A Practical Guide for the Systemic Treatment of Biliary Tract Cancer in Canada.

Biliary tract cancers (BTC) are rare and aggressive tumors with poor prognosis. Radical surgery offers the best chance for cure; however, most patients present with unresectable disease, and among those receiving curative-intent surgery, recurrence rates remain high. While other locoregional therapies for unresectable disease may be considered, only select patients may be eligible. Consequently, systemic therapy plays a significant role in the treatment of BTC. In the adjuvant setting, capecitabine is recommended following curative-intent resection. In the neoadjuvant setting, systemic therapy has mostly been explored for downstaging in borderline resectable tumours, although evidence for its routine use is lacking. For advanced unresectable or metastatic disease, gemcitabine-cisplatin plus durvalumab has become the standard of care, while the addition of pembrolizumab to gemcitabine-cisplatin has also recently demonstrated improved survival compared to chemotherapy alone. Following progression on gemcitabine-cisplatin, several chemotherapy combinations and biomarker-driven targeted agents have been explored. However, the optimum regimen remains unclear, and access to targeted agents remains challenging in Canada. Overall, this article serves as a practical guide for the systemic treatment of BTC in Canada, providing valuable insights into the current and future treatment landscape for this challenging disease.

How We Manage Patients with Indolent B-Cell Malignancies on Bruton's Tyrosine Kinase Inhibitors: Practical Considerations for Nurses and Pharmacists.

The most common forms of B-cell malignancy, non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), have seen a drastic shift in the treatment landscape over the last two decades with the introduction of targeted agents. Among them are Bruton's tyrosine kinase (BTK) inhibitors, which have demonstrated excellent efficacy in indolent B-cell NHLs and CLL. Although BTK inhibitors are generally thought to be more tolerable than chemoimmunotherapy, they are associated with a unique safety profile including varying rates of rash, diarrhea, musculoskeletal events, cardiovascular events, and bleeding. Ibrutinib was the first BTK inhibitor to gain a Health Canada indication, followed by second-generation BTK inhibitors acalabrutinib and zanubrutinib, which have better safety profiles compared to ibrutinib, likely due to their improved selectivity for BTK. As BTK inhibitors are oral agents given continuously until disease progression, long-term adverse event (AE) monitoring and management as well as polypharmacy considerations are important for maintaining patient quality of life. This paper intends to serve as a reference for Canadian nurses and pharmacists on dosing, co-administration, and AE management strategies when caring for patients with indolent B-cell NHL or CLL being treated with BTK inhibitors.

Management of Marginal Zone Lymphoma: A Canadian Perspective.

Marginal zone lymphomas (MZL) are a rare, heterogenous group of lymphomas, accounting for 5-17% of indolent non-Hodgkin lymphomas in the western world. They can be further divided into three subtypes: extranodal MZL, splenic MZL, and nodal MZL. These subtypes differ in clinical presentation and behavior, which influences how they are managed. There is currently no standard of care for the treatment of MZL, owing to the difficulty in conducting phase 3 randomized trials in MZL, and the fact that there are limited data on the efficacy of therapy in individual subtypes. Treatment practices are thus largely borrowed from other indolent lymphomas and are based on patient and disease characteristics, as well as access to therapy. This review summarizes the Canadian treatment landscape for MZL and how these therapies may be sequenced in practice.

Emerging Systemic Therapies in Advanced Unresectable Biliary Tract Cancer: Review and Canadian Perspective.

Biliary tract cancer (BTC) is a group of rare and aggressive malignancies with a dismal prognosis. There is currently a significant lack in effective treatment options for BTC, with gemcitabine-cisplatin remaining the first-line standard of care treatment for over a decade. A wave of investigational therapies, including new chemotherapy combinations, immunotherapy, and biomarker-driven targeted therapy have demonstrated promising results in BTC, and there is hope for many of these therapies to be incorporated into the Canadian treatment landscape in the near future. This review discusses the emerging therapies under investigation for BTC and provides a perspective on how they may fit into Canadian practice, with a focus on the barriers to treatment access.

