Emerging therapies for the treatment of relapsed or refractory diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (dlbcl) is an aggressive non-Hodgkin lymphoma, accounting for approximately 30% of lymphoma cases in Canada. Although most patients will achieve a cure, up to 40% will experience refractory disease after initial treatment, or relapse after a period of remission. In eligible patients, salvage therapy followed by high-dose therapy and autologous stem-cell transplantation (asct) is the standard of care. However, many patients are transplant-ineligible, and more than half of those undergoing asct will subsequently relapse. For those patients, outcomes are dismal, and novel treatment approaches are a critical unmet need. In this paper, we present available data about emerging treatment approaches in the latter setting and provide a perspective about the potential use of those approaches in Canada.

A network approach to developing immuno-oncology combinations in Canada.

Immune checkpoint inhibitors have revolutionized care for many cancer indications, with considerable effort now being focused on increasing the rate, depth, and duration of patient response. One strategy is to combine immune strategies (for example, ctla-4 and PD-1/L1-directed agents) to harness additive or synergistic efficacy while minimizing toxicity. Despite encouraging results with such combinations in multiple tumour types, numerous clinical challenges remain, including a lack of biomarkers that reliably predict outcome, the emergence of therapeutic resistance, and optimal management of immune-related toxicities. Furthermore, the selection of ideal combinations from the myriad of immune, systemic, and locoregional therapies has yet to be determined. A longitudinal network-based approach could offer advantages in addressing those critical questions, including long-term follow-up of patients beyond individual trials. The molecular cancer registry Personalize My Treatment, managed by the Networks of Centres of Excellence nonprofit organization Exactis Innovation, is uniquely positioned to accelerate Canadian immuno-oncology (io) research efforts throughout its national network of cancer sites. To gain deeper insight into how a pan-Canadian network could advance research in io combinations, Exactis invited preeminent clinical and scientific advisors from across Canada to a roundtable event in November 2017. The present white paper captures the expert advice provided: leverage longitudinal patient data collection; facilitate network collaboration and assay harmonization; synergize with existing initiatives, networks, and biobanks; and develop an io combination trial based on Canadian discoveries.

Canadian perspectives: update on inhibition of ALK-positive tumours in advanced non-small-cell lung cancer.

Background: Inhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK-positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update. Methods: Clinical trials of alk inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK-positive nsclc. Results: Randomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naïve patients and as second-line therapy after crizotinib. Phase ii trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows:■ Patients with advanced nonsquamous nsclc have to be tested for the presence of an ALK rearrangement.■ Treatment-naïve patients with ALK-positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially.■ Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially.■ Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially.■ Patients progressing on alk tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy.■ Other systemic therapies should be exhausted before immunotherapy is considered. Summary: Multiple lines of alk inhibition are now recommended for patients with advanced nsclc with an ALK rearrangement.

Management of EGFR-mutated non-small-cell lung cancer: practical implications from a clinical and pathology perspective.

Starting in the early 2000s, non-small-cell lung cancer (nsclc) subtypes have evolved from being histologically described to molecularly defined. Management of lung adenocarcinomas now generally requires multiple molecular tests at baseline to define the optimal treatment strategy. More recently, second biopsies performed at progression in patients treated with tyrosine kinase inhibitors (tkis) have further defined the continued use of molecularly targeted therapy. In the present article, we focus on one molecular subtype: EGFR-mutated nsclc. For that patient population, multiple lines of tki therapy are now available either clinically or in clinical trials. Each line of treatment is guided by the specific mutations (for example, L858R, T790M, C797S) identified in EGFR. We first describe the various mechanisms of acquired resistance to EGFR tki treatment. We then focus on strategies that clinicians and pathologists can both use during tissue acquisition and handling to optimize patient results. We also discuss future directions for the molecular characterization of lung cancers with driver mutations, including liquid biopsies. Finally, we provide an algorithm to guide treating physicians managing patients with EGFR-mutated nsclc. The same framework can also be applied to other molecularly defined nsclc subgroups as resistance patterns are elucidated and additional lines of treatment are developed.

Neurointerventional management of carotid webs associated with recurrent and acute cerebral ischemic syndromes.

