Citations

Importance High-quality evidence guiding opioid prescribing decisions for acute pain across common diagnoses is lacking. Objective To describe pain trajectories and patterns of opioid and nonopioid treatment use among individuals who were offered opioids for the treatment of acute pain. Design, Setting, and Participants This was a prospective cohort study of patients recruited from 5 US health systems between September 2020 and March 2023 in emergency departments (EDs), primary care clinics, dental practices, or after cesarean delivery or knee replacement. Eligible patients were opioid-naive adults aged 18 years or older at all study sites, as well as adolescents aged 15 to17 years undergoing impacted molar extraction at 1 site, who were offered an opioid prescription for acute pain. Analysis was conducted April 2023 through February 2026. Exposure Offer of a prescription for an opioid analgesic. Main Outcomes and Measures Time to pain resolution (3 consecutive reports of no pain), patterns of opioid and nonopioid treatment use, and opioid-related adverse effects, ascertained from digital questionnaires. Results Among 1708 enrolled patients (median age, 38 years [IQR, 28-52 years]; 615 [36.0%] reporting race or ethnicity underrepresented in studies of acute pain management) followed up for 180 days, 915 (53.6%) were recruited in EDs, 307 (18.0%) in primary or urgent care, 263 (15.4%) in dental settings, and 223 (13.1%) in inpatient settings. Pain sources included dental (302 patients [17.7%]), trauma or injury (302 [17.7%]), obstetric (176 [10.3%]), musculoskeletal (131 [7.7%]), and low back (100 [5.9%]). Among 1502 patients reporting pain level at least once, median time to pain resolution irrespective of the treatment approach was 20 days (IQR, 8-88 days), with longer durations for surgical pain (74 days [IQR, 30 days to not reached]) and low back pain (69 days [IQR, 18 days to not reached]). The median time to opioid discontinuation among 1189 patients (69.6%) who reported any opioid use was 7 days (IQR, 2-31 days); an estimated 10.0% (95% CI, 7.7%-12.7%) of patients used opioids for at least 90 days, with higher rates in people reporting frequent pain before enrollment. Of 1482 patients (86.8%) completing at least 1 survey during the first 2 weeks of follow-up, 1153 (77.8%) reported using any opioids and 1287 (86.8%) reported using acetaminophen or ibuprofen. Among 619 (52.1%) patients with any opioid use who reported the dose of opioids taken in the first 15 days, daily doses were low (median, 10 [IQR, 5-15] morphine milligram equivalents). Most respondents reported leftover opioids (657 of 982 responding [66.9%]). Conclusions and Relevance In this cohort study of opioid-naive patients with acute pain, opioid use was generally low dose and of short duration, although some patients reported prolonged opioid use; most reported achieving pain resolution within 3 weeks, with longer times for surgical and low back pain. The findings suggest current guidelines for multimodal treatment and for short-duration opioid prescriptions if needed will serve many but not all patients, and treatment should be tailored to address individual patients’ needs.

Multiplex immunofluorescence and immunohistochemistry (mIF/IHC) are increasingly employed antibody-based technologies that use tissue sparingly and facilitate the detection of co-localized or neighboring biomarkers. Specifically, these platforms enable spatial analyses of the tumor microenvironment as well as extended applications, for example, describing normal tissue anatomy, autoimmunity, infectious diseases, etc. mIF/IHC has greatly enhanced biomarker discovery efforts, and a growing number of studies suggest superiority to traditional IHC. Standardization of staining approaches, reporting of image analysis strategies and resultant data is critical for facilitating cross-study comparisons, validation, deployment, and generalization of findings. To address this challenge, The Society for Immunotherapy of Cancer (SITC) previously published two articles providing best practice guidelines for mIF/IHC staining, image analysis, and data sharing. Here, SITC convened stakeholders to develop the third article in the series, a consensus checklist for scientific reporting of mIF/IHC data to support and complement the best practice guidelines. The checklist includes critical components of mIF/IHC applications to be defined within publications such as detailed descriptions of analytical validation; image acquisition, selection, and registration methods; and cell clustering and spatial analysis strategies, amongst others. Such information will help with data reproducibility and comparison across studies towards future drug and assay development.

Abstract Recent advances in the field of immuno‐oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high‐throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi‐marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Abstract Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector‐based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well‐described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.

