Fecal microbiota transplantation for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients.

Recurrent Clostridium difficile infection (CDI) is a consequence of intestinal dysbiosis and is particularly common following hematopoietic stem cell transplantation (HSCT). Fecal microbiota transplantation (FMT) is an effective method of treating CDI by correcting intestinal dysbiosis by passive transfer of healthy donor microflora. FMT has not been widely used in immunocompromised patients, including HSCT recipients, owing to concern for donor-derived infection. Here, we describe initial results of an FMT program for CDI at a US HSCT center. Seven HSCT recipients underwent FMT between February 2015 and February 2016. Mean time post HSCT was 635 days (25-75 interquartile range [IQR] 38-791). Five of the patients (71.4%) were on immunosuppressive therapy at FMT; 4 had required long-term suppressive oral vancomycin therapy because of immediate recurrence after antibiotic cessation. Stool donors underwent comprehensive health and behavioral screening and laboratory testing of serum and stool for 32 potential pathogens. FMT was administered via the naso-jejunal route in 6 of the 7 patients. Mean follow-up was 265 days (IQR 51-288). Minor post-FMT adverse effects included self-limited bloating and urgency. One patient was suspected of having post-FMT small intestinal bacterial overgrowth. No serious adverse events were noted and all-cause mortality was 0%. Six of 7 (85.7%) patients had no recurrence; 1 patient recurred at day 156 post FMT after taking an oral antibiotic and required repeat FMT, after which no recurrence has occurred. Diarrhea was improved in all patients and 1 patient with gastrointestinal graft-versus-host disease was able to taper off systemic immunosuppression after FMT. With careful donor selection and laboratory screening, FMT appears to be a safe and effective therapy for CDI in HSCT patients and may confer additional benefits. Larger studies are necessary to confirm safety and efficacy and explore other possible effects.

The clinical impact of vancomycin-resistant Enterococcus colonization and bloodstream infection in patients undergoing autologous transplantation.

BACKGROUND: Although several studies have documented adverse outcomes for vancomycin-resistant Enterococcus (VRE) colonization and infection in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, data are inadequate for patients undergoing autologous (auto-)HSCT. METHODS: We conducted a retrospective cohort study of 300 consecutive patients receiving an auto-HSCT between 2006 and 2014. Patients had stool cultures for VRE on admission and weekly during hospitalization. RESULTS: Thirty-six percent of patients had VRE gastrointestinal (GI) colonization and 3% developed a VRE bloodstream infection (BSI), all of whom were colonized. VRE strain typing of BSI isolates showed that some patients shared identical patterns. Rates of colonization and BSI in colonized patients were similar to simultaneous patients undergoing allo-HSCT, except that the latter had a higher rate of colonization at admission. A diagnosis of lymphoma was associated with an increased risk of colonization. VRE BSI was associated with longer lengths of stay and possibly higher costs, but no decrease in overall survival, and colonized patients had no VRE infections during the year following discharge. Repeat stool cultures in patients subsequently undergoing allo-HSCT suggested that most, if not all, VRE-positive auto-HSCT patients lose their detectable GI colonization within a few months of discharge. CONCLUSION: VRE colonization is frequent but carries a low risk for infection in patients undergoing auto-HSCT. However, these patients can serve as reservoirs for transmission to higher risk patients. Moreover, patients may remain colonized if proceeding to an allo-HSCT shortly after auto-HSCT, potentially increasing the risk of the allogeneic procedure.

Disseminated histoplasmosis in allogeneic bone marrow transplant: a diagnosis not to be missed.

Immunosuppressed patients are at highest risk for disseminated histoplasmosis, but only a few cases have been reported in hematopoietic stem cell transplant recipients. We report a case of disseminated histoplasmosis in an allogeneic bone marrow transplant recipient residing in a non-endemic area. Diagnosis was first suspected based on a peripheral blood smear.

A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study.