BACKGROUND: A carotid web can be defined as an endoluminal shelf-like projection often noted at the origin of the internal carotid artery (ICA) just beyond the bifurcation. Diagnosis of a carotid web as an underlying cause of recurrent ischemic stroke is infrequent and easily misdiagnosed as an atheromatous plaque. Surgery has traditionally been used to resect symptomatic lesions while there is no enough evidence supporting medical therapy as the sole management. To our knowledge there is only one report about carotid artery stenting (CAS) as a definite management of carotid web and no previous reports of acute large-vessel occlusions undergoing mechanical thrombectomy in the setting of carotid web as the etiology. CASE REPORT: We report two cases: The first presented with recurrent ischemic stroke in the same arterial territory and the other with an emergent left middle cerebral artery (MCA) occlusion that underwent endovascular mechanical thrombectomy in which initial computed tomographic angiograms (CTA) suggested carotid web etiologies. Following confirmation with digital subtraction angiography (DSA), both patients ultimately underwent endovascular carotid stenting instead of surgical resection for definitive carotid web treatment. CONCLUSIONS: Carotid webs are a rare cause of ischemic stroke in young and middle-aged adults that can readily be identified by CTA. Endovascular management may include emergent mechanical thrombectomy for large-vessel thromboembolic complications, and for definitive treatment with carotid stenting across the carotid web as an alternative to surgical resection and medical management for secondary stroke prevention.

Management of egfr tki-induced dermatologic adverse events.

Targeting the epidermal growth factor receptor (egfr) pathway has become standard practice for the treatment of advanced non-small-cell lung cancer. Compared with chemotherapy, egfr tyrosine kinase inhibitors (tkis) have been associated with improved efficacy in patients with an EGFR mutation. Together with the increase in efficacy comes an adverse event (ae) profile different from that of chemotherapy. That profile includes three of the most commonly occurring dermatologic aes: acneiform rash, stomatitis, and paronychia. Currently, no randomized clinical trials have evaluated the treatments for the dermatologic aes that patients experience when taking egfr tkis. Based on the expert opinion of the authors, some basic strategies have been developed to manage those key dermatologic aes. Those strategies have the potential to improve patient quality of life and compliance and to prevent inappropriate dose reductions.

Digestion in relation to feeding strategies exhibited by crustacean larvae.

Decapod crustaceans have adopted a full range of reproductive strategies from the release of large numbers of small eggs (Penaeoidea) to the release of relatively low numbers of large advanced larvae (Nephropidae). As larval size determines trophic position in planktonic food webs, all food sources from phyto- to zooplankton are exploited, with many species changing trophic level during ontogenetic development. Comparative studies on digestive enzymes, levels of activity and changes during ontogeny, together with measurements of gastroevacuation rates and food energy values appear to reveal a general pattern. While herbivorous decapod larvae adapt to low food energy values with high enzyme activity levels, rapid food turnover and low assimilation efficiency, carnivorous larvae exhibit low levels of enzyme activity but compensate by extending retention time of high-energy food to maximise assimilation efficiency. New studies on digestive enzyme levels during development in the penaeid Litopenaeus vannamei, the caridean Lysmata debelius and the cirriped Elminius modestus, appear to agree with previous observations.

Ontogeny of hepatocyte growth factor (HGF) and its receptor (c-met) in human placenta: reduced HGF expression in intrauterine growth restriction.

Severe intrauterine growth restriction (IUGR) is characterized by abnormal placentation. Mouse gene knockout studies show that an absence of either hepatocyte growth factor (HGF) or its receptor, c-met, leads to intrauterine death secondary to severe IUGR with deficient placentation. In this study, immunocytochemistry localized HGF protein throughout placental villi across gestation, whereas c-met protein was localized only to the perivillous trophoblast and vascular endothelium. Within the IUGR placentae, a reduction in HGF immunostaining within the villous stroma was observed. HGF mRNA was strongly expressed in the perivascular tissue around the stem villous arteries throughout gestation, with weaker expression within the villous stroma and the terminal villi. c-met mRNA expression was limited to the perivillous trophoblast, particularly in the first trimester, with only a faint hybridization signal from the villous stroma. Placental mRNA expression was examined quantitatively using a ribonuclease protection assay: HGF and c-met mRNA expression increased from the first to the second trimester, reaching a zenith before decreasing again through the third trimester to term. HGF mRNA levels were significantly reduced in the IUGR placentae (P = 0.036), whereas c-met mRNA expression was within the normal range for gestation. These findings suggest that HGF derived from the perivascular tissue of stem villous arteries may play an important role in controlling normal villous development. Whereas reduced expression of HGF within IUGR placentae does not prove a causative link with abnormal villous development, the association lends support to this possibility.