A Canadian Perspective on the Treatment of Waldenström Macroglobulinemia.

Waldenström macroglobulinemia (WM) is a slowly progressing B-cell non-Hodgkin lymphoma characterized by monoclonal IgM gammopathy in the blood and infiltration of the bone marrow by clonal lymphoplasmacytic cells. As an incurable disease, the goals for therapy for WM are to relieve symptoms, slow disease progression, prevent organ damage, and maintain quality of life. However, given the rarity of WM, clinical trials comparing treatments for WM are limited and there is no definitive standard of care. The selection of first-line WM therapy is thus based on patient factors, disease characteristics, and drug access, with bendamustine-rituximab and Bruton's tyrosine kinase (BTK) inhibitor therapy considered preferred treatments. Other treatments such as proteasome inhibitor- or purine analogue-based therapy, alternative chemoimmunotherapy, and autologous stem cell transplantation are generally reserved for the relapsed setting but may be used in rare circumstances in earlier lines of therapy. This paper summarizes the efficacy and safety of these WM therapies and discusses considerations for treatment from a Canadian perspective.

A Pan-Canadian Consensus Statement on First-Line PARP Inhibitor Maintenance for Advanced, High-Grade Serous and Endometrioid Tubal, Ovarian, and Primary Peritoneal Cancers.

The majority of patients with advanced, high-grade epithelial-tubo ovarian cancer (EOC) respond well to initial treatment with platinum-based chemotherapy; however, up to 80% of patients will experience a recurrence. Poly(ADP-ribose) Polymerase (PARP) inhibitors have been established as a standard of care maintenance therapy to prolong remission and prevent relapse following a response to first-line platinum-chemotherapy. Olaparib and niraparib are the PARP inhibitors currently approved for use in the first-line maintenance setting in Canada. Selection of maintenance therapy requires consideration of patient and tumour factors, presence of germline and somatic mutations, expected drug toxicity profile, and treatment access. This paper discusses the current clinical evidence for first-line PARP inhibitor maintenance therapy in patients with advanced, high-grade EOC and presents consensus statements and a treatment algorithm to aid Canadian oncologists on the selection and use of PARP inhibitors within the Canadian EOC treatment landscape.

A Canadian Perspective on the Challenges for Delivery of Curative-Intent Therapy in Stage III Unresectable Non-Small Cell Lung Cancer.

Stage III non-small cell lung cancer (NSCLC) comprises a highly heterogenous group of patients with regards to patient fitness and tumour size and distribution, resulting in a wide range of treatment goals and therapy options. Curative-intent multimodality treatment should be considered in all patients with stage III NSCLC. For patients with unresectable disease who are fit, have adequate lung function, and have a disease that can be encompassed within a radical radiation volume, concurrent chemoradiation therapy (cCRT) is the standard of care and can produce cure rates of 20-30%. Recently, consolidation immunotherapy with durvalumab has been recognized as the standard of care following cCRT based on significant improvement rates in overall survival at 4 years. The large heterogeneity of the stage III NSCLC population, along with the need for extensive staging procedures, multidisciplinary care, intensive cCRT, and now consolidation therapy makes the delivery of timely and optimal treatment for these patients complex. Several logistical, communication, and education factors hinder the delivery of guideline-recommended care to patients with stage III unresectable NSCLC. This commentary discusses the potential challenges patients may encounter at different points along their care pathway that can interfere with delivery of curative-intent therapy and suggests strategies for improving care delivery.

Lactate Metabolism in Human Lung Tumors.

Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small-cell lung cancers (NSCLCs) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here, we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell-autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo.

Early parent-child relationships and risk of mood disorder in a Canadian sample of offspring of a parent with bipolar disorder: findings from a 16-year prospective cohort study.

