Measuring the impact of COVID-19 on cancer survival using an interrupted time series analysis.

BACKGROUND: Few studies have investigated the impact of the COVID-19 pandemic on cancer survival. Those studies that have included pandemic vs prepandemic comparisons can mask differences during different periods of the pandemic such as COVID-19 waves. The objective of this study was to investigate the impact of the COVID-19 pandemic on cancer survival using an interrupted time series analysis and to identify time points during the pandemic when observed survival deviated from expected survival. METHODS: A retrospective population-based cohort study that included individuals diagnosed with cancer between January 2015 and September 2021 from Manitoba, Canada, was performed. Interrupted time series analyses with Royston-Parmar models as well as Kaplan-Meier survival estimates and delta restricted mean survival times at 1 year were used to compare survival rates for those diagnosed before and after the pandemic. Analyses were performed for 11 cancer types. RESULTS: Survival at 1 year for most cancer types was not statistically different during the pandemic compared with prepandemic except for individuals aged 50-74 years who were diagnosed with lung cancer from April to June 2021 (delta restricted mean survival times = -31.6 days, 95% confidence interval [CI] = -58.3 to -7.2 days). CONCLUSIONS: With the exception of individuals diagnosed with lung cancer, the COVID-19 pandemic did not impact overall 1-year survival in Manitoba. Additional research is needed to examine the impact of the pandemic on long-term cancer survival.

Cancer incidence during the COVID-19 pandemic by region of residence in Manitoba, Canada: A cancer registry-based interrupted time series study.

INTRODUCTION: Health care in Manitoba, Canada is divided into five regions, each with unique geographies, demographics, health care access, and health status. COVID-19-related restrictions and subsequent responses also differed by region. To understand the impact of the pandemic on cancer incidence in the context of these differences, we examined age-standardized cancer incidence rates by region over time before and after the COVID-19 pandemic. METHODS: We used a population-based quasi-experimental study design, population-based data, and an interrupted time series analysis to examine the rate of new cancer diagnoses before (January 2015 until December 2019) and after the start of COVID-19 and the interventions implemented to mitigate its impact (April 2020 until December 2021) by region. RESULTS: Overall cancer incidence differed by region and remained lower than expected in Winnipeg (4.6% deficit, 447 cases), Prairie Mountain (6.9% deficit, 125 cases), and Southern (13.0% deficit, 238 cases). Southern was the only region that had a significantly higher deficit in cases compared to Manitoba (ratio 0.92, 95% CI 0.86, 0.99). Breast and colorectal cancer incidence decreased at the start of the pandemic in all regions except Northern. Lung cancer incidence decreased in the Interlake-Eastern region and increased in the Northern region. Prostate cancer incidence increased in Interlake-Eastern. CONCLUSIONS: The impact of the COVID-19 pandemic on cancer incidence differed by region. The deficit in the number of cases was largest in the southern region and was highest for breast and prostate cancers. Cancer incidence did not significantly decrease in the most northern, remote region.

New Cancer Diagnoses Before and During the COVID-19 Pandemic.

Importance: Disruptions to health care during the COVID-19 pandemic may have led to missed cancer diagnoses. It is critical to evaluate the association between the COVID-19 pandemic and cancer incidence to address public and patient anxiety, inform recovery efforts, and identify strategies to reduce the system's vulnerability to future disruptions. Objective: To examine the association between the COVID-19 pandemic and cancer incidence in Manitoba, Canada. Design, Setting, and Participants: A population-based cross-sectional study design was conducted using data from the Manitoba Cancer Registry and an interrupted time-series analysis. All individuals diagnosed with cancer in Manitoba, Canada, from January 1, 2015, until December 31, 2021, were included. Individuals diagnosed with breast, colon, rectal, or lung cancer were grouped by age as follows: younger than 50 years, 50 to 74 years, and 75 years and older. Exposures: COVID-19 pandemic. Main Outcomes and Measures: Age-standardized cancer incidence rates and the estimated cumulative difference between the number of cases in the absence of COVID-19 and observed (fitted) number of cancer cases. Results: A total of 48 378 individuals were included. The median (IQR) age at diagnosis was 68 (59-77) years and 23 972 participants (49.6%) were female. In April 2020, there was a 23% decrease in overall cancer incidence. Cancer incidence decreased by 46% for breast, 35% for colon, 47% for rectal, 50% for head and neck, 65% for melanoma, and 33% for endocrine cancer diagnoses and increased by 12% for hematological cancer diagnoses and 8% for diagnoses of cancers with an unknown primary site. Lung cancer incidence remained stable until December 2020 when it decreased by 11%. Brain and central nervous system and urinary cancer diagnoses decreased consistently over time from April 2020 to December 2021 by 26% and 12%, respectively. No association was observed with gynecologic (1% increase), other digestive (1% decrease), or pancreatic (7% increase) cancer incidence. As of December 2021, Manitoba had an estimated deficit of 692 (5.3%) cancers. The largest estimated deficits were for breast (273 cases, 14.1% deficit), colon (133 cases, 12.2% deficit), and lung cancers (132 cases, 7.6% deficit). Conclusions and Relevance: In this study, the COVID-19 pandemic was associated with an initial decrease in cancer diagnosis incidence followed by a recovery for most cancer sites. However, the cumulative deficit for some cancers with high fatality needs immediate attention.

Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)-A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA.

Spermidine/spermine N1-acetyltransferase 1 (SAT1) responsible for cell polyamine catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor survival and promoting resistance towards radiation therapy has made it an interesting target for therapy. In this study, we prepared a lipid nanoparticle-based siRNA delivery system (LNP-siSAT1) to selectively knockdown (KD) SAT1 enzyme in a human glioblastoma cell line. The LNP-siSAT1 containing ionizable DODAP lipid was prepared following a microfluidics mixing method and the resulting nanoparticles had a hydrodynamic size of around 80 nm and a neutral surface charge. The LNP-siSAT1 effectively knocked down the SAT1 expression in U251, LN229, and 42MGBA GB cells, and other brain-relevant endothelial (hCMEC/D3), astrocyte (HA) and macrophage (ANA-1) cells at the mRNA and protein levels. SAT1 KD in U251 cells resulted in a 40% loss in cell viability. Furthermore, SAT1 KD in U251, LN229 and 42MGBA cells sensitized them towards radiation and chemotherapy treatments. In contrast, despite similar SAT1 KD in other brain-relevant cells no significant effect on cytotoxic response, either alone or in combination, was observed. A major roadblock for brain therapeutics is their ability to cross the highly restrictive blood-brain barrier (BBB) presented by the brain microcapillary endothelial cells. Here, we used the BBB circumventing approach to enhance the delivery of LNP-siSAT1 across a BBB cell culture model. A cadherin binding peptide (ADTC5) was used to transiently open the BBB tight junctions to promote paracellular diffusion of LNP-siSAT1. These results suggest LNP-siSAT1 may provide a safe and effective method for reducing SAT1 and sensitizing GB cells to radiation and chemotherapeutic agents.

Pretrained Neural Networks Accurately Identify Cancer Recurrence in Medical Record.

Cancer recurrence is the diagnosis of a second clinical episode of cancer after the first was considered cured. Identifying patients who had experienced cancer recurrence is an important task as it can be used to compare treatment effectiveness, measure recurrence-free survival, and plan and prioritize cancer control resources. We developed BERT-based natural language processing (NLP) contextual models for identifying cancer recurrence incidence and the recurrence time based on the records in progress notes. Using two datasets containing breast and colorectal cancer patients, we demonstrated the advantage of the contextual models over the traditional NLP models by overcoming the laborious and often unscalable tasks of composing keywords in a specific disease domain.

Cardiac and cardiometabolic phenotyping of trastuzumab-mediated cardiotoxicity: a secondary analysis of the MANTICORE trial.

