Treatment Outcomes of Low-grade Lymphoma of the Orbit.

AIMS: Radiation therapy can be used with curative intent in patients with low-grade orbital non-Hodgkin's lymphoma (NHL) stages IE and IVE (limited to the bilateral orbits). This study evaluated local control and survival outcomes of patients with unilateral or bilateral orbital lymphoma treated in a provincial population. MATERIALS AND METHODS: The study subjects were 176 patients with low-grade orbital or conjunctival lymphoma referred for management from 1980 to 2016. Demographic, tumour and treatment characteristics were abstracted by chart review. Recurrence-free survival (RFS) and overall survival were assessed with competing risks analysis and Gray's test. RESULTS: The median follow-up was 8.5 years (range 0.4-29.5 years). The median age at diagnosis was 65 years (range 20-97 years). The most common histological subtype was mucosa-associated lymphoid tissue (MALT) (73%). Stage IVE accounted for 20.5% of the cohort. Orbital radiation therapy was used in 122 patients with stage IE (87%) and 12 patients with stage IVE (28%). The median dose was 25 Gy (range 2-35 Gy). Other treatments were antibiotics (seven patients), chemotherapy (10 patients), radioimmunotherapy (six patients), surgery (three patients) and observation (16 patients). Within the group treated with orbital external beam radiation therapy (EBRT) there were no local recurrences. Among those with stage IE NHL, EBRT was associated with improved local RFS (P ≤ 0.001) but did not have an impact on contralateral or distant RFS. In patients with stage IVE NHL limited to the bilateral orbit, bilateral EBRT was associated with improved RFS (P = 0.012) but did not affect distant recurrences or overall survival. CONCLUSION: There were no local recurrences after EBRT for stage IE and IVE orbital low-grade NHL. The treatments offered over the study period varied, but only EBRT for stage IVE disease improved RFS. This supports EBRT as the preferred primary treatment for patients with localised orbital low-grade lymphoma, including those with bilateral disease.

Survival Outcomes Following Discontinuation of Ipilimumab and Nivolumab for Advanced Melanoma in a Population-based Cohort.

AIMS: Induction ipilimumab and nivolumab followed by maintenance nivolumab improve overall survival compared with ipilimumab alone in patients with advanced melanoma, but immune-related adverse events (irAE) occur commonly. The need for induction discontinuation because of irAE and the relationship between irAE and survival in non-trials patients are unclear. MATERIALS AND METHODS: Patients with unresectable stage III-IV melanoma receiving first-line combination immunotherapy at one of six centres between December 2017 and February 2020 outside of trials were identified retrospectively. Landmark 12-week Kaplan-Meier analyses and log-rank tests were used to evaluate associations between discontinuation of induction therapy on overall survival and time to treatment failure (TTF). Multivariable analysis of factors influencing overall survival and TTF was undertaken. RESULTS: Among 95 patients, the median age was 62 years, 38.9% had Eastern Cooperative Oncology Group performance status ≥1 and 22.1% had brain metastases. The median follow-up for the whole cohort was 19.8 months by the reverse Kaplan-Meier method. Any grade and grade 3-4 irAE were noted in 78.9% and 44.2% of the cohort, respectively. 44.2% of patients completed induction immunotherapy, whereas 41.1% did not due to irAE. Twelve-week landmark overall survival and TTF were similar in patients who completed induction versus those who did not due to irAE. On multivariable analysis, any grade irAE (versus none) was associated with longer overall survival (hazard ratio = 0.35, 95% confidence interval 0.15-0.82, P = 0.02) and TTF (hazard ratio = 0.38, 95% confidence interval = 0.17-0.81, P = 0.01). Grade 3-4 irAE correlated with longer TTF (hazard ratio = 0.45, 95% confidence interval = 0.20-1.01, P = 0.05). CONCLUSION: In this population-based cohort, discontinuation of induction immunotherapy as a result of irAE did not adversely affect overall survival or TTF. irAE observed during ipilimumab and nivolumab induction were associated with improved survival outcomes.