This is a Southwest Oncology Group (SWOG) prospective randomized trial of cisplatin, vinblastine, and bleomycin (PVB) versus vinblastine, cisplatin, and etoposide (VP-16) (VPV) in the treatment of advanced germ cell tumors of the testis. The study objective was to determine what effect the replacement of bleomycin with VP-16 has on complete response (CR), survival, and drug toxicity. One hundred sixty-nine patients were registered and randomized. Of these patients, 160 were assessable for response. All had histologically confirmed disseminated germ cell neoplasms of testicular origin. Forty-six had minimal metastatic disease, and 114 had maximal disease. Seventy-seven were randomized to PVB and 83 to VPV chemotherapy. There was no significant difference in pretreatment characteristics between the two arms with regard to tumor burden, histologic type, and overall performance status. Patients received four courses of induction chemotherapy, either PVB (cisplatin 120 mg/m2 day 3, vinblastine 12 mg/m2 day 1, bleomycin 15 U/m2 twice per week) or VPV (vinblastine 8 mg/m2 day 1, cisplatin 120 mg/m2 day 3, VP-16 50 mg/m2 days 2 to 5). Chemotherapy was given every 3 weeks. Cytoreductive surgery was done postinduction if a chemotherapy CR was not achieved. There was no difference in the percentage of patients achieving a disease-free status between PVB (77%) and VPV (73%). The mean leukocyte nadir was similar for both treatments, but the mean platelet nadir was significantly lower (P = .003) in the VPV arm. All bleomycin-related toxicities (pulmonary, mucositis, skin) were avoided in the VPV arm. We conclude that bleomycin can be replaced in first-line therapy for advanced germ cell tumors without sacrificing efficacy and with the advantage of avoiding unnecessary drug toxicity.

Streptococcus mitis sepsis in bone marrow transplant patients receiving oral antimicrobial prophylaxis.

PURPOSE: Streptococcal infection has increasingly become a problem in neutropenic patients. We report on an outbreak of Streptococcus mitis sepsis in six bone marrow transplant patients receiving oral antimicrobial prophylaxis. PATIENTS AND METHODS: We performed an epidemiologic study of all patients in our bone marrow transplant program from 1986 to 1988. The hospital and microbiology records for all patients were reviewed. All bone marrow patients were treated according to specified protocols, including an oral prophylactic antimicrobial regimen that was changed in late 1987 from vancomycin/polymyxin/tobramycin to norfloxacin. Identification, susceptibility testing, and whole cell protein analysis of streptococcal isolates were performed at the Reference and Antimicrobial Investigations Laboratories at the Centers for Disease Control. RESULTS: We detected six cases of S. mitis sepsis among 21 patients undergoing bone marrow transplantation. No other concurrent pathogen was isolated from any patient at the time of the S. mitis bacteremia. Bacteremia developed within 72 hours of transplant in five of six patients and was associated with severe mucositis in four patients. An environmental study failed to reveal any common source for the outbreak, and whole cell protein analysis of all six S. mitis isolates revealed each to be distinct. Of 12 patients receiving oral vancomycin/polymyxin/tobramycin, one developed S. mitis bacteremia, versus five of nine patients receiving norfloxacin (p less than 0.03). CONCLUSION: We believe S. mitis bacteremia is a potential complication of bone marrow transplantation and is associated with antimicrobial prophylaxis with norfloxacin, especially in the setting of mucositis.

Effect of prior chemotherapy on hematopoietic stem cell mobilization.