AIM: Exposure to parental bipolar disorder (BD) early in life may increase the risk of developing a mood disorder. However, the impact of early parent-child relationships when a parent is affected and how this impacts an offspring's risk remains unclear. The primary objective of this study was to determine the association between parent-child relationships and risk of mood disorder in offspring of parents with BD and, secondly, to determine the interaction of temperament and life stress on this association. METHODS: Two hundred and thirty-three offspring completed annual clinical assessments following Kiddie Schedule for Affective Disorders (KSADS) format interviews as part of an ongoing Canadian prospective cohort study conducted from 1996 to 2013. Offspring completed measures of early adversity, life stress and temperament. Clinical data from the affected parents were prospectively collected over the first decade of their offspring's life using SADS format interviews. RESULTS: Higher perceived neglect from mother and offspring emotionality were significantly associated with the hazard of mood disorder (hazard ratio (HR): 1.1, 95% confidence interval (CI): 1.0-1.2 and HR: 1.7, 95% CI: 1.0-3.1, respectively). Duration of exposure to parental BD significantly interacted with offspring emotionality to predict mood disorder (P = 0.01). Further, perceived neglect from mother was associated with offspring high emotionality (P = 0.02). CONCLUSIONS: Neglect from mother is a significant early predictor of mood disorder in offspring at familial risk for BD and may increase emotional sensitivity. Psychosocial support and interventions for high-risk families could be beneficial in reducing early adversity, maternal neglect and the risk of subsequent mood disorders in offspring.

The developmental trajectory of bipolar disorder.

BACKGROUND: Bipolar disorder is highly heritable and therefore longitudinal observation of children of affected parents is important to mapping the early natural history. AIMS: To model the developmental trajectory of bipolar disorder based on the latest findings from an ongoing prospective study of the offspring of parents with well-characterised bipolar disorder. METHOD: A total of 229 offspring from families in which 1 parent had confirmed bipolar disorder and 86 control offspring were prospectively studied for up to 16 years. High-risk offspring were divided into subgroups based on the parental long-term response to lithium. Offspring were clinically assessed and DSM-IV diagnoses determined on masked consensus review using best estimate procedure. Adjusted survival analysis and generalised estimating equations were used to calculate differences in lifetime psychopathology. Multistate models were used to examine the progression through proposed clinical stages. RESULTS: High-risk offspring had an increased lifetime risk of a broad spectrum of disorders including bipolar disorder (hazard ratio (HR) = 20.89; P = 0.04), major depressive disorder (HR = 17.16; P = 0.004), anxiety (HR = 2.20; P = 0.03), sleep (HR = 28.21; P = 0.02) and substance use disorders (HR = 2.60; P = 0.05) compared with controls. However, only offspring from lithium non-responsive parents developed psychotic disorders. Childhood anxiety disorder predicted an increased risk of major mood disorder and evidence supported a progressive transition through clinical stages, from non-specific psychopathology to depressive and then manic or psychotic episodes. CONCLUSIONS: Findings underscore the importance of a developmental approach in conjunction with an appreciation of familial risk to facilitate earlier accurate diagnosis in symptomatic youth.

Immunological and neurotrophic markers of risk status and illness development in high-risk youth: understanding the neurobiological underpinnings of bipolar disorder.

Bipolar disorder is a highly heritable illness that onsets in adolescence and young adulthood. We examined gene expression (mRNA) and protein levels of candidate immune and neurotrophic markers in well-characterized offspring of bipolar parents in order to identify reliable indicators of illness risk status and the early clinical stages of illness development. We measured mRNA expression and protein levels in candidate immune (TNF-α, IL-1ß, IL-10, IFN-δ) and neurotrophic (brain-derived neurotrophic factor (BDNF)) markers from plasma. High-risk offspring were identified from families in which one parent had confirmed bipolar disorder. Control offspring were identified from families in which neither parent met lifetime criteria for a major psychiatric disorder. All parental Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnoses were based on Schedule for Affective Disorders - Lifetime Version (SADS-L) interviews and blind consensus review. As part of an ongoing study, all offspring were prospectively assessed using KSADS-PL format interviews and diagnoses confirmed on blind consensus review. High-risk offspring had significantly increased IL-6 (p = 0.050) and BDNF (p = 0.006) protein levels compared to controls. Those high-risk offspring in earlier compared to later clinical stages of illness development had higher IL-6 (p = 0.050) and BDNF (p = 0.045) protein levels. After adjustments, only differences in BDNF protein levels remained significant. There was a moderating effect of the BDNF genotype on both gene expression and protein levels in high-risk compared to control offspring. The BDNF genotype also moderated the association between clinical stage and gene expression levels in high-risk offspring. These findings provide support for detectable differences in candidate immune and neurotrophic markers in individuals at high risk of developing bipolar disorder and for detectable changes over the clinical stages of illness development. These associations appear to be moderated by genetic variants.