AIMS: An improved understanding of the pathophysiology of trastuzumab-mediated cardiotoxicity is required to improve outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to characterize the cardiac and cardiometabolic phenotype of trastuzumab-mediated toxicity and potential interactions with cardiac pharmacotherapy. METHODS AND RESULTS: This study was an analysis of serial magnetic resonance imaging (MRI) and circulating biomarker data acquired from patients with HER2-positive early-stage breast cancer participating in a randomized-controlled clinical trial for the pharmaco-prevention of trastuzumab-associated cardiotoxicity. Circulating biomarkers (B-type natriuretic peptide, troponin I, MMP-2 and -9, GDF-15, neuregulin-1, and IGF-1) and MRI of cardiac structure and function and abdominal fat distribution were acquired prior to trastuzumab, post-cycle 4 and post-cycle 17. Ninety-four participants (51 ± 8 years) completed the study with 30 on placebo, 33 on perindopril, and 31 on bisoprolol. Post-cycle 4, global longitudinal strain deteriorated from baseline in both placebo (+2.0 ± 2.7%, P = 0.002) and perindopril (+0.9 ± 2.5%, P = 0.04), but not with bisoprolol (-0.2 ± 2.1%, P = 0.55). In all groups combined, extracellular volume fraction and GDF-15 increased post-cycle 4 (+1.3 ± 4.4%, P = 0.004; +130 ± 150%, P ≤ 0.001, respectively). However, no significant change in troponin I was detected throughout trastuzumab. In all groups combined, visceral and intermuscular fat volume increased post-cycle 4 (+7 ± 17%, P = 0.02, +8 ± 23%, P = 0.02, respectively), while muscle volume and IGF-1 decreased from post-cycle 4 to 17 (-2 ± 10%, P = 0.008, -18 ± 28%, P < 0.001, respectively). CONCLUSION: Trastuzumab results in impaired cardiac function and early myocardial inflammation. Trastuzumab is also associated with deleterious changes to the cardiometabolic phenotype which may contribute to the increased cardiovascular risk in this population.

Novel CTRP8-RXFP1-JAK3-STAT3 axis promotes Cdc42-dependent actin remodeling for enhanced filopodia formation and motility in human glioblastoma cells.

C1q tumor necrosis factor-related peptide 8 (CTRP8) is the least studied member of the C1Q-TNF-related peptide family. We identified CTRP8 as a ligand of the G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1) in glioblastoma multiforme (GBM). The CTRP8-RXFP1 ligand-receptor system protects human GBM cells against the DNA-alkylating damage-inducing temozolomide (TMZ), the drug of choice for the treatment of patients with GBM. The DNA protective role of CTRP8 was dependent on a functional RXFP1-STAT3 signaling cascade and targeted the monofunctional glycosylase N-methylpurine DNA glycosylase (MPG) for more efficient base excision repair of TMZ-induced DNA-damaged sites. CTRP8 also improved the survival of GBM cells by upregulating anti-apoptotic BCl-2 and BCL-XL. Here, we have identified Janus-activated kinase 3 (JAK3) as a novel member of a novel CTRP8-RXFP1-JAK3-STAT3 signaling cascade that caused an increase in cellular protein content and activity of the small Rho GTPase Cdc42. This is associated with significant F-actin remodeling and increased GBM motility. Cdc42 was critically important for the upregulation of the actin nucleation complex N-Wiskott-Aldrich syndrome protein/Arp3/4 and actin elongation factor profilin-1. The activation of the RXFP1-JAK3-STAT3-Cdc42 axis by both RXFP1 agonists, CTRP8 and relaxin-2, caused extensive filopodia formation. This coincided with enhanced activity of ezrin, a key factor in tethering F-actin to the plasma membrane, and inhibition of the actin filament severing activity of cofilin. The F-actin remodeling and pro-migratory activities promoted by the novel RXFP1-JAK3-STAT3-Cdc42 axis were blocked by JAK3 inhibitor tofacitinib and STAT3 inhibitor STAT3 inhibitor VI. This provides a new rationale for the design of JAK3 and STAT3 inhibitors with better brain permeability for clinical treatment of the pervasive brain invasiveness of GBM.

Slow Off-Rate Modified Aptamer (SOMAmer) Proteomic Analysis of Patient-Derived Malignant Glioma Identifies Distinct Cellular Proteomes.

