A two-in-one Janus NIR-II AIEgen with balanced absorption and emission for image-guided precision surgery.

Fluorescence imaging in the near-infrared II (NIR-II, 1000-1700 nm) region opens up new avenues for biological systems due to suppressed scattering and low autofluorescence at longer-wavelength photons. Nonetheless, the development of organic NIR-II fluorophores is still limited mainly due to the shortage of efficient molecular design strategy. Herein, we propose an approach of designing Janus NIR-II fluorophores by introducing electronic donors with distinct properties into one molecule. As a proof-of-concept, fluorescent dye 2 TT-m, oC6B with both twisted and planar electronic donors displayed balanced absorption and emission which were absent in its parent compound. The key design strategy for Janus molecule is that it combines the merits of intense absorption from planar architecture and high fluorescence quantum yield from twisted motif. The resulting 2 TT-m, oC6B nanoparticles exhibit a high molar absorptivity of 1.12 ⨯104 M-1 cm-1 at 808 nm and a NIR-II quantum yield of 3.7%, displaying a typical aggregation-induced emission (AIE) attribute. The highly bright and stable 2 TT-m, oC6B nanoparticles assured NIR-II image-guided cancer surgery to resect submillimeter tumor nodules. The present study may inspire further development of molecular design philosophy for highly bright NIR-II fluorophores for biomedical applications.

Real-world Effectiveness and Safety of Vedolizumab for the Treatment of Inflammatory Bowel Disease: The Scottish Vedolizumab Cohort.

BACKGROUND & AIMS: Vedolizumab is an anti-a4b7 monoclonal antibody that is licensed for the treatment of moderate to severe Crohn's disease and ulcerative colitis. The aims of this study were to establish the real-world effectiveness and safety of vedolizumab for the treatment of inflammatory bowel disease. METHODS: This was a retrospective study involving seven NHS health boards in Scotland between June 2015 and November 2017. Inclusion criteria included: a diagnosis of ulcerative colitis or Crohn's disease with objective evidence of active inflammation at baseline (Harvey-Bradshaw Index[HBI] ≥5/Partial Mayo ≥2 plus C-reactive protein [CRP] >5 mg/L or faecal calprotectin ≥250 µg/g or inflammation on endoscopy/magnetic resonance imaging [MRI]); completion of induction; and at least one clinical follow-up by 12 months. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, and deep remission [clinical remission plus mucosal healing]. Rates of serious adverse events were described quantitatively. RESULTS: Our cohort consisted of 180 patients with ulcerative colitis and 260 with Crohn's disease. Combined median follow-up was 52 weeks (interquartile range [IQR] 26-52 weeks). In ulcerative colitis, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 57.4%, 47.3%, and 38.5%, respectively. In Crohn's disease, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 58.4%, 38.9%, and 28.3% respectively. The serious adverse event rate was 15.6 per 100 patient-years of follow-up. CONCLUSIONS: Vedolizumab is a safe and effective treatment for achieving both clinical remission and mucosal healing in ulcerative colitis and Crohn's disease.

Untangling the Complexity of Liver Fluke Infection and Cholangiocarcinoma in NE Thailand Through Transdisciplinary Learning.

This study demonstrates how a transdisciplinary learning approach provided new insights for explaining persistent Opisthorchis viverrini infection in northern Thailand, as well as elucidating problems of focusing solely on the parasite as a means of addressing high prevalence of cholangiocarcinoma. Researchers from diverse backgrounds collaborated to design an investigative homestay program for 72 Singaporean and Thai university students in five northeast Thai villages. The students explored how liver fluke infection and potential cholangiocarcinoma development are influenced by local landscape dynamics, aquatic ecology, livelihoods, food culture and health education. Qualitative fieldwork was guided daily by the researchers in a collaborative, co-learning process that led to viewing this health issue as a complex system, influenced by interlinked multidimensional factors. Our transdisciplinary experience has led us to believe that an incomplete understanding of these linkages may reduce the efficacy of interventions. Further, viewing liver fluke infection and cholangiocarcinoma as the same issue is inadvisable. Although O. viverrini infection is an established risk factor for the development of cholangiocarcinoma, multiple factors are known to influence the likelihood of acquiring either. Understanding the importance of the current livelihood transition, landscape modification and the resulting mismatch between local cultures and new socio-ecological settings on cholangiocarcinoma initiation and liver fluke transmission is of critical importance as it may help readjust our view of the respective role of O. viverrini and other socioeconomic risk factors in cholangiocarcinoma etiology and refine intervention strategies. As demonstrated in this study, transdisciplinary approaches have the potential to yield more nuanced perspectives to complex diseases than research that focuses on specific aspects of their epidemiology. They may therefore be valuable when designing effective solutions to context-sensitive diseases such as liver fluke infection and cholangiocarcinoma.