Childhood anxiety: an early predictor of mood disorders in offspring of bipolar parents.

BACKGROUND: Anxiety disorders are common among the offspring of parents with bipolar disorder (BD). This study investigated the nature of the association between anxiety disorders and mood disorders in a prospectively studied high-risk cohort. METHODS: High-risk offspring were identified from families in which one parent had confirmed BD based on SADS-L interviews and best estimate diagnostic procedures. All agreeable offspring aged 8-25 years were enrolled in a longitudinal study involving repeated KSADS-PL format clinical assessments. Control (C) offspring from families in which neither parent met lifetime criteria for a psychiatric disorder were similarly assessed. All DSM-IV diagnoses in the offspring were confirmed on blind consensus review. Cumulative incidence and adjusted Cox Proportional Hazards models were used to calculate the risk of anxiety disorders and the predictive association with mood disorders. RESULTS: The cumulative incidence of anxiety disorders was higher (23.40% vs. 10.42%; HR=2.136; p=.0382) and occurred earlier (9.79 vs. 14.84 years; p=.0125) in high-risk compared to C offspring. In high-risk offspring generalized anxiety disorders (GAD) followed by social phobia were the most incident anxiety subtypes; while high emotionality (HR 1.111; p=.0096) and shyness (HR 1.144; p=.0053) increased the risk of anxiety disorders. Anxiety disorders increased the adjusted risk of mood disorders (HR 2.166; p=.0004), on average 8.49 years later (SD 5.97). LIMITATIONS: The cumulative incidence of BD is relatively low, as the cohort is still in the period of risk. CONCLUSIONS: Findings highlight the need for longitudinal surveillance of symptomatic high-risk children and suggest anxiety disorders are an important early intervention target.

Bipolar disorder and socioeconomic status: what is the nature of this relationship?

BACKGROUND: In psychiatric literature stretching over a century, there have been glaring discrepancies in the findings describing the relationship between bipolar disorder (BD) and socioeconomic status (SES). Early studies indicated an overall association between manic-depressive illness and higher social class. However, recent epidemiologic studies have failed to find an association between BD and SES. Instead, they report a similar distribution of BD among social classes and educational levels, and in one particular study, a lower family income was reported. The determinants of SES are complex, and the early findings are now interpreted as having been incorrect and stemming from past methodological weaknesses. METHODS: For this analysis we explored the relationship between SES and BD in a sample of patients who had participated in prior clinical and therapeutic studies. These patients met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for BD, required long-term stabilizing treatment, and were assessed in terms of their response to lithium stabilization and a number of other clinical characteristics in accordance with research protocol. Good response to lithium stabilization (LiR) served as a proxy for identifying a subtype of manic-depressive illness, the classical form of BD. Non-responders to stabilizing lithium (LiNR) were considered belonging to other subtypes of bipolar spectrum disorder. The SES of the parents was measured upon entry into treatment using the Hollingshead SES scale, which despite its limitations has been used in psychiatry most widely to determine SES. The groups of LiR and LiNR were compared statistically in terms of SES. The influence of bipolar subtype and gender on SES was investigated. RESULTS AND DISCUSSION: A significantly higher SES was associated with the lithium-responsive form (LiR) of BD when compared with patients continuing to relapse despite adequate lithium treatment (representing other types of bipolar spectrum). Our observation suggests that the discrepant literature findings about SES and BD may be better explained by the change in diagnostic practices: early studies describing a positive relationship included mostly classical manic-depressive disorder, while the patients in recent studies have been diagnosed according to much broader criteria, reflecting the era of bipolar spectrum disorder.