Localization, quantification, and activation of platelet-activating factor receptor in human endometrium during the menstrual cycle: PAF stimulates NO, VEGF, and FAKpp125.

Implantation is characterized by an inflammatory-like response with expansion of extracellular fluid volume, increased vascular permeability, and vasodilatation. These effects are believed to be mediated at the paracrine level by prostaglandin E2 and platelet-activating factor (PAF), but the cellular mechanism (or mechanisms) remains largely unknown. We demonstrate that PAF receptor (PAF-R) immunoreactivity and mRNA are detected in proliferative and secretory endometrial glands, however, the responsiveness of endometrium to physiological concentrations of PAF is confined predominantly to the secretory endometrium. Semiquantitative reverse transcription-polymerase chain reaction revealed that PAF-R transcript levels were highest in the mid-late proliferative and late secretory phases of the cycle. Interaction of PAF with its receptor resulted in the rapid release of nitric oxide (NO), increased expression of vascular endothelial growth factor (VEGF), and activation of FAKpp125, a focal adhesion kinase, demonstrating that the PAF-R is functionally active. Inhibition of NO synthesis by NG-monomethyl-L-arginine produced dose-dependent attenuation of PAF-evoked NO release, indicating NOS activation; the dependency of PAF-evoked NO release on PKC and extracellular Ca2+ was confirmed by PKC inhibitor Ro 31-8220 and by the removal of extracellular Ca2+. PAF up-regulated VEGF gene expression in a concentration- and time-dependent fashion in human endometrial epithelial cell lysates. Transcription of VEGF was rapidly followed by secretion of the protein. These data support our premise that this autocoid acts as an angiogenic mediator in the regeneration of the endometrium after menses and as a vasodilator to promote blastocyst attachment during the implantation process.

Fibroblast growth factor receptor-1 is a critical component for endometrial remodeling: localization and expression of basic fibroblast growth factor and FGF-R1 in human endometrium during the menstrual cycle and decreased FGF-R1 expression in menorrhagia.

Angiogenic growth factors play a critical role in the cyclic growth and vascularization of normal endometrium. Herein, we report the expression and localization of both basic fibroblast growth factor (FGF-2) and its receptor (FGF-R1; flg) in human endometrium and demonstrate the markedly decreased FGF-R1 levels in menorrhagia. In situ hybridization using [35S]-labeled riboprobe demonstrated distinct autoradiographic signals for FGF-2 mRNA in glandular epithelial and stromal cells in endometrium throughout the menstrual cycle, with the strongest hybridization signal in stromal cells of the proliferative endometrium relative to that of the secretory endometrium. Moreover, RNAse protection assay revealed that the mRNA encoding FGF-2 and FGF-R1 was significantly higher in proliferative than in secretory endometrium (p < 0.05, p < 0.01). Immunohistochemistry using anti-flg antibody showed that the intensity of FGF-R1 staining was markedly diminished in the stromal cells of secretory endometrium, which corresponded with the reduced FGF-2 mRNA expression. In contrast, the endometrial glandular epithelial cells showed intense localization of FGF-R1 protein throughout the menstrual cycle, which paralleled FGF-2 mRNA expression. Colocalization of FGF-2 and FGF-R1 in stroma and stimulation of DNA synthesis and phospholipase C activation by FGF-2 in these cells demonstrates that FGF-2 acts in an autocrine manner in endometrial stroma. Western immunoblotting showed that FGF-R1 immunoprotein was markedly reduced or absent in women with menorrhagia throughout the cycle relative to that of normal cycling women, suggesting that FGF-R1 is critical for endometrial "maturation" and regeneration of the normal endometrium following menstruation.

