The acquisition order of leukemic drug resistance mutations is directed by the selective fitness associated with each resistance mechanism.

In Chronic Myeloid Leukemia, the transition from drug sensitive to drug resistant disease is poorly understood. Here, we used exploratory sequencing of gene transcripts to determine the mechanisms of drug resistance in a dasatinib resistant cell line model. Importantly, cell samples were collected sequentially during drug exposure and dose escalation, revealing several resistance mechanisms which fluctuated over time. BCR::ABL1 overexpression, BCR::ABL1 kinase domain mutation, and overexpression of the small molecule transporter ABCG2, were identified as dasatinib resistance mechanisms. The acquisition of mutations followed an order corresponding with the increase in selective fitness associated with each resistance mechanism. Additionally, it was demonstrated that ABCG2 overexpression confers partial ponatinib resistance. The results of this study have broad applicability and help direct effective therapeutic drug usage and dosing regimens and may be useful for clinicians to select the most efficacious therapy at the most beneficial time.

Induction of phagocytosis and intracellular signaling by an inhibitory channel catfish leukocyte immune-type receptor: evidence for immunoregulatory receptor functional plasticity in teleosts.

Immunoregulatory receptors are categorized as stimulatory or inhibitory based on their engagement of unique intracellular signaling networks. These proteins also display functional plasticity, which adds versatility to the control of innate immunity. Here we demonstrate that an inhibitory catfish leukocyte immune-type receptor (IpLITR) also displays stimulatory capabilities in a representative myeloid cell model. Previously, the receptor IpLITR 1.1b was shown to inhibit natural killer cell-mediated cytotoxicity. Here we expressed IpLITR 1.1b in rat basophilic leukemia-2H3 cells and monitored intracellular signaling and functional responses. Although IpLITR 1.1b did not stimulate cytokine secretion, activation of this receptor unexpectedly induced phagocytosis as well as extracellular signal-related kinase 1/2- and protein kinase B (Akt)-dependent signal transduction. This novel IpLITR 1.1b-mediated response was independent of an association with the FcRγ chain and was likely due to phosphotyrosine-dependent adaptors associating with prototypical signaling motifs within the distal region of its cytoplasmic tail. Furthermore, compared to a stimulatory IpLITR, IpLITR 1.1b displayed temporal differences in the induction of intracellular signaling, and IpLITR 1.1b-mediated phagocytosis had reduced sensitivity to EDTA and cytochalasin D. Overall, this is the first demonstration of functional plasticity for teleost LITRs, a process likely important for the fine-tuning of conserved innate defenses.

Stimulatory catfish leukocyte immune-type receptors (IpLITRs) demonstrate a unique ability to associate with adaptor signaling proteins and participate in the formation of homo- and heterodimers.

Channel catfish leukocyte immune-type receptors (IpLITRs) are immunoglobulin superfamily (IgSF) members believed to play a role in the control and coordination of cellular immune responses. Some IpLITR-types encode a transmembrane (TM) region containing a single positive charged lysine (K) residue, which is a key feature of stimulatory immune receptors that associate with immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor proteins. In this study we focused on identifying the signaling adaptor molecules recruited by putative stimulatory IpLITRs as a first step towards elucidating their ability to regulate catfish immune cell effector functions. Using HEK 293T cells co-transfected with epitope-tagged catfish proteins, we demonstrate that IpLITRs associated with the IpFcRgamma, IpFcRgamma-L, and IpCD3zeta-L adaptors, which all encode a negative charged aspartic acid (D) residue within their TM regions. Association of IpLITRs with IpFcRgamma and IpFcRgamma-L also enhanced cell surface expression of the receptor, which was not observed after co-transfections with IpCD3zeta-L, IpDAP12, or IpDAP10. Mutating the lysine residue (at amino acid position 199) within the TM region of IpLITR 2.6b to alanine (A(199)) did not prevent the association with IpFcRgamma-L and only slightly reduced receptor expression levels on the cell surface. Surprisingly, this mutation also facilitated IpLITR 2.6b association with IpDAP12 that correlated with an enhanced expression of the receptor. Conversely, an aspartic acid (D(30)) to A(30) switch within the IpFcRgamma-L TM region completely abrogated its assembly with the receptor and inhibited the IpFcRgamma-L induced surface expression of IpLITR 2.6b. In addition, co-transfections and immunoprecipitation of single (i.e. N-terminal HA) and double (i.e. N-terminal HA and C-terminal 3xFLAG) epitope-tagged stimulatory IpLITR-types revealed that these immune receptors formed non-covalent homo- and heterodimers through interaction(s) likely mediated by their extracellular immunoglobulin (Ig)-like domains. Combined with their unique association with adaptor proteins, dimerization may have profound effects on IpLITR-mediated regulation of teleost immune responses by influencing their signaling potential and/or ligand-binding properties.

