomized trial of beta-lactam regimens in febrile neutropenic cancer patients.

A three-arm prospective randomized trial was designed to compare the efficacies of piperacillin plus vancomycin, ceftazidime plus vancomycin, or all three drugs as initial therapy for fever in neutropenic cancer patients. The objectives were to determine whether a broad-spectrum penicillin was as effective as a broad-spectrum cephalosporin and whether two beta-lactam antibiotics were more effective than one. Four hundred and seventy of the 519 febrile episodes entered in the study could be evaluated for response. Ceftazidime plus vancomycin was significantly more effective than piperacillin plus vancomycin, considering all febrile episodes (79 percent versus 61 percent, p = 0.001), documented infections (79 percent versus 57 percent, p = 0.004), gram-negative infections (88 percent versus 47 percent, p = 0.001), and bacteremias (81 percent versus 51 percent, p = 0.01). The addition of piperacillin to ceftazidime (piperacillin plus ceftazidime and vancomycin versus ceftazidime plus vancomycin) did not improve the response rate and was associated with a significantly higher incidence of skin rash. Vancomycin plus ceftazidime provides adequate antibiotic coverage for initial treatment of fever in neutropenic patients. This combination was equally effective, less expensive, and less toxic than the double beta-lactam combination used in this study.

Randomized comparison between antibiotics alone and antibiotics plus granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived in cancer patients with fever and neutropenia.

PURPOSE: A prospective, randomized study was conducted to determine if recombinant human granulocyte-macrophage colony-stimulating factor (rh-GMCSF) (Escherichia coli-derived) could improve response rates to antibiotic therapy and shorten the duration of neutropenia in cancer patients. PATIENTS AND METHODS: A total of 107 febrile neutropenic cancer patients were randomly assigned to empiric therapy with ticarcillin-clavulanate (4 g ticarcillin + 0.1 g clavulanate i.v. every 4 hours) plus netilmicin (2 mg/kg i.v. every 8 hours) with or without rh-GMCSF (3 micrograms/kg per day i.v.). Clinical improvement, duration of neutropenia, and toxicity were monitored. RESULTS: Addition of rh-GMCSF to the antibiotics significantly improved the response rate (96% versus 82%, P = 0.03), but not the survival rate (93% versus 93%), in the evaluable patients. This difference in response rate was not significant when considering all patients in an intent-to-treat analysis. The number of patients who recovered from severe neutropenia ( < 100 cells/microliter) during the period of observation in the study was significantly greater among patients receiving the colony-stimulating factor, although the median duration of neutropenia was not affected. Superinfections and subsequent infections were not significantly different among the two treatment regimens. Side effects were more common among patients treated with the colony-stimulating factor. CONCLUSIONS: Our data do not support the routine administration of rh-GMCSF with antibiotics for patients with fever and neutropenia. Further studies should be conducted to identify those patients most likely to benefit from rh-GMCSF therapy, such as patients with persistent profound neutropenia and refractory infections.

Fluconazole versus amphotericin B in the treatment of hematogenous candidiasis: a matched cohort study.

PURPOSE: To compare the efficacy and toxicity of fluconazole and amphotericin B in the treatment of hematogenous candidiasis in cancer patients. PATIENTS AND METHODS: A matched cohort study of cancer patients with hematogenous candidiasis was conducted. Forty-five patients with hematogenous candidiasis who received fluconazole (200 to 600 mg/day) in an open-label trial at the University of Texas M. D. Anderson Cancer Center, Houston, Texas, between February 1990 and June 1992 were matched to 45 patients treated with amphotericin B (0.3 to 1.2 mg/kg/day) for the same diagnosis. Criteria for matching included the following prognostic variables at the initiation of therapy: pneumonia, neutropenia (< 1,000 cells/mm3), number of positive blood cultures before therapy, infecting Candida species, underlying disease, and the simplified acute physiology score. Response and survival at 48 hours, after 5 days of therapy, and at the end of therapy, as well as toxicity rates were obtained. Other post hoc analyses were performed. Differences in outcomes were assessed by the McNemar, the sign, and the log rank tests. RESULTS: Patients were similar with respect to the matching criteria, age, sex, status of underlying disease, use of antibiotics and growth factors, duration of treatment, presence and removal of central venous catheters, disseminated disease, and concomitant infections. Response rates at 48 hours and 5 days were similar between the two study groups. Overall response rates at the end of therapy were 73% for patients treated with fluconazole and 71% for patients treated with amphotericin B (P = 0.78). There were no differences in survival rates or causes of death. Toxicity was observed in 9% of patients treated with fluconazole and in 67% of patients treated with amphotericin B (P < 0.0001). Toxic effects of amphotericin B included nephrotoxicity, hypokaliemia, and fever and chills. CONCLUSION: Fluconazole is effective and better tolerated than amphotericin B for the treatment of hematogenous candidiasis in cancer patients.

Bronchoalveolar lavage in the diagnosis of pulmonary infiltrates in patients with acute leukemia.

The utility of bronchoalveolar lavage (BAL) in determining the causative agent of pulmonary infiltrates in patients with acute leukemia is not known. We retrospectively evaluated the diagnostic yield of BAL in 22 adults with acute leukemia and compared the results with those at autopsy performed within three weeks of BAL. All patients had neutropenia and thrombocytopenia at the time of BAL, were receiving broad-spectrum antibacterial agents, and 15 were also receiving amphotericin B before BAL. The median interval between the detection of pulmonary infiltrates and BAL was seven days (range, 0 to 23 days); the median interval between BAL and autopsy was nine days (range, 1 to 20 days). The diagnostic yield of BAL was 15 percent (3 of 20 specific diseases); all three were Candida pneumonia. The sensitivity of BAL was 75 percent and its specificity 100 percent, for Candida pneumonia. BAL did not result in a specific diagnosis for the 17 remaining diseases, nine of which were Aspergillus pneumonia. In seven patients in whom autopsy was performed within 72 hours of BAL, lavage results correlated with those of autopsy in only one who had Candida pneumonia. All BAL cultures were falsely positive, except in four cases of Candida pneumonia. The therapeutic regimen was not modified according to the BAL results in any of the 22 patients. There were no major complications associated with the procedure.