Biological indicators of suicide risk in youth with mood disorders: what do we know so far?

Suicidal behaviour in youth is a major public health concern worldwide, and youth in the early stages of a primary mood disorder are an identifiable high-risk population. Neurobiological research in youth at risk for suicidality has sought to investigate the most promising parameters from research in adults. The present paper provides an overview of the current findings of neurobiological research in children and adolescents with mood disorders and suicidality including genetic/epigenetic findings, neuro-hormonal and immunological investigations. Longitudinal research in high-risk youth is a powerful way to investigate the influences and their pathways in determining suicidal risk in the context of a developing mood disorder. In the meantime, there are clear clinical indicators of risk to help identify youth who would benefit from close surveillance and early intervention.

Adolescent substance use disorder during the early stages of bipolar disorder: a prospective high-risk study.

BACKGROUND: There is a paucity of longitudinal data characterizing the relationship between substance use disorder (SUD) and the early clinical course of bipolar disorder (BD). We studied this relationship in a prospectively assessed cohort of high-risk offspring. METHODS: Eligible families had one parent with confirmed BD based on SADS-L interviews and best estimate diagnostic procedure. Offspring completed KSADS-PL interviews at baseline and were reassessed prospectively. DSM-IV diagnoses were made on blind consensus review using all available information. This analysis included 211 offspring ≥12 years, and used GEE and linear mixed models to determine clinical characteristics differentiating those with compared to those without SUD, and CPH models to assess the relationship between SUD and the early stages of BD. RESULTS: Lifetime SUD was diagnosed in 24% of offspring; cannabis use being most common. The peak hazard of SUD was between 14 and 20 years of age. Male sex (HR 3.285; p=.0007), a prior mood disorder (HR 2.437; p=.0091) and parental history of SUD (HR 2.999; p=.0027) contributed to the risk of SUD in the offspring, while SUD predicted an increased risk of psychosis (HR 3.225; p=.0074). The estimated hazard of a major mood disorder in those offspring with compared to those without a prior SUD was almost 3-fold (HR 2.990 (p≤0.01). LIMITATIONS: The novel clinical staging model requires independent replication. CONCLUSIONS: SUD is a common comorbidity arising during the early course of BD, even before the first activated episode. Further research is needed to understand causative factors and to develop effective early intervention and prevention strategies.

Biological indicators of illness risk in offspring of bipolar parents: targeting the hypothalamic-pituitary-adrenal axis and immune system.

AIM: The study aims to provide a selective review of the literature pertaining to the hypothalamic-pituitary-adrenal (HPA) axis and immune abnormalities as informative biological indicators of vulnerability in bipolar disorder (BD). METHOD: We summarize key findings relating to HPA axis and immunological abnormalities in bipolar patients and their high-risk offspring. Findings derive from a review of selected original papers published in the literature, and supplemented by papers identified through bibliography review. Neurobiological findings are discussed in the context of emergent BD in those at genetic risk and synthesized into a neurodevelopmental model of illness onset and progression. RESULTS: BD is associated with a number of genetic and possibly epigenetic abnormalities associated with neurotransmitter, hormonal and immunologically mediated neurobiological pathways. Data from clinical and high-risk studies implicate HPA axis and immune system abnormalities, which may represent inherited vulnerabilities important for the transition to illness onset. Post-mortem and clinical studies implicate intracellular signal transduction processes and disturbance in energy metabolism associated with established BD. Specifically, long-standing maladaptive alterations such as changes in neuronal systems may be mediated through changes in intracellular signalling pathways, oxidative stress, cellular energy metabolism and apoptosis associated with substantial burden of illness. CONCLUSIONS: Prospective longitudinal studies of endophenotypes and biomarkers such as HPA axis and immune abnormalities in high-risk offspring will be helpful to understand genetically mediated biological pathways associated with illness onset and progression. A clinical staging model describing emergent illness in those at genetic risk should facilitate this line of investigation.

