Blood transfusions in total knee arthroplasty: a retrospective analysis of a multimodal patient blood management programme.

PURPOSE: Transfusion is associated with increased perioperative morbidity and mortality in patients undergoing total knee arthroplasty (TKA). Patient blood management (PBM) is an evidence-based approach to maintain blood mass via haemoglobin maintenance, haemostasis optimisation, and blood loss minimisation. The aim of the present study was to assess the effectiveness of a multimodal PBM approach in our centre. METHODS: This was a single-centre retrospective study of patients who underwent primary TKA in Queen Mary Hospital in Hong Kong in 2013 or 2018, using data from the Clinical Data Analysis and Reporting System and a local joint registry database. Patient demographics, preoperative haemoglobin, length of stay, readmission, mean units of transfusion, postoperative prosthetic joint infection, and mortality data were compared between groups. RESULTS: In total, 262 and 215 patients underwent primary TKA in 2013 and 2018, respectively. The mean transfusion rate significantly decreased after PBM implementation (2013: 31.3%; 2018: 1.9%, P<0.001); length of stay after TKA also significantly decreased (2013: 14.49±8.10 days; 2018: 8.77±10.14 days, P<0.001). However, there were no statistically significant differences in readmission, early prosthetic joint infection, or 90-day mortality rates between the two groups. CONCLUSION: Our PBM programme effectively reduced the allogeneic blood transfusion rate in patients undergoing TKA in our institution. Thus, PBM should be considered in current TKA protocols to reduce rates of transfusions and related complications.

Sporopachydermia cereana fungaemia in refractory leukaemia presenting as breakthrough infection during micafungin therapy.

The Sporopachydermia cereana species lives in decaying stems of cactus and is exceptionally rare as a human pathogen. A 57-year-old man with therapy-refractory acute promyelocytic leukaemia developed severe neutropaenia. After about 3 weeks of micafungin used as prophylaxis, he developed high fever, multiple pulmonary nodular infiltrates and a painful leg lesion. Blood culture yielded a yeast which was not identified by the Vitek 2 system. On ITS1-5.8S-ITS2 gene sequencing, the isolate was identified as S. cereana. Antifungal sensitivity by the Etest showed that the minimum inhibitory concentration for fluconazole was 0.75 µg/mL, and for anidulafungin, it was >32 µg/mL. He responded to liposomal amphotericin B but later died of Escherichia coli septicaemia. There were no cactus plants in the vicinity, suggesting that S. cereana might have alternative habitats.

Antifungal drug usage in haematologic patients during a 4-year period in an Asian university teaching hospital.

BACKGROUND: Invasive fungal disease (IFD) is an important problem complicating the therapy of haematologic patients. AIM: This study aimed to provide data on the epidemiology of IFD in an Asian teaching hospital, as well as the prescription practice of antifungal drugs. METHOD: We conducted a retrospective review of 275 haematologic patients who were prescribed antifungal drugs in a 4-year period (2007-2010), of whom 130 (47%) had undergone haematopoietic stem cell transplantation. RESULTS: Antifungal prophylaxis with either fluconazole or itraconazole was given in 214 patients (78%). There were 414 prescriptions of antifungal drugs (including liposomal amphotericin B, voriconazole, caspofungin, micafungin, anidulafungin), of which 361 prescriptions were empirical. There were 14 patients with proven IFD, 11 of whom had breakthrough infection while on itraconazole prophylaxis. Interestingly, seven of these cases were due to infection by itraconazole-sensitive candida. CONCLUSION: These results provide important epidemiologic data necessary for the formulation of strategies for prevention and treatment of IFD in Asian patients.

Haemophagocytic lymphohistiocytosis: an uncommon clinical presentation of tuberculosis.

Secondary haemophagocytic lymphohistiocytosis is a rare but fatal complication of tuberculosis. We describe two cases, and review the local and international experience on the management of this clinical entity. Prompt treatment with anti-tuberculous drugs forms the cornerstone of therapeutic success.

Granzyme B PET Imaging of Immune Checkpoint Inhibitor Combinations in Colon Cancer Phenotypes.