Cell surface expression of channel catfish leukocyte immune-type receptors (IpLITRs) and recruitment of both Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 and SHP-2.

Channel catfish leukocyte immune-type receptors (IpLITRs) are immunoglobulin superfamily (IgSF) members believed to play a role in the control and coordination of cellular immune responses in teleost. Putative stimulatory and inhibitory IpLITRs are co-expressed by different types of catfish immune cells (e.g. NK cells, T cells, B cells, and macrophages) but their signaling potential has not been determined. Following cationic polymer-mediated transfections into human cell lines we examined the surface expression, tyrosine phosphorylation, and phosphatase recruitment potential of two types of putative inhibitory IpLITRs using 'chimeric' expression constructs and an epitope-tagged 'native' IpLITR. We also cloned and expressed the teleost Src homology 2 domain-containing protein tyrosine phosphatases (SHP)-1 and SHP-2 and examined their expression in adult tissues and developing zebrafish embryos. Co-immunoprecipitation experiments support the inhibitory signaling potential of distinct IpLITR-types that bound both SHP-1 and SHP-2 following the phosphorylation of tyrosine residues within their cytoplasmic tail (CYT) regions. Phosphatase recruitment by IpLITRs represents an important first step in understanding their influence on immune cell effector functions and suggests that certain inhibitory signaling pathways are conserved among vertebrates.

Haemangiopericytoma of the central nervous system.

The records of four patients presenting with a histological diagnosis of haemangiopericytoma of the central nervous system, in Auckland, New Zealand, between 1970 and 1990 were reviewed retrospectively, with the aim of determining the natural history of the disease and response to various treatment modalities. Three out of the four patients reviewed presented with primary cerebral disease and the fourth with a primary spinal cord tumour. All three cerebral primary patients were initially treated with local surgical excision. All three patients received radical radiotherapy following local recurrence. The first two patients remained disease-free locally although one patient developed a solitary liver metastasis 5 years after radiotherapy. The third patient was referred with multiple cerebral metastases and failed to respond to radiotherapy. The patient with the primary lesion in the spinal cord was treated with local excision followed by post-operative radiotherapy and remains disease-free 17 years after treatment. One patient failed to respond to chemotherapy, prescribed to treat a local recurrence adjacent to the previous radiotherapy field. This was successfully excised subsequently. The patient presenting with multiple cerebral metastases was the only patient to die of this disease. Results suggest that local recurrence is avoidable with adequate wide excision of the primary tumour followed by local radical radiotherapy. The role of chemotherapy remains controversial and no conclusion could be drawn regarding the role of palliative radiotherapy from this study. Active treatment and long-term follow-up are necessary because of the relative aggressiveness of this disease and the propensity for late relapses.

A 20-year review of haemangiopericytoma in Auckland, New Zealand.

The records of all patients registered with a histological diagnosis of haemangiopericytoma in Auckland between 1970 and 1990 were reviewed retrospectively, with the aim of determining the natural history of the disease and the response to various treatment modalities. A total of 24 patients were identified, having a median age of 45 years. Twenty-one patients (87.5%) underwent surgery; the remaining three were deemed to be unfit for surgery. Seven patients (29%) were treated with surgery alone; nine (37.5%) received a radical course of radiotherapy and three (12.5%) received palliative radiation therapy for pain relief and/or dyspnoea. Five patients (21%) received chemotherapy during the course of their disease. Eight of the 24 patients (33%) were alive and disease free, 13 (54%) having died and three (13%) being lost to follow-up. Seven patients (29%) died as a result of metastatic disease. Three of the seven (43%) who were treated with surgery alone are known to be alive and disease free. The three patients who had received palliative radiotherapy, died within 2 months of completing the latter treatment. Five of the nine patients (56%) receiving a course of radical radiotherapy are alive and disease free at present. No local recurrence was noted following surgical excision and postoperative radical radiotherapy, whilst eight (67%) of those initially treated by excision alone developed recurrent disease. None of the patients treated with chemotherapy obtained significant palliation. Results suggest that adequate surgical excision followed by postoperative radiotherapy is effective in controlling haemangiopericytoma and that metastatic disease is at present invariably fatal. The role of chemotherapy needs further investigation.

The value of routine computed tomography scanning of the chest in patients presenting with supradiaphragmatic Hodgkin's disease.

Six patients presenting with supradiaphragmatic Hodgkin's disease are presented to demonstrate the potential benefits of chest computed tomography (CT) scanning as a routine staging procedure. These cases show that CT scanning can detect mediastinal and lung involvement not readily detected by other investigations, and that such findings can influence the radiotherapy plan, the need for extended radiotherapy fields or the use of chemotherapy. Following treatment, CT scanning can be useful to assess treatment response and may permit earlier detection of relapse. The use of chest CT scanning as a routine staging procedure in all patients with supradiaphragmatic Hodgkin's disease is advocated.