Cingulate cortex aplasia and callosal dysgenesia combined with schizencephaly in a patient with chronic lying.

We report on a 19-year-old patient with a 4-year history of lying and cheating who presented neuropsychological abnormalities regarding attention deficits, hyperactivity and impulsivity. Cerebral magnetic resonance imaging scans revealed schizencephaly of the right central region, dysgenesia of the corpus callosum, a noneverted gyrus cinguli and hypoplasia of the left cerebellar hemisphere. Although the patient did not fulfill the diagnostic criteria for attention-deficit/hyperactivity disorder, we suggest that the patient's behavioral alteration could be related to the neuroanatomical alterations, especially the aplasia of the gyrus cinguli.

Findings from bipolar offspring studies: methodology matters.

AIM: High-risk studies provide the opportunity to describe the early natural history of bipolar disorder (BD); however, findings have varied substantially. In this review, we compare different methods of ascertainment and assessment, and their impact on study findings. METHODS: Through a literature search, we identified 11 high-risk studies meeting inclusion criteria for this review. Studies included were those that focused on lifetime psychopathology in the offspring as the main outcome and provided adequate information on the methods of family ascertainment, as well as on parent and offspring assessment. We compared and contrasted psychopathological outcomes in the offspring among the studies using different methods. RESULTS: High-risk studies that identified affected parents through their involvement in neurobiological research and confirmed diagnosis in the parent and offspring through best estimate procedures tended to report lower rates of co-morbidity in the proband parent, lower rates of psychopathology in the non-proband parent, lower rates of attention deficit hyperactivity disorder and externalizing disorders, and older ages of onset of major mood disorders in the offspring compared with studies that identified affected parents through self-referral and confirmed diagnosis in the parent and offspring through structured research interviews. Studies that identified severely ill parents and used semi-structured assessments tended to have an intermediate position in terms of outcomes. CONCLUSIONS: This review indicates that different methods of family ascertainment and of assessment of parent and offspring impact the findings pertaining to lifetime psychopathology and clinical course of BD in high-risk studies. The implications of this finding for mapping the natural history of BD are discussed.

Protection of rabbits against cutaneous papillomavirus infection using recombinant tobacco mosaic virus containing L2 capsid epitopes.

Cottontail rabbit papillomavirus (CRPV) and rabbit oral papillomavirus (ROPV) represent distantly related, cutaneous and mucosal tissue tropic papillomaviruses respectively that can infect the same host. These two viruses were used to test the effectiveness of an L2 peptide-based vaccine (aa 94-122) that was delivered on the surface of recombinant tobacco mosaic virus (rTMV) particles. Groups of NZW rabbits received combinations of CRPVL2, ROPVL2 and CRPV+ROPVL2 rTMV vaccines, and were then challenged with infectious CRPV and ROPV. The rabbits developed antibodies that reacted to whole L2 protein and these sera were able to neutralize CRPV pseudovirions at half-maximal titers that were between 50 and 500. Rabbits receiving the CRPV L2 vaccine alone or in combination with ROPV L2 vaccines were completely protected against CRPV infections. Those rabbits vaccinated with the ROPV L2 vaccines showed a weak response in some rabbits against CRPV infection. These studies demonstrate that L2-based vaccines provide strong protection against experimental papillomavirus infection that is most likely based upon the induction of virus-neutralizing antibody. Notably, we observed some limited cross-protection induced by the L2 sequences tested in these vaccines. Finally, the study demonstrated that rTMV were excellent agents for the induction of strong protection in a pre-clinical disease model of papillomavirus infection.