Malignant gliomas derive from brain glial cells and represent >75% of primary brain tumors. This includes anaplastic astrocytoma (grade III; AS), the most common and fatal glioblastoma multiforme (grade IV; GBM), and oligodendroglioma (ODG). We have generated patient-derived AS, GBM, and ODG cell models to study disease mechanisms and test patient-centered therapeutic strategies. We have used an aptamer-based high-throughput SOMAscan® 1.3K assay to determine the proteomic profiles of 1307 different analytes. SOMAscan® proteomes of AS and GBM self-organized into closely adjacent proteomes which were clearly distinct from ODG proteomes. GBM self-organized into four proteomic clusters of which SOMAscan® cluster 4 proteome predicted a highly inter-connected proteomic network. Several up- and down-regulated proteins relevant to glioma were successfully validated in GBM cell isolates across different SOMAscan® clusters and in corresponding GBM tissues. Slow off-rate modified aptamer proteomics is an attractive analytical tool for rapid proteomic stratification of different malignant gliomas and identified cluster-specific SOMAscan® signatures and functionalities in patient GBM cells.

Evaluating the Impact of the COVID-19 Pandemic on New Cancer Diagnoses and Oncology Care in Manitoba.

Individuals with cancer are vulnerable to infection with SARS-CoV-2, the virus causing COVID-19. Physical distancing, the reallocation of health care resources, and the implementation of procedures to reduce the spread of COVID-19 may also have serious consequences for people with cancer. We evaluated the impact of COVID-19 on new cancer diagnoses and oncology care in Manitoba, Canada using an interrupted time series design and data from the Manitoba Cancer Registry and CancerCare Manitoba's (CCMB) electronic medical record. In April 2020, there was a 23% decrease in new cancer diagnoses, a 21% decrease in pathology reports, and a 43% reduction in surgical resections. There was no difference in new cancer diagnoses by August 2020, surgery by July 2020, and pathology reports by September 2020. From April 2020 to June 2021, there was a 13% decrease in radiotherapy (RT) fractions, an 18% decrease in UCC visits, and a 52% decrease in in-person visits. There was no change in intravenous chemotherapy visits per month, first RT visits, or overall patient visits. The impact of COVID-19 on shifts in the stage at diagnosis and survival will be assessed in future analyses.

Evaluation of algorithms using administrative health and structured electronic medical record data to determine breast and colorectal cancer recurrence in a Canadian province : Using algorithms to determine breast and colorectal cancer recurrence.

BACKGROUND: Algorithms that use administrative health and electronic medical record (EMR) data to determine cancer recurrence have the potential to replace chart reviews. This study evaluated algorithms to determine breast and colorectal cancer recurrence in a Canadian province with a universal health care system. METHODS: Individuals diagnosed with stage I-III breast or colorectal cancer diagnosed from 2004 to 2012 in Manitoba, Canada were included. Pre-specified and conditional inference tree algorithms using administrative health and structured EMR data were developed. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) correct classification, and scaled Brier scores were measured. RESULTS: The weighted pre-specified variable algorithm for the breast cancer validation cohort (N = 1181, 167 recurrences) demonstrated 81.1% sensitivity, 93.2% specificity, 61.4% PPV, 97.4% NPV, 91.8% correct classification, and scaled Brier score of 0.21. The weighted conditional inference tree algorithm demonstrated 68.5% sensitivity, 97.0% specificity, 75.4% PPV, 95.8% NPV, 93.6% correct classification, and scaled Brier score of 0.39. The weighted pre-specified variable algorithm for the colorectal validation cohort (N = 693, 136 recurrences) demonstrated 77.7% sensitivity, 92.8% specificity, 70.7% PPV, 94.9% NPV, 90.1% correct classification, and scaled Brier score of 0.33. The conditional inference tree algorithm demonstrated 62.6% sensitivity, 97.8% specificity, 86.4% PPV, 92.2% NPV, 91.4% correct classification, and scaled Brier score of 0.42. CONCLUSIONS: Algorithms developed in this study using administrative health and structured EMR data to determine breast and colorectal cancer recurrence had moderate sensitivity and PPV, high specificity, NPV, and correct classification, but low accuracy. The accuracy is similar to other algorithms developed to classify recurrence only (i.e., distinguished from second primary) and inferior to algorithms that do not make this distinction. The accuracy of algorithms for determining cancer recurrence only must improve before replacing chart reviews.

Predictors of Urgent Cancer Care Clinic and Emergency Department Visits for Individuals Diagnosed with Cancer.