PURPOSE: Immune checkpoint inhibitor (ICI) monotherapy and combination regimens are being actively pursued as strategies to improve durable response rates in cancer patients. However, the biology surrounding combination therapies is not well understood and may increase the likelihood of immune-mediated adverse events. Accurate stratification of ICI response by non-invasive PET imaging may help ensure safe therapy management across a wide number of cancer phenotypes. PROCEDURES: We have assessed the ability of a fluorine-labelled peptide, [18F]AlF-mNOTA-GZP, targeting granzyme B, to stratify ICI response in two syngeneic models of colon cancer, CT26 and MC38. In vivo tumour uptake of [18F]AlF-mNOTA-GZP following ICI monotherapy, or in combination with PD-1 was characterised and correlated with changes in tumour-associated immune cell populations. RESULTS: [18F]AlF-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells; however, overall uptake and response to monotherapy or combination therapies was very different in the CT26 and MC38 tumours, likely due to the immunostimulatory environment imbued by the MSI-high phenotype in MC38 tumours. CONCLUSIONS: [18F]AlF-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations and is able to stratify tumour response to a range of ICIs administered as monotherapies or in combination. However, tracer uptake can be significantly affected by preexisting phenotypic abnormalities potentially confusing data interpretation.

Nonglycolytic acidification of murine radiation-induced fibrosarcoma 1 tumor via 3-O-methyl-D-glucose monitored by 1H, 2H, 13C, and 31P nuclear magnetic resonance spectroscopy.

The effects of 3-O-methyl-D-glucose (3-OMG) on subcutaneously implanted murine radiation-induced fibrosarcoma 1 tumor were examined with 2H, 13C, and 31P nuclear magnetic resonance (NMR) in situ. Using 31P NMR, changes in tumor high-energy phosphate metabolism were monitored for 2.5 h after i.p. administration of 3-OMG (8.1 g/kg body weight); tumor pH decreased by a mean maximum of 0.52 +/- 0.05 (SE) (n = 10), [PCr] decreased by 54%, [NTP] decreased by 35%, and [Pi] increased by 36%. Tumor blood flow, as measured by 2H NMR monitoring of D2O washout kinetics, decreased by 40% at 1 h and by 47% at 2 h after 3-OMG injection (n = 4). This substantial tumor acidification (pH decrease much greater than 0.1), expected to require a glycolytic substrate (Hwang et al., Cancer Res., 51: 3108-3118, 1991), is surprising in light of the previously documented metabolically inert nature of 3-OMG. In situ 13C NMR spectroscopy, following [6-13C]3-OMG i.p. injection, examined the possibility of the glycolytic metabolism of 3-OMG. However, only the C-6 resonance of 3-OMG was detected (n = 6); no resonances from [6-13C]3-OMG-6-phosphate or [3-13C]lactate were observed. These results confirmed that 3-OMG was not metabolized in radiation-induced fibrosarcoma 1 tumor. At the completion of the in situ 13C NMR experiments, tumors were freeze clamped, and perchloric acid extraction was performed. High-resolution 1H NMR measurement of lactate concentrations showed no statistically significant difference in control tumor extracts (from mice not receiving i.p. injection; n = 5) and in tumor extracts from mice administered i.p. [6-13C]3-OMG (n = 5), indicating that there was no significant increase in lactate level in the tumor extracts from mice administered i.p. 3-OMG due to increased plasma glucose concentration. The results of these 1H and 13C NMR studies indicated that the radiation-induced fibrosarcoma 1 tumor acidification caused by i.p. administration of 3-OMG was not due to a direct (3-OMG----lactate) or an indirect (systemic glucose----lactate) increase in tumor lactic acid levels.

Allogeneic hematopoietic stem cell transplantation in Philadelphia-negative adult ALL: myeloablative, non-myeloablative, and beyond.

OBJECTIVES: Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a matched sibling donor (MSD) in first complete remission (CR1) is an effective consolidation for adult acute lymphoblastic leukemia (ALL), and matched unrelated donor (MUD) is an alternative stem cell source. METHODS: Based on a search of the English literature for MUD transplant in Philadelphia-negative ALL, this review first compares the treatment outcomes of myeloablative allo-HSCT with MUD and MSD, followed by a mini-review of studies of non-myeloablative, reduced intensity conditioning (RIC) allo-HSCT in ALL, and finally measures to improve outcome of MUD allo-HSCT. RESULTS: Publications are inevitably confounded by inclusion of Philadelphia-positive cases, patients beyond CR1, and mismatched unrelated donors in addition to heterogeneity in the length of follow-up. Despite these limitations, the overall data showed that MUD allo-HSCT resulted in comparable survivals with matched related donor (MRD) transplant. Moreover, Asian studies reported a lower transplant-related mortality (TRM) than Western studies. As graft failure is infrequent even in the MUD setting, acute graft versus host disease (aGVHD) remains a major cause of TRM. In addition, RIC allo-HSCT produced promising long-term disease-free survival (DFS) with a low TRM in adult ALL if transplanted in CR1. DISCUSSION: Potential ways to reduce TRM further include antifungal prophylaxis and optimal management of life-threatening non-infective interstitial pneumonitis. Moreover, harnessing graft-versus-leukemia effect with hypomethylating agents warrants clinical trial. CONCLUSION: Myeloablative MUD allo-HSCT resulted in comparable survivals with MRD transplant. RIC allo-HSCT produced promising long-term DFS with a low TRM in adult ALL.