Individualized prescribing portraits to reduce inappropriate initiation of opioid analgesics to opioid naïve patients in primary care: Protocol for a randomized controlled trial.

Background Opioid analgesics are frequently initiated for chronic and acute pain despite weak evidence of benefit, although prescribing rates of some analgesics decreased in the context of the epidemic. In some populations, up to a quarter of opioid naïve persons prescribed opioids for non-cancer pain develop prescription opioid use disorder (OUD). Audit and feedback interventions rely on constructive use of routinely collected data to align professional behaviours and clinical practice with best evidence. These interventions have been shown to help reduce inappropriate initiation. However, effectiveness and acceptability of individualized "portraits" of physicians' prescribing patterns, to reduce inappropriate initiation of opioid analgesics to opioid naïve persons, have not been evaluated. Methods REDONNA is a mixed-methods randomized study testing the effectiveness of individualized prescribing Portraits to reduce inappropriate initiation of opioid analgesics. This intervention to improve safety of opioid prescribing in primary care in British Columbia (BC), Canada involves mailing individual prescribing portraits to an 'early group' of 2604 family physicians, followed in 6 months by a mailing to 2553 family physicians in the 'delayed group'. Primary outcome is number of new opioid prescriptions initiated in opioid naïve people, measured using administrative data from a centralized medication monitoring database covering all prescription opioids dispensed from BC community pharmacies. Secondary endpoints will compare prescribing impact between the two groups. A qualitative sub-study will examine feasibility among a purposive sample of physicians and patients. Discussion This trial provides important evidence on the intervention's potential to steer policy and practice on inappropriate opioid analgesics initiation. Trial registration: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).

Treatment of non-small-cell lung cancer after progression on nivolumab or pembrolizumab.

Background: Although PD-1 antibodies (PD1 Ab) are the standard of care for advanced non-small-cell lung cancer (ansclc), most patients will progress. We compared survival outcomes for patients with ansclc who received systemic therapy (st) after progression and for those who did not. Additionally, clinical characteristics that predicted receipt of st after PD1 Ab failure were evaluated. Methods: All patients with ansclc in British Columbia initiated on nivolumab or pembrolizumab between June 2015 and November 2017, with subsequent progression, were identified. Eligibility criteria for additional st included an Eastern Cooperative Oncology Group (ecog) performance status (ps) of 3 or less and survival for more than 30 days from the last PD1 Ab treatment. Post-progression survival (pps) was assessed by landmark analysis. Baseline characteristics associated with pps were identified by multivariable analysis. Results: Of 94 patients meeting the eligibility criteria, 33 received st after progression. In 75.6%, a PD1 Ab was received as first- or second-line treatment. The most common sts were erlotinib (36.4%) and docetaxel (27.3%). No statistically significant difference in median pps was observed between patients who did and did not receive st within 30 days of their last PD1 Ab treatment (6.9 months vs. 3.6 months, log-rank p = 0.15.) In multivariable analysis, factors associated with increased pps included an ecog ps of 0 or 1 compared with 2 or 3 [hazard ratio (hr): 0.42; 95% confidence interval (ci): 0.24 to 0.73; p = 0.002] and any response compared with no response to PD1 Ab (hr: 0.54; 95% ci: 0.33 to 0.90; p = 0.02). Conclusions: In this cohort, only 35.1% of patients eligible for post-PD1 Ab therapy received st. Post-progression survival was not significantly affected by receipt of post-progression therapy. Prospective trials are needed to clarify the benefit of post-PD1 Ab treatments.

Differential Proteomics for Distinguishing Ischemic Stroke from Controls: a Pilot Study of the SpecTRA Project.