A number of studies have suggested that prior chemotherapy correlates negatively with the efficiency of hematopoietic stem cell mobilization. However, little data exist with regard to the relative effects of the specific chemotherapeutic drug classes. We retrospectively reviewed the records of 201 consecutive patients with nonmyeloid malignancies undergoing CD34+ cell mobilization with chemotherapy+granulocyte colony-stimulating factor (G-CSF). The number of prior chemotherapy courses correlated negatively with the peripheral CD34+ cell concentration (pCD34) on the first day of collection (P<0.001). No significant correlation was found for age, gender, tumor primary, mobilization chemotherapy regimen, disease status, marrow involvement, prior radiation therapy, or dose and timing of G-CSF administration. When the number of courses of individual classes of chemotherapeutic agents was correlated with pCD34, only exposures to platinum compounds (P=0.001) and alkylating agents (P=0.01) were found to be independent negative predictive factors for pCD34. Within classes, DNA crosslinking agents and etoposide appeared possibly more damaging than DNA methylating agents and doxorubicin, respectively. None of the drug classes showed evidence of recovery. We conclude that exposure to chemotherapy, especially platinum compounds and alkylating agents, should be minimized prior to mobilization.

Blood transfusions and postoperative wound infection.

BACKGROUND: Several studies have suggested an association between blood transfusions and infection in surgical patients. However, previous reports have not documented the relationship of transfusion to specific infection sites and have not adequately explored the importance of timing and type of blood product. METHODS: We reviewed the records of all patients undergoing operation for colon cancer at a large community hospital during the years 1974 to 1987. Data on hospital wound and other infections, wound infection risk factors, and type and timing of transfusions were analyzed. RESULTS: Increased wound infection rates were associated with administration of both whole blood and packed red blood cells. However, multivariate analysis suggested that only the administration of packed red cells after operation independently predicted wound infections. Other independent variables were the presence of a colostomy and/or drain. A highly predictive model for wound infection was constructed with these three variables. CONCLUSIONS: Blood transfusions, especially with packed red cells, after operation are an independent risk factor for wound infection.

A simple treatment of post-lumbar-puncture headache.

We report a case of post-lumbar-puncture headache successfully treated with intravenous caffeine sodium benzoate. The patient presented to the emergency department with a severe headache three days after a myelogram of the lumbar region. Caffeine sodium benzoate (500 mg) in 1 liter of fluid (D5LR) intravenously over one and a half hours was administered. The patient reported complete resolution of symptoms and no recurrence of headache. Caffeine sodium benzoate is a simple treatment of post-lumbar-puncture headaches. It should be considered as a safe alternative to an epidural blood patch for the treatment of post-lumbar-puncture headaches.

Disposal of sharps: implications and control.

This paper describes the current federal and state regulations governing disposal of "sharps" by health care facilities. Recent data on the implications of exposure to waste containing sharps are summarized, and appropriate methods for sharps disposal are outlined. Three institutions are cited as examples of the costs associated with implementation of a sharps disposal system.

DNA damage and repair in patients receiving high-dose cyclophosphamide and radiation.

DNA damage and repair were assessed by alkaline sucrose gradients in the nonstimulated circulating mononuclear cells of 7 patients receiving high-dose cyclophosphamide (HDCy) and fractionated whole-body irradiation. Measurable damage produced by HDCy appeared to be repaired in about 60 hours. Damage from a radiation dose of 2 Gy was not completely repaired within 24 hours because DNA molecular weight was found to be decreased by an average of 22%. We attempted to assess the impact of HDCy on radiation damage repair by comparing blood irradiated and incubated in vitro before therapy with in vivo incubation following HDCy administration. Two hours after a radiation dose, repair appeared increased following HDCy. These results suggest the possibility that significant interaction at the DNA level may occur when HDCy and irradiation are administered together.

Comparison of CD34+ cell collection efficiency on the COBE Spectra and Fenwal CS-3000 Plus.