Synthesis and evaluation of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir.

A series of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (4-10) and 2-amino-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (1) were synthesized as potential prodrugs of penciclovir and evaluated for their oral penciclovir bioavailability in mice and rats. Treatment of 2-(2-benzyloxyethyl)propane-1,3-diol (11) with 1,1'-carbonyldiimidazole in THF followed by hydrogenolytic removal of the benzyl group of the resulting cyclic carbonate 12 gave 5-(2-hydroxyethyl)-1,3-dioxan-2-one (13). Mesylation of the alcohol 13 and then a coupling reaction of the resulting mesylate 14 with 2-amino-6-chloropurine using anhydrous Cs2CO3 in DMF afforded 2-amino-6-chloro-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (16) after purification by flash column chromatography on silica gel using EtOAc/MeCN/Et3N as eluent. Hydrogenation of the 6-chloro cyclic carbonate 16 followed by a ring-opening reaction of the 6-deoxy cyclic carbonate 1 in a mixture of an appropriate alcohol and CHCl3 using activated SiO2 as a Lewis acid afforded the corresponding alkyl monocarbonate derivatives 3-10 in fair to good yields. Of the prodrugs tested in mice, the isopropyl monocarbonate 6 achieved the highest mean urinary recovery of penciclovir (53%), followed in order by the propyl monocarbonate 5 (51%), the isopentyl monocarbonate 10 (51%), the ethyl monocarbonate 4 (50%), and famciclovir (48%). In rats, the methyl monocarbonate 3, 4, 6, the n-butyl monocarbonate 7, and 10 (39-41%) showed levels of mean urinary recovery of penciclovir similar to that from famciclovir (40%). The alkyl monocarbonates 4-10 were found to be quite stable in the aqueous buffer solutions, and among them, 6 was the most stable with the half-lives (t1/2) of 88, >200, 61, and 26 days at pH 1.2, 6.0, 7.4, and 8.0, respectively. In addition, 6 was highly soluble in H2O (138.8 mg/mL, 20 degrees C).

Effects of prophylactic chemotherapy for persistent trophoblastic disease in patients with complete hydatidiform mole.

Seventy-one patients with complete hydatidiform mole were prospectively randomized into two groups: one group (39 patients) was treated with a single course of methotrexate and citrovorum factor rescue as chemoprophylaxis; the other group (32 patients) was not treated. After molar evacuation, four patients from the treated group (10.3%) and ten patients from the untreated group (31.3%) developed persistent trophoblastic disease. The time interval from evacuation of the mole to diagnosis of persistent trophoblastic disease was longer in the treated group than in the untreated group (9.5 +/- 2.4 weeks versus 5.1 +/- 1.6 weeks, P less than .05). Among high-risk patients, there was a lower incidence of persistent trophoblastic disease in the treated group than in the untreated group (14.3 versus 47.4%, P less than .05). Among low-risk patients there was no difference between the groups (5.6 versus 7.7%, P greater than .05). All 14 patients with persistent trophoblastic disease achieved complete remission with therapeutic chemotherapy. More courses of chemotherapy were required until complete remission in the treated group than in the untreated group (2.5 +/- 0.5 versus 1.4 +/- 0.5, P less than .005). These findings suggest that even though chemoprophylaxis reduces the incidence of persistent trophoblastic disease in patients at high risk, it increases tumor resistance and morbidity. Although prophylactic chemotherapy with methotrexate and citrovorum factor rescue may be helpful for high-risk patients who cannot be followed or whose compliance is in question, careful follow-up remains the most important way to identify patients who should receive chemotherapy.

Characterization of a new ribotoxin gene (c-sar) from Aspergillus clavatus.

A new ribotoxin, c-sarcin, was isolated from a culture of Aspergillus clavatus. A full-length genomic DNA (c-sar) coding for c-sarcin was cloned and sequenced. The deduced amino acid sequence showed a high homology to restrictocin and alpha-sarcin. The native toxin as well as the recombinant protein hydrolysed ribosomes and naked RNA. The genomic structure of the c-sar gene had an intron located between the coding sequences for secretory signal peptide and the mature protein. The intron contained a stretch of 38 adenines. The intron sequence of c-sar was different from that of restrictocin but resembled that of alpha-sarcin. There was 34% identity between the intron of c-sarcin and alpha-sarcin, and this similarity was further increased to 83% if the stretch of polyadenine was omitted.