Bilineal T lymphoblastic and myeloid blast transformation in chronic myeloid leukemia with TP53 mutation-an uncommon presentation in adults.

Bilineal blast transformation of myeloid and T lymphoid type is a rare event in chronic myeloid leukemia. Here, we report a case in which an adult presented with high white cell counts and lymphadenopathy. Bone marrow studies confirmed the presence of 9 and 22 chromosomal translocation, and a diagnosis of chronic myeloid leukemia in chronic phase was made. Examination of a lymph node showed both myeloid and T lymphoblastoid blast crisis. Molecular studies demonstrated the presence of BCR-ABL fusion transcripts in both the myeloid and the T lymphoblastic component, indicating that the myeloid and T lymphoid blast crisis components shared common progenitors. TP53 deletion was demonstrated by fluorescence in situ hybridization.

A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.

BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).

Attainment of at least a very good partial response after induction treatment is an important surrogate of longer survival for multiple myeloma.

The importance of achieving a very good partial response or better (≥VGPR) after induction treatment of myeloma has traditionally only been discussed in the context of high-dose therapy with auto-SCT (HDT/auto-SCT). Of late, the advent of novel agents for induction treatment has resulted in improved CR and VGPR rates, which are comparable with those observed with HDT/auto-SCT. We show that in an unselected group of 179 myeloma patients with diverse baseline characteristics, and treated with different modern induction regimens within a single institution, the attainment of ≥VGPR with or without HDT/auto-ASCT represents a major surrogate marker of better clinical outcomes. On the basis of a 1-year landmark survival analysis, patients achieving ≥VGPR enjoy a significantly longer PFS, which translated to a longer OS. Superseding the adverse effects of advanced age, high International Staging System (ISS) stage, adverse cytogenetics and independent of the transplant status, the attainment of ≥VGPR emerged as the single most significant predictor of long-term survival on multivariate analysis.

Stem cell transplantation programme at Singapore General Hospital.

The adult transplant programme at Singapore General Hospital (SGH) was established in 1985 and more than 820 transplants have been performed to date. An average of about 60 adult transplants (autologous and allogeneic) are performed each year. Transplants offered at SGH run the range from autologous to mismatched cord and unrelated transplants. Special interests of the transplant programme include non-myeloablative transplants in aplastic anaemia, cell therapy protocols including cytokine-induced killer cells, patterns of GVHD, cord blood transplantation for autoimmune diseases and graft engineering. A cGMP (good manufacturing practice) cell therapy laboratory was recently established to facilitate bench-to-bedside translational cell therapy trials. A BMT consortium has been formed among the various paediatric and adult transplant centres for harmonization of protocols and research activities.

Pseudoretinoblastoma in enucleated eyes of Asian patients.

INTRODUCTION: Retinoblastomas of the eye are a cause of childhood blindness and have a high rate of mortality, as well as a hereditary mode of transmission. Other conditions that mimic retinoblastomas are known as pseudoretinoblastomas, and are managed differently. Although pseudoretinoblastoma and the accuracy of retinoblastoma diagnosis have been reviewed in Caucasian patients, published studies in Asian patients are lacking. The purpose of this article is to report our experience with pseudoretinoblastomas in two major ophthalmological centres in Asia. METHODS: A case series of 28 enucleations carried out for suspected retinoblastoma at the Singapore National Eye Centre and KK Women's and Children's Hospital, Singapore, between January 1991 and December 2002, is reported. All cases were subjected to a detailed history from parents, followed by external ocular examination, slit-lamp biomicroscopy and binocular indirect ophthalmoscopy. Ancillary studies, such as B-scan ultrasonography and computed tomography, were employed as necessary to confirm the diagnosis. Histology was obtained on all cases. RESULTS: Of the 28 cases, 25 (89 percent) were found on histological analysis to be retinoblastomas. Three (11 percent) were pseudoretinoblastomas. There were two cases of Coat's disease and a case of presumed ocular toxocariasis. These three cases were described in detail. CONCLUSION: Although our sample size is small, the percentage of confirmed retinoblastomas was found to be only slightly higher than that found in western countries. Our findings are consistent with their findings that Coat's disease and presumed ocular toxocariasis are the more common causes of pseudoretinoblastoma.

Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells.

Although imatinib mesylate has revolutionized the treatment of chronic myeloid leukaemia (CML), resistance to the drug, manifesting as relapse after an initial response or persistence of disease, remains a therapeutic challenge. In order to overcome this, alternative or additional targeting of signaling pathways downstream of Bcr-Abl may provide the best option for improving clinical response. Bisphosphonates, such as zoledronate, have been shown to inhibit the oncogenicity of Ras, an important downstream effector of Bcr-Abl. In this study, we show that zoledronate is equally effective in inhibiting the proliferation and clonogenicity of both imatinib-sensitive and -resistant CML cells, regardless of their mechanism of resistance. This is achieved by the induction of S-phase cell cycle arrest and apoptosis, through the inhibition of prenylation of Ras and Ras-related proteins by zoledronate. The combination of imatinib and zoledronate also augmented the activity of either drug alone and this occurred in imatinib-resistant CML cells as well. Since zoledronate is already available for clinical use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of CML.

Integrated hydroxyapatite implant and non-integrated implants in enucleated Asian patients.

INTRODUCTION: This study compares the outcome and complications of integrated hydroxyapatite implant and non-integrated orbital implants following enucleation in Asian patients. MATERIALS AND METHODS: This is a retrospective study of enucleated patients with coralline hydroxyapatite implants versus non-integrated implants (acrylic, glass and silicone) at the Singapore National Eye Centre from January 1991 to December 2000. The outcomes measured were implant migration, extrusion, socket infection, conjunctival dehiscence and implant exposure. Statistical analysis was done using the 2-sample t-test. RESULTS: Twenty-one patients had the hydroxyapatite implant and 38 non-integrated implants (27 acrylic, 9 glass and 2 silicone). The mean duration of follow-up was 2.7 years and 4 years for the hydroxyapatite implant and non-integrated implants respectively. Three patients with pre-existing severe socket contracture before enucleation surgeries were excluded from the study. Four cases of implant migration, 4 cases of implant extrusion and 3 cases of socket infection were encountered; all were sockets fitted with non-integrated implants. There was a higher rate of conjunctival dehiscence for sockets with hydroxyapatite implants (6 out of 21) compared to sockets with non-integrated implants (3 out of 35). This was statistically significant (P = 0.048). CONCLUSIONS: Implant complications of migration, extrusion and socket infection were found in non-integrated implants and none in coralline hydroxyapatite implants, which had a significantly higher rate of conjunctival dehiscence. Most of these were easily managed with only a small number progressing to implant exposure.

A randomized trial of amifostine as a cytoprotectant for patients receiving myeloablative therapy for allogeneic hematopoietic stem cell transplantation.

We initiated a randomized study of amifostine (the organic thiophosphate formerly known as WR-2721) given to patients during myeloablative conditioning therapy for allogeneic bone marrow transplantation. Amifostine was given at a dose of 1000 mg/day of conditioning and was well tolerated if attention was given to serum calcium levels, blood pressure and antiemetics. Since August 1998, 60 patients (30 on each arm) have completed the study. There was no significant difference in the days to neutrophil or platelet engraftment in either arm of the study. Significantly, the duration of grade I-IV mucositis was decreased in the group that received amifostine (P=0.02). Also grade III or IV infections (P=0.008), duration of antibiotic therapy (P=0.03) and duration of fever (P=0.04) were significantly reduced with amifostine. However, there were no differences in the incidence of grade III or IV mucositis, liver toxicity or renal toxicity. There were also no differences in early mortality, relapse and long-term survival. We conclude that amifostine, while reducing the duration of mucositis and infections (possibly through some preservation of gut mucosal integrity), has a modest effect in allogeneic bone marrow transplants given the multiplicity of factors influencing organ toxicity and survival in this setting.