A diagnostic blood test for stroke is desirable but will likely require multiple proteins rather than a single "troponin." Validating large protein panels requires large patient numbers. Mass spectrometry (MS) is a cost-effective tool for this task. We compared differences in the abundance of 147 protein markers to distinguish 20 acute cerebrovascular syndrome (ACVS) patients who presented to the Emergency Department of one urban hospital within < 24 h from onset) and from 20 control patients who were enrolled via an outpatient neurology clinic. We targeted proteins from the stroke literature plus cardiovascular markers previously studied in our lab. One hundred forty-one proteins were quantified using MS, 8 were quantified using antibody protein enrichment with MS, and 32 were measured using ELISA, with some proteins measured by multiple techniques. Thirty proteins (4 by ELISA and 26 by the MS techniques) were differentially abundant between mimic and stroke after adjusting for age in robust regression analyses (FDR < 0.20). A logistic regression model using the first two principal components of the proteins significantly improved discrimination between strokes and controls compared to a model based on age alone (p < 0.001, cross-validated AUC 0.93 vs. 0.78). Significant proteins included markers of inflammation (47%), coagulation (40%), atrial fibrillation (7%), neurovascular unit injury (3%), and other (3%). These results suggest the potential value of plasma proteins as biomarkers for ACVS diagnosis and the role of plasma-based MS in this area.

The benefit of participating to clinical research.

We assessed the impact of participating to clinical research among 1727 women with localized breast cancer. Using as referent individuals not treated according to guidelines for systemic therapy, the adjusted hazard ratio of death was 0.70 (95% confidence interval (CI): 0.54,0.90, p-value: 0.006) in those treated according to current guidelines and 0.45 (95% CI: 0.27,0.73, p-value: 0.001) in participants to research. Participation to clinical trials results in a substantial gain in survival.

Delay in adjuvant radiation treatment and outcomes of breast cancer--a review.

Recent meta-analyses have shown the importance of locoregional control as a long-term determinant of breast cancer survival. Whether factors related to the delivery of radiotherapy, such as delay, dose, fractionation or irradiated volume, are associated with outcome remains unclear. We performed a critical review of the literature on delay to radiation using a computerized search of papers published between 1985 and 2000. Periods of accrual, details of radiotherapy, surgical and systemic treatment, and information on prognostic factors were noted. Studies on sequencing of adjuvant therapy were compared to studies on delay to radiation, classified according to whether or not patients also received chemotherapy. Comparisons of patients receiving systemic therapy to individuals spared this option were considered uninformative since the impact of delaying radiation is then highly confounded by systemic treatment received. The single published experimental study on sequencing suggests that delay to radiation may compromise local control, and this is consistent with a few retrospective reports on delay to radiotherapy among patients receiving chemotherapy. However, indirect evidence from two randomized clinical trials of chemotherapy, and the majority of observational studies on delay to radiotherapy, suggest that it has no impact on either local, distant control or survival. Factors, methodological, and others, that could explain these inconsistencies are discussed. No study restricted to patients at low risk of recurrence suggested an impact of delaying radiation. Short chemotherapy regimens are likely to represent a safe option with respect to outcome of radiation treatment.

Crystallization and preliminary X-ray analysis of dmpFG-encoded 4-hydroxy-2-ketovalerate aldolase--aldehyde dehydrogenase (acylating) from Pseudomonas sp. strain CF600.

The final two steps of the meta-cleavage pathway for catechol degradation in Pseudomonas sp. strain CF600 involve the conversion of 4-hydroxy-2-ketovalerate to pyruvate and acetyl coenzyme A by the enzymes 4-hydroxy-2-ketovalerate aldolase and NAD(+)-dependent acylating aldehyde dehydrogenase. Biochemical studies indicate that these two enzymes comprise a bifunctional heterodimer (DmpFG, molecular mass 71 kDa) and suggest that the product of the aldolase reaction is transferred to the dehydrogenase active site via a channeling mechanism. Crystals of the DmpFG complex grow in multiple fan-like clusters of thin plates by the hanging-drop method and are improved by streak-seeding. The crystals belong to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 102.0, b = 140.7, c = 191.3 A, and diffract to 2.1 A resolution. The asymmetric unit contains four DmpFG heterodimers. Heavy-atom derivative screening identified three isomorphous derivatives.

Variations in the treatment of early-stage breast cancer in Quebec between 1988 and 1994.