Immunoreactive 15-hydroxyprostaglandin dehydrogenase (PGDH) is reduced in fetal membranes from patients at preterm delivery in the presence of infection.

Previously we reported that the proportion of trophoblast cells that were immunopositive for 15-OH prostaglandin dehydrogenase (PGDH) in the chorionic membranes was reduced in women in preterm labour without infection, compared with women at term, but was not altered in preterm labour patients with an underlying infective process. Subsequently, we found that PGDH activity and PGDH mRNA were significantly lower in membranes of this latter group of patients than in women at preterm labour without infection or at term. To resolve this issue we used immunohistochemistry to examine the distribution and frequency of immunoreactive (ir)-PGDH positive cells in full-thickness fetal membranes in patients at preterm labour in the presence or absence of infection. Trophoblast and decidual stromal cells were identified using antibodies against cytokeratin and vimentin, respectively. There was considerable variation in the number of chorionic trophoblast cells that were positive for ir-PGDH, but in some patients there was little or no ir-PGDH staining, and this was associated with loss of trophoblast cells from the tissue. The mean intensity and number of ir-PGDH positive cells was significantly lower in membranes from patients in preterm labour with infection than in idiopathic preterm labour at which the diagnosis of infection was not made. We conclude that in the setting of preterm labour with infection there may be loss of trophoblast cells from membranes, with corresponding reduction in the number of ir-PGDH positive cells. Loss of PGDH activity removes the initial step in activating primary prostaglandins, which are then able to pass unmetabolized to the decidua and myometrium, and contribute to the stimulus to preterm birth.

Immunoreactive parathyroid hormone-related protein: its association with preterm labor.

OBJECTIVE: Parathyroid hormone-related protein (PTHrP) is a 141 amino acid protein which contains a 1-36 N-terminal domain resembling parathyroid hormone which has smooth muscle relaxant activity and a mid (67-86) domain which reportedly alters placental calcium transport. Using specific antibodies to these regions of PTHrP, the objective of this study was to determine changes in the levels and localization of the peptides in placenta and membranes that might be indicative of their biological activity and role during term and preterm labor. STUDY DESIGN: Placenta and fetal membranes were collected from patients with preterm delivery (PTL) (n = 16), term cesarean section in the absence of labor (n = 10) and term vaginal delivery (n = 5). Immunohistochemistry was performed with specific antisera visualized by the avidin-biotin peroxidase method and the staining intensity was quantified with an image analysis system MCID. RESULTS: Immunoreactive (ir)-PTHrP(1-34) and ir-PTHrP(67-86) were localized to the amnionic epithelium chorionic trophoblasts, decidual cells and placental syncytiotrophoblast. Intense immunostaining was observed for ir-PTHrP(67-86) but not for ir-PTHrP(1-34) in the endothelial lining of the villous capillaries. Ir-PTHrP(1-34) staining was lower in placenta and fetal membranes of PTL patients compared with term cesarean section in the absence of labor (P < 0.05 Mann-Whitney test). In contrast, there was no difference in ir-PTHrP [67-86] staining intensity between delivery categories. CONCLUSION: These results showing differential localization of PTHrP(1-34) and PTHrP(67-86) suggest cell specific processing of PTHrP precursor in the human placenta. Moreover, the changes in ir-PTHrP(1-34) but not ir-PTHr(67-86) with labor are indicative of a particular role for this peptide in the delivery process.

Characterization of the prostanoid receptors mediating constriction and relaxation of human isolated uterine artery.