Lipid formulations of amphotericin B preserve and stabilize renal function in HSCT recipients.

The current study assessed renal function based on medical records in adult hematopoietic stem cell transplant (HSCT) recipients with proven or probable invasive fungal infection (IFI) transplanted between 1995 and 2000. We confirm that amphotericin B deoxycholate (AmB-d) is nephrotoxic in a large percentage of HSCT recipients. Due to nephrotoxicity, defined as serum creatinine (SCr) >2.5 mg/dl or a 100% increase in SCr from baseline, 88% of patients treated with AmB-d were switched to a lipid formulation of amphotericin B (LFAB). In total, 53% of patients initiated on AmB-d were switched within the first week of therapy. Significantly more patients (70.6%) treated with AmB-d experienced a 100% increase in SCr from baseline compared to patients treated with either AmBisome (44.4%) or Abelcet (41.2%). A Cox Proportional Hazards Model revealed that, compared to patients initiated on AmBisome or Abelcet, the risk of nephrotoxicity (RR=1.5 vs AmBisome; RR=1.7 vs Abelcet), dialysis (RR=2.4 vs AmBisome; RR=1.4 vs Abelcet), and death (RR=2.0 vs AmBisome; RR=1.1 vs Abelcet) were all increased for patients initiated on AmB-d. Study results suggest that renal function improves and mortality declines when an LFAB is given to HSCT patients as initial therapy rather than as second-line therapy, the current practice.

Investigation of an outbreak of gram-negative bacteremia among hematology-oncology outpatients.

OBJECTIVE: To identify risk factors associated with an outbreak of gram-negative bacteremia (GNB). SETTING: A university hospital. PATIENTS: Hematology-oncology outpatients. DESIGN: Retrospective case-control study. RESULTS: Thirty-eight patients developed GNB; 13 patients experienced more than one episode, and eight blood cultures grew more than one gram-negative organism. The most frequently isolated organisms were Stenotrophomonas maltophilia, Klebsiella pneumoniae, Acinetobacter baumannii, and Acinetobacter johnsonii. When the GNB patients (cases) were compared with randomly selected hematology-oncology patients (controls), central venous catheter (CVC) self-care (71% vs 39%; P=.02), and duration of recent hospital stay (median, 15 vs 4 days; P=.01) were identified as risk factors. In a logistic regression model, duration of recent hospital stay was the only risk factor significantly associated with GNB (odds ratio, 1.05; 95% confidence interval, 1.01-1.08; P<.02). CONCLUSIONS: Hematology-oncology patients providing their own CVC care who have recently been hospitalized for more than 2 weeks may be at increased risk of GNB. CVCs should be protected from possible environmental contamination in hematologyoncology patients. Patients providing their own CVC care should undergo continued rigorous education regarding proper CVC care.

Stenotrophomonas maltophilia meningitis. Report of two cases and review of the literature.

The authors report two cases of meningitis caused by Stenotrophomonas maltophilia in cancer patients following placement of an Ommaya reservoir for treatment of meningeal carcinomatosis. In addition, they review eight other cases of S. maltophilia that have been reported to date. Stenotrophomonas maltophilia meningitis is often associated with neurosurgical procedures; however, spontaneous infection may also occur, mainly in neonates. The disease's clinical presentation is similar to that of other forms of meningitis caused by Gram-negative bacilli. The overall mortality rate of this disease is 20% and is limited to neonates with spontaneous meningitis in whom effective antibiotic therapy is delayed. Meningitis caused by S. maltophilia in the modern era should be considered in immunocompromised hosts with significant central nervous system disease who have undergone neurosurgical procedures and who do not readily respond to broad-spectrum antimicrobial coverage.

gamma-Cyclodextrin:testosterone complex suitable for sublingual administration.

A crystalline complex of testosterone with gamma-cyclodextrin was evaluated for solubility and dissolution rate. Whereas these parameters were at least an order of magnitude lower than those of testosterone complexes with amorphous derivatives of cyclodextrins, the properties of the crystalline complex enabled the preparation of a suitable pharmaceutical form for the sublingual administration of hormone to humans. This is in contrast to the situation with similar beta-cyclodextrin complexes, in which such administration was ineffective. Sublingual administration of the gamma-cyclodextrin complex, as shown in previous work using amorphous complexes, avoided rapid first-pass loss of hormone and directed it effectively into the circulation; administration of the complex into the stomach resulted in much lower circulatory hormone levels.

Rhinocerebral mucormycosis with internal carotid occlusion: report of two cases and review of the literature.

Two fatal cases of rhinocerebral mucormycosis with fungal invasion and occlusion of the internal carotid artery are described. Review of the literature reveals 35 similar cases of whom only 6 survived. Emphasis is placed on the need for early diagnosis and prompt therapy which consists of correction of the underlying disease, aggressive surgical debridement, and amphotericin B.

Atypical B12 deficiency with nonresolving paraesthesia.

Vitamin B12 deficiency can present with various hematological, gastrointestinal and neurological manifestations. We report a case of elderly female who presented with neuropathy and vitamin B12 deficiency where the final work-up revealed polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS). This case suggests that, although POEMS syndrome is a rare entity, it can present with vitamin-B12 deficiency and thus specific work up for early diagnosis of POEMS should be considered in patients with B12 deficiency unresponsive to therapy.