BACKGROUND: The influence of organizational factors on the process and outcomes of the treatment of breast cancer has been extensively investigated. Although the quality of care is presumed to be better in larger centres, evidence is inconsistent. This study was conducted to determine whether therapies for patients with breast cancer varied according to hospital caseload. METHODS: Women newly diagnosed between 1988 and 1994 with early-stage node-negative primary breast cancer were randomly selected from the Quebec tumour registry and the Quebec hospital discharge database. Data were collected from medical charts, and only women having undergone dissection of the axilla were included in the analyses. Logistic regression analysis was used to adjust for case mix and organizational variables. RESULTS: The final sample included 1259 patients with node-negative stage I or II primary breast cancer. The proportion of women who underwent breast-conserving surgery increased significantly with hospital caseload (from 78.0% in hospitals admitting fewer than 25 new cases each year to 88.0% in those admitting 100 patients or more; p for trend < 0.001). This trend remained significant even after statistical adjustment for case mix and organizational factors (p for trend = 0.001). Of the 1039 women who underwent breast-conserving surgery 965 (92.9%) received radiotherapy. Use of systemic adjuvant therapy (tamoxifen or chemotherapy, or both) increased with the number of patients treated in a given centre (from 60.1% to 68.5%), but this trend disappeared after adjustment for case mix and other factors. The proportion of patients receiving systemic adjuvant therapy consistent with published consensus guidelines tended to increase with caseload for those treated in hospitals participating in multicentre clinical trials but decrease with caseload for patients in hospitals not involved in clinical research. INTERPRETATION: The care of patients in Quebec with early-stage breast cancer is characterized by a high prevalence of both breast-conserving surgery and systemic adjuvant therapy. Large centres, especially those actively involved in clinical research, rapidly adopt innovative therapeutic modalities.

Time trends in systemic adjuvant treatment for node-negative breast cancer.

PURPOSE: We conducted a population-based study in Quebec, Canada, to assess longitudinal changes in systemic adjuvant therapy for node-negative breast cancer. MATERIALS AND METHODS: A stratified random sample was selected among women with newly diagnosed node-negative breast cancer in 1988, 1991, and 1993. Information on the patient, her tumor, source of care, and treatment was abstracted from medical charts. Patients were classified as being at minimal, moderate, or high risk of recurrence on the basis of criteria proposed at the 4th International Conference on Adjuvant Therapy of Primary Breast Cancer (St. Gallen, Switzerland, 1992), and systemic adjuvant treatment received was dichotomized as being consistent or not consistent with consensus recommendations. RESULTS: Overall, 1,578 cases of invasive breast carcinoma were reviewed. The proportion of patients who were given hormonal or cytotoxic treatment increased from 51.7% to 73.1% from 1988 to 1993. Virtually all women at minimal risk were treated in 1991 and 1993 according to the consensus statement. The proportions of women so treated were 75.0% and 65.4% in the moderate- and high-risk categories, respectively, in 1991. In 1993, these proportions were 71.4% and 67.0%, respectively. Omission of chemotherapy, especially in high-risk women with estrogen receptor-negative tumors who were 50 to 69 years of age, was the most frequent inconsistency with guidelines. CONCLUSION: Systemic adjuvant therapy for node-negative breast cancer has gained acceptance. Better understanding of the decision-making process, of the perception of the risks and benefits involved, and of the impact of alternative strategies for the dissemination of consensus recommendations are needed to promote the use of chemotherapy in specific categories of women who are at high risk of recurrence.

Crystallization and preliminary X-ray analysis of the formiminotransferase domain from the bifunctional enzyme formiminotransferase-cyclodeaminase.