AbstractThe clinical significance of the tumor‐immune interaction in breast cancer is now established, and tumor‐infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple‐negative (estrogen receptor, progesterone receptor, and HER2‐negative) breast cancer and HER2‐positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state‐of‐the‐art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false‐positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in‐depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple‐negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Introduction Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. Methods and analysis This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients’ patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. Ethics and dissemination This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. Trial registration number NCT04509115 .

Abstract Background: Niraparib is a selective poly(ADP-ribose) polymerase 1/2 inhibitor that has demonstrated antitumor activity in advanced triple-negative breast cancer (TNBC) in combination with a programmed cell death 1 inhibitor, with the greatest clinical activity seen in tumors with breast cancer susceptibility gene (BRCA) mutations. Pharmacologically, niraparib has demonstrated a wide volume of distribution and high cell membrane permeability. In breast and ovarian cancer xenograft mouse models, niraparib achieved tumor exposures that were 3.3 times greater than plasma exposure. The objective of this study is to evaluate the antitumor activity of single-agent niraparib in the neoadjuvant treatment of patients with localized, human epidermal growth factor receptor 2 (HER2)-negative, BRCA-mutated breast cancer. The relative concentration of niraparib in tumor versus plasma was also assessed. Methods: Eligible patients were ≥18 years old, with HER2-negative, BRCA-mutated (germline or somatic) resectable breast cancer with a tumor size of ≥1 cm who had not received prior treatment for the current malignancy. Patients received niraparib 200 mg once daily for 2 months. At the end of 2 months, at their treating physician’s discretion, patients proceeded directly to surgery, received additional cycles of niraparib (maximum of 6 months), or received neoadjuvant chemotherapy. The primary endpoint was tumor response rate measured by magnetic resonance imaging (MRI) after 2 months of treatment. Response was defined as a ≥30% reduction in tumor volume from baseline. Secondary endpoints included tumor response rate measured by ultrasound, quantified percent change in tumor volume measured by MRI or ultrasound, pathological complete response, and safety and tolerability. Additionally, niraparib concentrations were measured in tumor and plasma samples using qualified liquid chromatography-tandem mass spectrometry. Results: Twenty-one patients were enrolled. As of June 2019, 18 patients had both an MRI and ultrasound scan at the end of month 2 and were evaluable for response. Ten patients are currently on treatment. The median age of patients was 43 years (range, 21-73). Fourteen patients had a BRCA1 mutation, 6 patients had a BRCA2 mutation, and 1 patient had both. Fifteen patients had TNBC, and 6 patients had hormone receptor-positive disease. All 18 response-evaluable patients had a clinical response after 2 months of treatment by at least one imaging modality; no patient experienced disease progression. Tumor response rate measured by MRI after 2 months of treatment was 89% (n/N = 16/18). Results measured by ultrasound were similar, with a 94% response rate at cycle 2 (n/N = 17/18). The median percent decrease in tumor volume after 2 months of treatment was 88% (range, 26-100%) and 89% (range, 23-100%) as measured by MRI and ultrasound, respectively. In the 5 samples measured thus far, niraparib concentrations in tumor biopsies after 2 months of treatment ranged from approximately 4-131-fold higher than those in corresponding plasma samples. Efficacy and tumor concentration data for all patients will be presented at the meeting. The most common (≥10%) drug-related treatment-emergent adverse events (TEAEs) of any grade were nausea, fatigue, anemia, insomnia, and decreased appetite. The only drug-related grade ≥3 toxicity in ≥10% of patients was anemia (3 patients). Three patients had a dose reduction due to a TEAE; no patient discontinued treatment due to a TEAE. Conclusion: Niraparib was well tolerated and showed promising antitumor activity in the neoadjuvant treatment of patients with localized HER2-negative, BRCA-mutated breast cancer. Niraparib achieved 4-131-fold higher concentrations in tumor than in plasma. Clinical trial information: NCT03329937. Funding: TESARO: A GSK Company (Waltham, MA, USA) sponsored the study. Citation Format: Hyo Han, Minetta C Liu, Erika Hamilton, Hanna Irie, Cesar A Santa-Maria, James Reeves, Andre Liem, Adrianna Milillo Naraine, Julie Nangia, David Page, Meghan Duncan, Ming Shan, Yongqiang Tang, Julie R Graham, Leif W Ellisen, Steven Isakoff, Laura Spring. Pilot neoadjuvant study of niraparib in HER2-negative, BRCA-mutated resectable breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-03.