Malignant lympho-epithelial lesion of the salivary gland: a case report and review of the literature.

Malignant lympho-epithelial lesion of the salivary gland is an undifferentiated squamous cell carcinoma which is associated with a prominent lymphocyte-rich stroma. This study reviews the current literature pertaining to this rare tumour with reference to the single recorded case of malignant lympho-epithelial lesion of the salivary gland presenting in Auckland, New Zealand. This 26 year old Caucasian male developed a rapidly growing lesion in the right parotid gland and multiple ipsilateral cervical lymph nodes. Treatment consisted of surgery and radiotherapy. The patients is currently disease free. One hundred and eight other cases have been reported in the literature, 82 of whom have Mongolian ancestry (Eskimos and southern Chinese) and 15 of whom are Caucasian. More than 50% of these patients (all Mongolian) have elevated titres of serum immunoglobulin A against Epstein-Barr virus capsid antigen. The age at presentation is variable, ranging from 10 to 86 years, with a slight female predominance. Forty-one per cent of patients present with regional lymph node metastases and 20% with distant metastases. Given the rarity of this disease, treatment is controversial. Current data suggest that early radical combined modality treatment using surgery and radiotherapy leads to prolonged survival and cure with 5 year survival rates greater than 50%.

Bone involvement in Hodgkin's disease.

Bone involvement in Hodgkin's disease is uncommon and seldom encountered at initial diagnosis. Seven cases with osseous involvement were identified from a series of 147 patients with Hodgkin's disease treated at Auckland Hospital from 1980 to 1988. Only one patient was found to have bone lesions at the time of initial presentation. Two patients had multiple lesions and 5 had a solitary lesion. Sites of involvement included the spine, pelvis, femur, humerus, ribs, sternum, scapula and base of skull. Six patients had nodular sclerosing histology and one had mixed cellularity disease. All 7 patients were treated with systemic chemotherapy for their advanced disease, and 5 patients needed local radiotherapy to sites of bone involvement. The radiation dosage schedules were individualized, ranging from 30 Gy to 40 Gy, using either a 6 MeV linear accelerator or cobalt machine. At the time of analysis of this study, 4 patients were in complete remission, 2 patients completed chemotherapy with good response and only 1 patient died of disseminated disease. The current review has demonstrated an encouraging response to treatment and good long term control. We believe that combined-modality therapy is effective in the treatment of osseous involvement in Hodgkin's disease.

Incidence of 'unsuspected' extranodal head and neck lymphoma.

A series of 100 consecutive patients presenting with non-Hodgkin's lymphoma in the head and neck region was reviewed. An examination of the contribution made to the staging classification by an otolaryngological examination showed that one-third of patients presenting with cervical nodes had unsuspected extranodal disease in Waldeyer's ring. Overall 14% of patients undergoing an otolaryngological examination had their disease upstaged because of that examination.

The management of metastases to eye and orbit from carcinoma of the breast.

This report describes 11 patients who developed visual symptoms due to choroidal or orbital metastases from carcinoma of the breast. All patients were treated using palliative radiotherapy with regression of metastases in five of six patients (83%) having choroidal involvement and three of five patients (60%) having orbital metastases. There were no complications due to radiotherapy. All these patients had advanced metastatic breast cancer with poor survival following development of orbital or choroidal metastases.

Kaposi's sarcoma in AIDS: the role of radiation therapy.

Radiotherapy can provide good palliation for AIDS patients with symptomatic Kaposi's sarcoma. We have retrospectively reviewed the treatment of 13 lesions in 5 patients. All treated tumours demonstrated significant regression with moderate doses of radiation. Side effects were acceptable and treatment provided good pain relief, functional improvement, and restoration of cosmesis. Our experience confirms that radiotherapy has a meaningful role in the management of AIDS-related Kaposi's sarcoma.

Eosinophilic granuloma of mandible in an adult (a case report).

A case of mono-ostotic eosinophilic granuloma localised to the mandible of an adult patient is described. The role of low dose radiation therapy as a curative modality is discussed.

A case report of central nervous system lymphoma following immunosuppression.

Lymphoma is a well recognised complication of immunosuppression. A case is presented of a patient who developed CNS lymphoma thirty-three months after renal transplantation. The incidence and characteristics of lymphoma developing post-transplantation and the treatment of central nervous system (CNS) lymphomas are discussed.

Primary non-Hodgkins lymphoma of bone (case report).

Early stage primary bone lymphoma may be cured by irradiation alone with few complications using moderate doses of radiation. Some points regarding the presentation and radiological features of the disease are highlighted.