Formiminotransferase-cyclodeaminase (E.C. 2.1.2.5-E.C. 4.3.1.4) is a bifunctional enzyme involved in the histidine-degradation pathway which exhibits specificity for polyglutamylated folate substrates. The first function of the enzyme transfers the formimino group of formiminoglutamate to the N5 position of tetrahydrofolate, while the second function catalyses the cyclodeamination of the formimino group, yielding N5,10-methenyl-tetrahydrofolate, with efficient channeling of the intermediate between these activities. Initial studies have shown that the enzyme consists of eight identical subunits of 62 kDa each, arranged as a circular tetramer of dimers. It is this formation which results in two different dimeric interfaces, which are necessary for the two different activities. The identical subunits have been shown to consist of two domains, each of which can be obtained as dimers. The formiminotransferase domain has been crystallized in the presence of the substrate analogue folinic acid. The crystals belong to space group P212121, with unit-cell dimensions a = 64.4, b = 103.7, c = 122.3 A. Both a native data set and a mercurial derivative data set have been collected to 2.8 A resolution.

Compliance with consensus recommendations for the treatment of early stage breast carcinoma in elderly women.

BACKGROUND: The goal of this study was to assess variations with age in the management of breast carcinoma and to identify determinants of care received. METHODS: A stratified random sample was selected among women age > or = 50 newly diagnosed with lymph node negative breast carcinoma in Quebec in 1988, 1991, and 1993. Information was abstracted from medical charts. Predictors of definitive locoregional treatment (total mastectomy with lymph node dissection or breast-conserving surgery with both axillary lymph node dissection and radiation therapy) were identified by multiple logistic regression analysis. RESULTS: Overall, 1174 patients age > or = 50 years with breast carcinoma were included. Women age > or = 70 years were much less likely to receive definitive locoregional treatment compared with women ages 50-69 years (48.7% vs. 83.5%; P < 0.0001). Older women were less likely to undergo surgery with breast preservation (76.7% vs. 86.3%; P < 0.0001), radiation therapy (54.7% vs. 90.5%; P < 0.0001), dissection of the axillary lymph nodes (55.6% vs. 86.3%; P < 0.0001), or chemotherapy (1.2% vs. 13.9%; P < 0.0001), but not treatment with tamoxifen (66.4% vs. 64.7%; P = 0.41). Adjusting for comorbidity and other characteristics related to the disease, the hospital, and the attending physician, age remained a strong determinant of the probability of receiving definitive locoregional treatment (odds ratio [OR], 0.14; 95% confidence interval [95% CI], 0.12-0.18 for women age > or = 70 years vs. women ages 50-69 years). The same association was observed when women who did not undergo lymph node dissection but who received systemic adjuvant treatment were considered to have received definitive therapy (OR, 0.13; 95% CI, 0.10-0.17) for women age > or = 70 years vs. women ages 50-69 years). CONCLUSIONS: Less aggressive patterns of care are provided to elderly breast carcinoma patients, independent of comorbidity. This could explain, at least in part, the sustained breast carcinoma mortality in this population.

A meta-analysis of hormone replacement therapy and colon cancer in women.

The influence of endocrine factors on colorectal tumor development remains unclear. We performed a meta-analysis of studies of the association between the use of menopausal hormones and colon cancer in women, published up to December 1996. We derived summary measures of relative risk (RR) by fitting both fixed and random effects models. We also performed analyses by tumor location to the right or left colon, as well as by recency and duration of use. Heterogeneity was assessed according to study design, chronology, or other criteria. Overall, the 20 independent estimates of the association between ever use of menopausal hormones and colon cancer led to a summary RR of 0.85, (0.73, 0.99), using a random effects model. There was substantial heterogeneity among studies. The suggested protective effect of hormones was estimated to be stronger in studies published since 1990 [RR: 0.83, (0.66, 1.04), versus 0.93, (0.78, 1.10), for those published previously]. The estimated RRs were lower among current or recent users [RR: 0.69, (0.52, 0.91)] and among users of more than 5 years [RR: 0.73, (0.53, 1.02)] as compared with short-term users [RR: 0.88, (0.64, 1.21)]. The current state of knowledge suggests a 0-25% risk reduction among ever users of hormone replacement therapy. Inadequate assessment of exposure, poor control of confounding factors, and changing patterns of use over time might have contributed to the slow emergence of this association postulated almost two decades ago. Additional large studies are needed to replicate this finding and explain the exact mechanism of this putative protective effect.