1005 Background: We previously reported that in the E5194 clinical trial patients with ductal carcinoma in situ (DCIS) treated with wide local excision (WLE) without radiation (RT), the DCIS Score was significantly associated with 10 year risk of an ipsilateral breast event (IBE - recurrence of in situ or invasive carcinoma), whether evaluated as a continuous or categorical variable (P=0.02 for both). Here we evaluate correlation between DCIS Score and clinicopathologic (CP) features and if DCIS Score provides independent recurrence risk information. Methods: The study population included 327 women with DCIS prospectively selected for treatment with WLE without RT, including low-intermediate grade tumors ≤2.5 cm or high-grade ≤1 cm. CP variables included age, menopausal status, tamoxifen treatment (used in 29%) and expert centrally determined tumor size, grade, comedo necrosis, tumor type, and margin status. The association between DCIS Score and CP variables was examined by spearman rank correlation, and proportional hazards regression models were used to determine variables significantly associated with IBE. Results: Lesion size (p=0.009) and menopausal status (p=0.03) were significantly associated with IBE, while grade (p=0.69) and comedo necrosis (p=0.47) were not. DCIS Score was significantly associated with IBE after adjustment for CP features and tamoxifen use (p=0.02). DCIS Score was moderately correlated with grade (rs=0.46; 95% CI 0.37,0.54), percentage comedo necrosis (rs=0.49; CI 0.41,0.57), and lesion size (rs=0.18; CI 0.08,0.29) but not other features. Exploratory analyses in all CP subgroups, including the multicomponent Van Nuys Prognostic Index, showed a wide range of DCIS Scores in each subgroup. Concordance of the grades among readers was low: local vs parent central, 68%; local vs central nuclear grade, 45%; parent central vs central nuclear grade, 37%. Conclusions: DCIS Score is moderately correlated with grade, comedo necrosis, and tumor size. DCIS Score provides recurrence risk information independent of these features and identifies subjects with DCIS who are at high risk for local invasive and in-situ local recurrence after WLE alone.

Abstract Background: Neoadjuvant chemotherapy is administered to patients with operable breast cancer to downstage the tumor to allow for less extensive surgery and to provide prognostic information about drug efficacy and risk of disease recurrence. Patients who achieve a pathological complete response (pCR) following neoadjuvant treatment have a more favorable outcome than patients with residual invasive disease. Single-agent poly(ADP-ribose) polymerase (PARP) inhibitors have clinical efficacy in BRCA-mutated breast cancer. Niraparib, a potent and selective PARP1/2 inhibitor, is approved for maintenance treatment of patients with recurrent ovarian cancer and has demonstrated strong antitumor activity in in vivo studies with BRCA1-mutant breast cancer. The objective of this study is to evaluate the antitumor activity of single-agent niraparib in the neoadjuvant treatment of patients with localized, human epidermal growth factor receptor 2 (HER2)-negative, BRCAmut breast cancer. Trial Design: This is an open-label, single-arm pilot study with a target enrollment of 20 evaluable patients. Eligible patients are those ≥18 years old with histologically-confirmed HER2-negative localized breast cancer and either a BRCA1 or BRCA2 mutation (germline or somatic) and no prior anti-cancer therapies for the current malignancy. Patients will receive 200 mg of oral niraparib once daily for 2 months, after which they may either proceed directly to surgery or receive chemotherapy at the discretion of the physician. The primary endpoint is tumor response rate based on the change in tumor volume as measured by breast MRI after 2 months of treatment with niraparib; a response is defined as ≥30% reduction of tumor volume from baseline. Secondary endpoints include pCR rate, tumor response rate based on the change in tumor volume as measured by breast ultrasound, and safety and tolerability. Data will be summarized in a descriptive nature by frequency distributions (number and percentage of patients) for categorical variables and by the mean, median, and standard deviation for continuous variables. Tumor response rate will be tabulated together with its 95% binomial exact confidence interval. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Han H, Hamilton E, Irie H, Isakoff S, Jelovac D, Liem A, Liu MC, Milillo A, Nangia J, Page D, Reeves J, Santa-Maria C, Duncan M, Graham JR, Chen J, Dezube BJ, Spring L. Open-label, single-arm study evaluating the antitumor activity and safety of niraparib as neoadjuvant treatment in patients with localized, HER2-negative, BRCA-mutant breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-01.