1. This study was undertaken to characterize pharmacologically the prostanoid receptor subtypes mediating constriction and relaxation of human isolated uterine artery. 2. U-46619 was a potent constrictor agonist on human uterine artery (EC50 [95% CL] = 3.5 [1.8-6.7] nM). Prostaglandin E2 (PGE2), PGF2 alpha, PGD2 and PGI2 only weakly constricted the uterine artery, being at least 100 times less potent than U-46619. The PGE2 and PGI2 constrictor effects may be modified by the potent dilator effects of these compounds. A number of agonists which show selectivity for FP-, DP- and EP-receptors including ICI 81008, BW 245C, sulprostone, rioprostil and butaprost, failed to cause any constriction at concentrations up to 30 microM. 3. Constrictor responses induced by all agonists tested were reduced or abolished by the TP-receptor blocking drugs, GR 32191 and EP 092. pA2 estimates for both antagonists versus U-46619 were 8.50, values which are consistent with their affinities at TP-receptors. 4. In preparations pre-constricted with phenylephrine (1 microM) both PGI2 and PGE2 were potent relaxant agonists. The selective IP-receptor agonists, cicaprost and iloprost, also dilated human uterine artery and were approximately 10 fold more potent than PGI2. The EP2-receptor agonists, butaprost and rioprostil and the selective DP-agonist, BW 245C, were at least 100 fold weaker than PGI2 and PGE2 suggesting that neither DP- nor EP2 receptors were involved. 5. We conclude that TP-receptors mediate constriction, whereas IP- and possibly EP4-receptors mediate relaxation of human uterine artery.

Immunohistochemical localization, messenger ribonucleic acid abundance, and activity of 15-hydroxyprostaglandin dehydrogenase in placenta and fetal membranes during term and preterm labor.

Type 1 15-hydroxyprostaglandin dehydrogenase (PGDH) is the main enzyme responsible for the metabolism of prostaglandin E2 (PGE2) and PGF2 alpha. To examine the possibility that a deficiency of PGDH might contribute to preterm labor, we measured localization of immunoreactive (IR-) PGDH, PGDH mRNA, and PGDH enzyme activity in chorio-decidua, placenta, and amnion in patients after term elective cesarean section (n = 9), after spontaneous vaginal term delivery (n = 10), and at idiopathic preterm labor (PTL) in the absence of infection (< 36 weeks gestation; n = 11). Localization of IR-PGDH was determined in additional specimens of membranes after PTL with infection (n = 13) and without (n = 37). IR-PGDH was localized in syncytiotrophoblast and intermediate trophoblasts in placenta and in the trophoblast layer of extraplacental chorion, but was absent from amnion in all patient groups. In chorion, the number of IR-positive trophoblasts was significantly reduced in the idiopathic PTL group compared to those in the other groups. The relative abundance of PGDH mRNA in the chorio-decidua, but not the placenta, from spontaneous labor and PTL was significantly less than that after cesarean section. PGDH mRNA in chorio-decidua from preterm patients correlated with PGDH enzyme activity. Undetectable or low IR-PGDH in chorionic trophoblasts was also associated with low enzyme activity. These results suggest that there exists a subset of patients that present in PTL because of reduced PGDH expression in chorionic trophoblasts. We suggest that this relative deficiency would allow PGs synthesized in the amnion or chorion to escape metabolism in the chorion and thereby contribute to the stimulus to idiopathic PTL.

Effects of stem cell factor (kit-ligand) and interleukin-3 on the growth and serine proteinase expression of rat bone-marrow-derived or serosal mast cells.

The effects of rat stem-cell factor (SCF) and interleukin-3 (IL-3), alone or in combination, on the in vitro growth and serine proteinase expression of rat serosal/connective-tissue mast cells (CTMC) or bone marrow-derived mast cells (BMMC) were examined. Rat SCF stimulated the growth of both CTMC and BMMC. IL-3 stimulated BMMC growth to a lesser extent than did SCF, whereas CTMC numbers did not increase in IL-3. However, SCF and IL-3 had synergistic effects on the growth of both BMMC and CTMC. SCF favoured the maintenance of rat mast cell proteinase-I (RMCP-I) in CTMC, but did not induce detectable production of RMCP-I in BMMC. In contrast, when IL-3 or lymph node-conditioned medium (LNCM) was added to SCF, a subpopulation of CTMC expressed and stored the soluble proteinase RMCP-II. In BMMC, the RMCP-II content of cells maintained in SCF was significantly less than that of cells maintained in IL-3 or LNCM. RMCP-II also appeared in the supernatants of BMMC, especially when BMMC numbers were increasing rapidly in SCF with or without IL-3 or LNCM. Thus, SCF and IL-3 can regulate the growth of rat BMMC and CTMC, as well as influence their production and release of proteinases.