Estimation of breast cancer risk by women aged 40 and over: a population-based study.

OBJECTIVE: Identify factors associated with knowledge of breast cancer and estimation of risk. METHODS: Telephone survey of 412 women aged 40 and over, living in Montreal and selected by random digit dialing. RESULTS: The majority of the respondents had recently been exposed to some information on breast cancer, but only a third quoted the average lifetime probability estimate of about 1 in 10. Older individuals systematically considered themselves at low risk (odds ratio (OR) of perceiving risk as lower than average for women aged 50 or over versus under 50: 2.6, 95% confidence interval: (1.5, 4.6)). In addition, both a first-degree family history of breast cancer (OR: 5.3 (1.7, 17.0)) and a recent mammogram (OR: 3.0 (1.4, 6.2)) were strongly associated with a woman's probability of perceiving herself at high risk. CONCLUSIONS: Information campaigns should emphasize the frequency of breast cancer in different age groups and the strength of the established associations with specific risk factors. Better knowledge of risk could promote sustained participation in breast screening programs.

Crystallization and preliminary X-ray analysis of aldehyde dehydrogenase from Vibrio harveyi.

Aldehyde dehydrogenase from Vibrio harveyi catalyzes the oxidation of long-chain aliphatic aldehydes to acids. The enzyme is unique among the family of aldehyde dehydrogenases in that it exhibits much higher specificity for the cofactor NADP+ than for NAD+. The sequence of this form of the enzyme varies significantly from the NAD+ dependent forms, suggesting differences in the three-dimensional structure that may be correlated to cofactor specificity. Crystals of the enzyme have been grown both in the presence and absence of NADP+ using the hanging drop vapor diffusion technique. In order to improve crystal size and quality, iterative seeding techniques were employed. The crystals belong to space group P2(1), with unit cell dimensions a = 79.4 A, b = 131.1 A, c = 92.2 A, and beta = 92.4 degrees. Freezing the crystal to 100 K has enabled a complete set of data to be collected using a rotating anode source (lambda = 1.5418 A). The crystals diffract to a minimum d-spacing of 2.6 A resolution. Based on density calculations, two homodimers of molecular weight 110 kDa are estimated to be present in the asymmetric unit. Self-rotation functions show the presence of 3 noncrystallographic twofold symmetry axes.

Crystallization and preliminary X-ray analysis of cholesterol oxidase from Brevibacterium sterolicum containing covalently bound FAD.

Single crystals of cholesterol oxidase from Brevibacterium sterolicum containing a covalently bound form of the FAD cofactor have been obtained. The crystals are grown by vapor diffusion using the hanging drop technique from 12% polyethylene glycol, Mr 8000, and 75 mM MnSO4 as the precipitant at pH 5.2. In order to obtain large diffraction quality crystals, nucleation must occur at 22 degrees C with subsequent growth at 17 degrees C. The crystals belong to the monoclinic space group P21 with cell dimensions a = 78. 5 A, b = 126.7 A, c = 82.4 A and beta = 108.9 degrees with two protein molecules per asymmetric unit. Diffraction of these crystals has been observed to at least 2.2 A resolution and they are suitable for an X-ray structure analysis.

Trends in medical visits and surgery for otitis media among children.

We conducted a population-based descriptive study of medical visits and surgical interventions for otitis media among 3- and 7-year-old children from the Montreal, Canada, area over the period 1981 to 1983. The number of children seen annually for otitis media increased over that time. An increase in the event rate of otitis was observed; there was also an increase in the rate of myringotomy with ventilatory tube insertion. The rate of surgery reached a level, among 3-year-old children in particular (25.0 per 1000 cases of otitis among boys, 23.9 per 1000 cases of otitis among girls), that some authors have termed "epidemic." Comparison of the trends in the rates of surgical interventions and the rates of medical consultations for otitis suggest that most of this so-called surgical epidemic for middle ear effusion is related to a higher frequency of the underlying condition and not to more aggressive patterns of therapy during the years studied.