In 2013, CancerCare Manitoba (CCMB) launched an urgent cancer care clinic (UCC) to meet the needs of individuals diagnosed with cancer experiencing acute complications of cancer or its treatment. This retrospective cohort study compared the characteristics of individuals diagnosed with cancer that visited the UCC to those who visited an emergency department (ED) and determined predictors of use. Multivariable logistic mixed models were run to predict an individual's likelihood of visiting the UCC or an ED. Scaled Brier scores were calculated to determine how greatly each predictor impacted UCC or ED use. We found that UCC visits increased up to 4 months after eligibility to visit and then decreased. ED visits were highest immediately after eligibility and then decreased. The median number of hours between triage and discharge was 2 h for UCC visits and 9 h for ED visits. Chemotherapy had the strongest association with UCC visits, whereas ED visits prior to diagnosis had the strongest association with ED visits. Variables related to socioeconomic status were less strongly associated with UCC or ED visits. Future studies would be beneficial to planning service delivery and improving clinical outcomes and patient satisfaction.

Impact of consultation recordings on patient-reported outcomes in patients with brain tumors: a parallel randomized controlled trial.

OBJECTIVE: We aimed to determine the impact of a primary treatment consultation recording on perception of being informed, satisfaction with cancer care, satisfaction with the oncologist, and psychological distress in patients with brain tumors. METHODS: This was a prospective, double-blind, parallel, randomized controlled trial conducted in 3 Canadian cities, in which patients who had their initial treatment consultation recorded were assigned to either receive their digital recording or not. It was hypothesized that patients who received their recording would realize statistically significant benefit on the outcomes of interest at 1 week, 3 months, and 6 months post-consultation in comparison to patients who did not receive their recording. Outcome measures included the following: Patient Satisfaction with Cancer Scale, Hospital Anxiety and Depression Scale, PrestMan Satisfaction with Doctor Scale, and Perception of Being Informed Scale. RESULTS: Of the 246 eligible patients, 133 participated (60.9% male; age M=52.4 years; 53.4% grade IV disease). Of these, 63 received their consultation recording and 70 did not. Intention-to-treat analysis showed that, compared to baseline, patients who received their consultation recording reported being more fully informed about their disease and treatment at 1 week post-consultation than patients who did not receive their recording (p = 0.007), but this finding was no longer significant at 3 and 6 months. There were no statistically significant differences observed between the two groups on the measures of satisfaction with cancer care, satisfaction with the doctor, and depression or anxiety at any assessment time point, though the study was under-powered. CONCLUSION: The study findings show that primary treatment consultation recordings may provide limited benefit beyond brain tumor patients' perception of being informed, despite being highly valued by these patients, and high listening rates among their significant others. The lack of statistical power should be considered when interpreting the findings. TRIAL REGISTRATION: ClinicalTrials.gov - NCT01866228.

Recurrent melanoma development in a Caucasian female with CDKN2A+ mutation and FAMMM syndrome: A case report.

Melanoma is a form of skin cancer originating from melanocytes that has an increasing incidence over the past few decades. From 1992 to 2010, the overall incidence of melanoma was 12.29 cases per 100,000 person-years in Canada. Approximately 10% of cases are attributed to a hereditary component, with one of the most common being familial atypical multiple mole melanoma syndrome. In this case report, we highlight the atypical case of a middle-aged Caucasian female with familial atypical multiple mole melanoma syndrome, who has developed dozens of primary melanomas over the past decade. We highlight the management of her case, as well as the importance of monitoring by multiple other subspecialists given the propensity for the development of alternate malignancies.

An Exploratory Randomized Trial of Physical Therapy for the Treatment of Chemotherapy-Induced Peripheral Neuropathy.

Background. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxane treatment and cannot currently be prevented or adequately treated. Physical therapy is often used for neural rehabilitation following injury but has not been evaluated in this patient population. Methods. Single-blind, randomized controlled exploratory study compared standard care to a physical therapy home program (4 visits) throughout adjuvant taxane chemotherapy for stage I-III patients with breast cancer (n = 48). Patient questionnaires and quantitative sensory testing evaluated the treatment effect throughout chemotherapy to 6 months post treatment. Nonrandomized subgroup analysis observed effect of general exercise on sensory preservation comparing those reporting moderate exercise throughout chemotherapy to those that did not exercise regularly. Clinical Trial Registration. clinicaltrials.gov (NCT02239601). Results. The treatment group showed strong trends toward less pain (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.17-1.01; P = .053) and pain decreased over time (OR 0.85, 95% CI 0.76-0.94; P = .002). Pain pressure thresholds (P = .034) and grip dynamometry (P < .001) were improved in the treatment group. For the nonrandomized subgroup analysis, participants reporting general exercise had preservation of vibration (Left P = .001, Right P = .001) and normal heat pain thresholds (Left P = .021, Right P = .039) compared with more sedentary participants. Conclusion. Physical therapy home program may improve CIPN pain in the upper extremity for patients with breast cancer, and general exercise throughout chemotherapy treatment was observed to have correlated to preservation of sensory function. Further research is required to confirm the impact of a physical therapy home program on CIPN symptoms.