Optimal collections of mobilized CD34+ cells are important in terms of both patient toxicity and cost. The factors that determine CD34+ collection efficiency (CD34eff) of cell separators have not been well studied. In addition, because several cell separators are available, the type of collection device may also be a significant variable. Previous studies comparing the Baxter-Fenwal CS3000 and the COBE Spectra have not yielded consistent conclusions. Therefore, we retrospectively analyzed the collection outcomes of 163 consecutive donors with a peripheral CD34+ cell concentration (pCD34) of > or =5 cells/microl on the first collection that had been harvested on one or the other device. The CS3000 was found to yield a significantly higher CD34eff (50% vs. 39%, P = 0.006). However, donors were not balanced for several prognostic factors, which may contribute to CD34eff including mobilization with G-CSF vs. chemotherapy+G-CSF, average flow rate, and total volume of peripheral blood processed. When appropriate variables were included in a stepwise multiple variable analysis, cell separator type emerged as a significant independent predictive factor for CD34eff (P = 0.018). Our data indicates that the CS3000 will, on average, show a higher absolute CDeff of 8%. Furthermore, since the two devices differ in mechanism, prognostic factors may also differ. Comparisons suggest that peripheral blood WBC and hematocrit may be more important predictors for the CS3000.

Natural killer cells in in utero diethylstilbesterol-exposed patients.

The observations that limited neonatal diethylstilbesterol (DES) exposure in mice produces persistent natural killing defects and that natural killer (NK) cells have an origin early in gestation suggested the possibility that NK abnormalities may exist in in utero DES-exposed women. However, when compared to controls, these women showed slightly higher NK activity with no evidence of stimulation by accessory mononuclear cells. Altered natural killing cannot be invoked in this population as a contributing factor to increased cancer risk.

Factors affecting the efficiency of collection of CD34-positive peripheral blood cells by a blood cell separator.

BACKGROUND: The yield of CD34-positive cells obtained from an apheresis procedure is determined, in part, by the efficiency of collection. Optimization of the efficiency of CD34-positive peripheral blood cell collection requires identification of predictive factors. STUDY DESIGN AND METHODS: Demographic, stem cell collection, mobilization, and disease-related measures from autologous and allogeneic donors undergoing 252 progenitor cell apheresis procedures were retrospectively reviewed. Statistical relationships between CD34 collection efficiency and the various measures were determined by correlation and multiple linear regression analysis. RESULTS: CD34 collection efficiency inversely correlated with the peripheral white cell count, hematocrit, and serum albumin concentration (R2 = 0.29). White cell count was the single best predictor of CD34 efficiency (R2 = 0.19). Donor groups with cytopenias (patients vs. normal donors; increased cycles of prior chemotherapy; bone marrow involvement; chemotherapy plus growth factor mobilization) had higher collection efficiencies. Only 29 percent of the variability in the data could be attributed to white cell count, hematocrit, and albumin concentration. The majority of the remaining variability was due to unexplained differences between donors. CONCLUSION: CD34 collection efficiencies show considerable variation. Higher peripheral white cell counts, hematocrits, and/or albumin concentrations result in decreased CD34 collection efficiency, but most of the variability in the data is not accounted for by these three factors.

Identification of a p53 response element in the promoter region of the hMSH2 gene required for expression in A2780 ovarian cancer cells.

Defects in the human MSH2 mismatch repair system have been implicated in cellular mutagenesis, tumorigenesis, and chemotherapeutic resistance. The current studies characterized the 5' upstream proximal promoter region of the hMSH2 gene using transient transfection of A2780 ovarian cancer cells. Serial deletions of a 1.88-kb fragment of the proximal promoter region of the hMSH2 gene revealed that promoter activity was restricted to the first -281 bp. Targeted deletions within this -281 bp region coupled with specific sequence mutagenesis identified a response element for the p53 tumor suppressor protein located between -242 and -222 bp. The -242 hMSH2 p53 element is configured as a direct tandem repeat palindrome with 80% homology to the p53 consensus binding sequence. Co-transfection of an hMSH2 reporter and p53 expression vector into the p53-null cell line SK-OV-3 produced 10-fold enhanced transcription, which was lost when the -242 to -222 p53 binding site was mutated. These results clearly demonstrate the presence of a previously unidentified p53 response element in the hMSH2 proximal promoter. Its location at -242 bp upstream of the start site of transcription is distinct from two previously reported p53 sites at -447 and -416, which transactivate in Saos-2 cells (Scherer, S. J., Maier, S. M., Seifert, M., Hanselmann, R. G., Zang, K. D., Muller-Hermelink, H. K., Angel, P., Welter, C., and Schartl, M. (2000) J. Biol. Chem. 275, 37469-37473). Finally, in sharp contrast to their activity in Saos-2 cells, deletion of the -447 and -416 sites in A2780 cells had no effect on hMSH2 promoter activity. Thus, it appears that p53 regulates hMSH2 expression through multiple cell type-specific DNA response elements.