Long term follow-up of Asian patients with chronic myeloid leukemia (CML) receiving allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling-evaluation of risks and benefits.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for patients with chronic myeloid leukemia (CML), but is associated with significant morbidity and mortality. The recent introduction of imatinib mesylate (STI-571) and reduced intensity transplant regimens has made the choice of primary treatment for patients with CML increasingly difficult. We have evaluated the outcome of 53 patients who have received allogeneic HSCT from human leukocyte antigen (HLA)-identical sibling donors between October 1985 and March 2002, determined the variables affecting the outcome, and tried to define indications for this aggressive approach. Successful engraftment occurred in 49 (98%) of evaluable patients. Acute graft-versus-host disease (GVHD) of grade II to IV severity was observed in 63% of the evaluable patients whereas the incidence of chronic GVHD was 57.5%. The Kaplan-Meier estimate of survival at 10 years was 54% [95% confidence interval (CI): 38-70%] and 31% (95% CI: 6-56%) for patients with first chronic phase and more advanced diseases, respectively. Multivariate analysis showed that younger age, absence of grade III-IV GVHD, the use of busulphan and cyclophosphamide (BuCy) as preparative regimen, and transplantation performed after January 1992 were factors associated with improved survival. Patients who were 30 years of age or younger who had transplantation done within 1 year after diagnosis during their first chronic phase of disease had a particularly good prognosis, with a probability of surviving 10 years of 72% (95% CI: 52-92%). We conclude that allogeneic HSCT remains a feasible option for Asian patients with CML. The most favorable outcome is observed in younger patients with early phase of the disease.

Imatinib mesylate (STI-571) given concurrently with nonmyeloablative stem cell transplantation did not compromise engraftment and resulted in cytogenetic remission in a patient with chronic myeloid leukemia in blast crisis.

The main obstacles to successful hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in blast crisis (BC) are increased post-transplant relapse and high treatment-related mortality. We report a patient with CML in BC who was treated initially with imatinib mesylate and was then concurrently treated with a nonmyeloablative stem cell transplant. Successful engraftment of donor cells followed by complete cytogenetic remission was achieved in the absence of severe therapy-related toxicities. This case demonstrates that imatinib mesylate given through nonmyeloablative transplant is a minimally toxic therapeutic approach, which does not compromise engraftment and may result in a favorable outcome in patients with CML in BC.

Case report: acute tumour lysis syndrome.

INTRODUCTION: Acute tumour lysis syndrome (ATLS) is a potentially lethal but preventable complication of oncological treatment. CLINICAL PICTURE: We report a case of a patient with Burkitt's leukaemia who developed ATLS after treatment with chemotherapy. TREATMENT: Standard preventive measures using aggressive hydration, urine alkalinisation and uricosuric agents were instituted before chemotherapy. OUTCOME: However in spite of adequate measures, the patient succumbed to the sequelae of ATLS. CONCLUSIONS: It is therefore important to identify patients who are at a high risk of developing ATLS so that additional measures can be taken to prevent it from occurring.

Atypical peripheral ameloblastoma of the palate.

Clinical, radiological and histological characteristics of the peripheral ameloblastoma are briefly outlined. A case found occurring in the palate and presenting with atypical histological features is reported. The differential diagnosis of this lesion, its treatment and histogenesis are discussed.

Cerebral metastases from choriocarcinoma. Results of chemotherapy.

Of 36 cases of choriocarcinoma treated at the University Hospital Kuala Lumpur during 1980-84 inclusive, 6 patients were found to have cerebral metastases. Intrathecal methotrexate and combination chemotherapy were started in all cases, with monitoring of tumor growth by serial beta-HCG assays and CT scanning of brain and lung. Chemotherapy was reduced because of severe toxicity in 2 patients, one of whom received radiotherapy to the brain. Four patients (66%) have now been in remission for 2.5-6 years. Two did not respond to therapy and died. The factors involved in therapy and response are discussed.