Canadian Cancer Centre Response to COVID-19 Pandemic: A National and Provincial Response.

BACKGROUND: COVID-19 has spread rapidly, requiring health delivery systems to undertake dramatic transformations. To evaluate these system changes, we undertook one of the first Canadian health delivery system reviews and the first Canadian cancer centre evaluation of pandemic system modifications. METHODS: Questionnaires were distributed to the Canadian Association of Provincial Cancer Agencies (CAPCA) members in order to assess changes to cancer centre services and patient management. Documentation relating to COVID-19 from the CAPCA electronic space was accessed, and all publicly available cancer centre documentation related to COVID-19 was reviewed. RESULTS: Seven provinces completed the questionnaire and had documentation available from the CAPCA electronic space. All screening programs across Canada were suspended. In most provinces surveyed, ≥50% of outpatient appointments were occurring virtually, with <25% using video platforms. Generally, the impact on diagnostic imaging and new patient referrals correlated with the impact of COVID-19. Most provinces had a reduction in operating room availability, with chemotherapy and radiation treatments continuing. Public health modification, including personal protective equipment and screening staff, varied across the country. CONCLUSION: Canadian cancer centres underwent a rapid and aggressive transformation of services in response to COVID-19, with many similarities and differences across provinces. In part, this response was facilitated by communication under a national association, which in Canada remains unique to cancer. This response may serve to inform changes in other jurisdictions or disease states now and in future waves of the pandemic, as well as a record of changes for future health services and patient outcome research.

Institutional review of glial tumors treated with chemotherapy: the first description of PCV-related pseudoprogression.

BACKGROUND: Pseudoprogression refers to areas of enhancement on MRI postadjuvant chemoradiation that arise as a result of treatment-related effects. Pseudoprogression has been well described with temozolomide-based chemoradiation but has not been studied in the setting of procarbazine, lomustine, and vincristine (PCV) chemotherapy. We reviewed patients treated with PCV to investigate the occurrence of pseudoprogression. METHODS: Adults diagnosed with World Health Organization grade II or III gliomas between 2010 and 2015 and treated with PCV or temozolomide were identified. Patient, tumor, treatment, and MRI data were retrospectively collected and analyzed. Pseudoprogression was defined as new enhancement seen on MRI within 6 months of completion of adjuvant radiotherapy or concurrent chemoradiation, which improved or remained stable on subsequent scans without therapeutic intervention. If MRI showed areas of new enhancement outside the 6-month post-treatment window, which resolved or remained stable without treatment, or in patients who did not receive adjuvant treatment, it was referred to as "atypical pseudoprogression." RESULTS: Fifty-seven patients were identified. Nine (16%) patients were identified as having pseudoprogression on MRI. Two (4%) of these patients were treated with PCV and 7 (12%) were treated with temozolomide. Seventeen (30%) patients had atypical pseudoprogression: 8 (14%) treated with temozolomide, 8 (14%) treated with PCV, and 1 (2%) treated with both types of chemotherapy. CONCLUSIONS: We describe the first 2 cases of PCV-related pseudoprogression and 17 cases of atypical pseudoprogression. As the re-emergence of adjuvant PCV occurs in clinical practice, the occurrence of classical and atypical pseudoprogression could have a significant impact on clinical decision making.

Neuropathic Pain in Taxane-Induced Peripheral Neuropathy: Evidence for Exercise in Treatment.