Uterine papillary serous carcinoma following radiation therapy for carcinoma of cervix: a case report.

Uterine papillary serous carcinoma (UPSC) is a clinically aggressive and morphologically distinctive variant of endometrial carcinoma that has been recognized recently as a distinct entity. The association between radiation therapy (RT) and UPSC is rarely described in the literature. We describe the clinicopathologic features of a 71-year-old patient with UPSC that developed 15 years after radiation therapy for squamous cell carcinoma of cervix, stage IIB. In the subtotal hysterectomy specimen the endometrium was irregular with multifocally raised masses. Microscopically, the tumor was composed of high-grade papillary serous carcinoma focally admixed with solid transitional cell carcinomatous areas and multifocal intraepithelial carcinoma in adjacent atrophic endometrium. The tumor exhibited diffuse infiltrative growth with frequent lymphatic tumor emboli in the myometrium. Immunohistochemical staining for p53 and c-erbB-2 were positive in about 70% of the tumor cells. Carcinoembryonic antigen (CEA) was focally positive. Ki-67 positive cells were present in about 60% of the tumor cells. The tumor directly extended to the cervix and perirectal soft tissue and metastasized to the omentum. Intraoperative pelvic washing cytology was positive for papillary adenocarinoma cells. The possible etiologic role of radiation is discussed, and the literature on endometrial carcinomas developing after RT is reviewed.

Development of a novel dosage form for intramuscular injection of titrated extract of Centella asiatica in a mixed micellar system.

Titrated extract of Centella asiatica (TECA), a drug used in treating systemic scleroderma, is poorly water-soluble. A conventional dosage form for the intramuscular injection of TECA, propylene glycol (PG)-based TECA solution, causes severe pain after intramuscular injection. To improve the solubility of TECA and reduce pain after injection, mixed micellar systems composed of 10% surfactant mixture (Tween 20 and Tween 85) and 90% phosphate-buffered saline, pH 7.0 (PBS) were prepared. As the ratio of Tween 20 to Tween 85 increased from 0:10 to 10:0, the solubility of TECA in the mixed micellar systems increased from 7- to 26-fold compared to that in PBS (pH 7.0). The droplet size of micelles gradually decreased with the increasing ratio of Tween 20 to Tween 85 from 0:10 to 4:6, followed by an abrupt decrease in size above the ratio of 6:4. Furthermore, the micellar systems prepared with Tween 20 and Tween 85 at the ratio of 6:4, 8:2 or 10:0 could solubilize TECA more than 10 mg/ml and the resultant droplet sizes were less than 2 microm. No significant changes were observed in the droplet sizes and asiaticoside contents in these micellar formulations during storage, indicating these systems are stable for at least 60 days. Their osmotic pressures were remarkably lower than those of PG-based TECA solution and similar to that of saline solution, irrespective of dilution ratios. Most importantly, they markedly reduced the number of writhes compared with PG-based TECA solution after injection to mice. All of these results suggest that these three TECA micellar formulations prepared with Tween 20 and Tween 85 improved the solubility of TECA and reduced pain following injection, possibly due to the decrease in osmotic pressure. Thus, these micellar formulations composed of optimum ratios of Tween 20 and Tween 85 may have a potential as dosage forms for the intramuscular injection of a poorly water-soluble TECA.

Hepatitis C in haematological patients.

There is no consensus guideline concerning the management of chronic hepatitis C patients during chemotherapy, and immunosuppression. However, there are some suggestions in literature that hepatitis C viral load increases during chemotherapy and there is a risk of rebound immunity against hepatitis C after discontinuation of immunosuppression with a consequent liver injury. A close monitoring of liver function of these patients is prudent during treatment of haematological malignancy. Antiviral treatment is deferred after the completion of chemotherapy and recovery of patients' immunity to minimize the toxicity of treatment. A combination of pegylated interferon and ribavirin is the standard therapy in hepatitis C infected haematological patients.

An update in management of noncutaneous T-cell lymphomas.

T-cell lymphoma is a heterogeneous group of diseases. Except for ALK positive anaplastic large cell lymphoma, T-cell lymphoma responds to conventional chemotherapy unfavourably, and most patients carry poor prognosis. In recent years, efforts have been made to improve the outcome of T-cell lymphoma patients. Novel agents, high-dose therapy, and allogeneic stem cell transplantation are studied, and various results are reported in literature. This paper looks into the prognostication and treatment approach of different entities of noncutaneous T-cell lymphoma and would focus on the latest updates in its management.