Transfusion and second malignancy.

BACKGROUND: Perioperative blood transfusion has been reported to cause a variety of immunosuppressive effects, including increased rates of malignancy recurrence. The effect of perioperative transfusion on second malignancy risk has not previously been investigated. STUDY DESIGN AND METHODS: Second malignancy risk was evaluated in 1053 patients previously operated upon for colon cancer, and these findings are related to perioperative transfusion history. RESULTS: Transfusion history did not relate to the probability of a patient's remaining free of second malignancy. CONCLUSION: An increased risk of total or second malignancies (with the possible exception of lung cancer) was not associated with transfusion.

An evaluation of predictive factors for CD34+ cell harvest yields from patients mobilized with chemotherapy and growth factors.

BACKGROUND: Accurately predicting the outcomes of peripheral blood stem cell harvests is important because unproductive collections are expensive and subject the donor to unnecessary toxicity. STUDY DESIGN AND METHODS: Predictive factors for stem cell mobilization and collection by a retrospective review of 104 consecutive donors were evaluated. RESULTS: Of several previously suggested measures, the peripheral CD34+ cell concentration on the day of harvest (pCD34DH) correlated best with total numbers of CD34+ collected (r = 0.88). This was followed by the pCD34 on the day before harvest (pCD34Day -1) (r = 0.74). The peripheral WBC count on the day of harvest (pWBC) was inferior (r = 0.39). When ratios of potential predictive factors divided by the previous day's value were examined, pWBC ratio was found to be a significant independent predictive factor for cells collected (r = 0.45). Furthermore, the predictive value of both the pCD34Day -1 and the pWBC can be improved by combining with the pWBC ratio. To examine whether the chosen collection starting days were optimal, serial pCD34 obtained daily during the harvest procedures was examined. Poorly mobilizing donors, who required several days of collection, did not reach maximal harvest yields until the fourth collection day. CONCLUSIONS: pCD34DH is the optimal predictive factor for harvest yields. If pCD34DH is not available, pCD34Day -1 or pWBC combined with the pWBC ratio may offer the best prediction of harvest outcomes. The best harvest yields on poorly mobilizing donors occur 3 to 4 days after the usual collection starting times.

Oral antimicrobial prophylaxis in bone marrow transplant recipients: randomized trial of ciprofloxacin versus ciprofloxacin-vancomycin.

The optimal oral antimicrobial prophylactic regimen for bone marrow transplant recipients remains to be elucidated. We randomized 84 patients to receive either oral ciprofloxacin or ciprofloxacin plus vancomycin at hospital admission. Patients were monitored for bacteremias and clinical parameters, and stool and throat swab surveillance cultures were performed. The addition of vancomycin resulted in a significant decrease in the frequency of patients with surveillance cultures positive for coagulase-negative staphylococci (stool cultures, 44 versus 23%; throat swab cultures, 37 versus 19%) and alpha-hemolytic streptococci (throat swab cultures, 90 versus 60%). The frequencies of positivity for Candida spp. and gram-negative organisms on surveillance cultures were comparable. Despite these results, no differences in the incidences of bacteremias (12 of 41 versus 12 of 43 patients) or clinical parameters such as number of days to first fever, total number of febrile days, length of stay, and number of transfusions could be demonstrated. Because of a lack of efficacy of vancomycin and emerging problems with vancomycin-resistant isolates, vancomycin should not be used in oral antimicrobial prophylaxis regimens.