One in 2 Canadians is expected to acquire cancer in their lifetime. Many cancers, including breast, ovarian, and lung cancer, are treated using taxane chemotherapy with curative intent. A major adverse effect with the use of taxane chemotherapeutic agents is taxane-induced peripheral neuropathy (TIPN). Both positive (spontaneous pain, heightened sensitivity with light touch, tingling, itching, burning) and negative (loss of touch, loss of hot/cold sensations, and loss of pain) sensory symptoms can be experienced in the hands and feet and worsen with increasing dose and treatment duration. The pathophysiology of TIPN is still unknown but likely involves multiple mechanisms, including microtubule impairment, neuroimmune and inflammatory changes, ion channel remodeling, impaired mitochondrial function, and genetic predisposition. This review highlights current theories on the pathophysiology for TIPN, the cellular responses thought to maintain neuropathic pain, and the growing support for exercise in the treatment and prevention of peripheral neuropathy and neuropathic pain in both animal and human models.

Dairy product consumption and development of cancer: an overview of reviews.

OBJECTIVES: To provide a comprehensive systematic overview of current evidence from pooled analyses/meta-analyses and systematic reviews (PMASRs) pertaining to dairy consumption and incident cancer and/or all-cause or cancer-specific mortality. DESIGN: Overview of reviews. SETTING: Community setting. PARTICIPANTS: The unit of analysis is PMASRs. A total of 42 PMASRs was included in this overview of reviews. INTERVENTIONS/EXPOSURES: Any dairy product consumption (eg, milk, yogurt, etc). PRIMARY AND SECONDARY OUTCOMES MEASURES: Primary outcome measure is development of any type of cancer. Secondary outcome measures are all-cause mortality and cancer-specific mortality. RESULTS: From 9693 citations identified, we included 42 PMASRs (52 study reports) published between 1991 and 2017. Thirty-one (74%) of these was pooled analyses/meta analyses, and only 11 (26%) were systematic reviews and meta-analyses. There was a wide variability in the type of study designs included within the other PMASRs, thus contributing to variable and, in instances, divergent estimates of cancer risk for several cancer subtypes. For example, only one systematic review and meta-analysis exclusively included prospective study designs. Most PMASRs were of low to moderate quality based on the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) scores. The median AMSTAR score was 5 (IQR 2-7). Our overview identified conflicting evidence from PMASRs on association between dairy consumption and incident cancers or mortality. Heterogeneity in summary estimates reflected the inclusion of variable study designs and overall low methodological quality of individual PMASRs. CONCLUSIONS: The association between dairy consumption and cancer risk has been explored in PMASRs with a variety of study designs and of low to moderate quality. To fully characterise valid associations between dairy consumption and risk of cancer and/or mortality rigorously conducted, PMASRs including only high-quality prospective study designs are required. TRIAL REGISTRATION NUMBER: CRD42017078463.

Claudin 1 Is Highly Upregulated by PKC in MCF7 Human Breast Cancer Cells and Correlates Positively with PKCε in Patient Biopsies.

Recent studies provide compelling evidence to suggest that the tight junction protein claudin 1, aberrantly expressed in several cancer types, plays an important role in cancer progression. Dysregulation of claudin 1 has been shown to induce epithelial mesenchymal transition (EMT). Furthermore, activation of the ERK signaling pathway by protein kinase C (PKC) was shown to be necessary for EMT induction. Whether PKC is involved in regulating breast cancer progression has not been addressed. The PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA) was used to investigate the effect of PKC activity on claudin 1 transcription and protein levels, subcellular distribution, and alterations in EMT markers in human breast cancer (HBC) cell lines. As well, tissue microarray analysis (TMA) of a large cohort of invasive HBC biopsies was conducted to investigate correlations between claudin 1 and PKC isomers. TPA upregulated claudin 1 levels in all HBC cell lines analyzed. In particular, a high induction of claudin 1 protein was observed in the MCF7 cell line. TPA treatment also led to an accumulation of claudin 1 in the cytoplasm. Additionally, we demonstrated that the upregulation of claudin 1 was through the ERK signaling pathway. In patient biopsies, we identified a significant positive correlation between claudin 1, PKCα, and PKCε in ER+ tumors. A similar correlation between claudin 1 and PKCε was identified in ER- tumors, and high PKCε was associated with shorter disease-free survival. Collectively, these studies demonstrate that claudin 1 and the ERK signaling pathway are important players in HBC progression.