Oncologists Must Consider Participant Data When Using Large-Scale Cancer Data Sets.

Primer that helps clarify large-scale clinical data sets and participant demographics for oncologists.

The Chicagoland Free Clinics Consortium: A Model for Student-Run Free Clinic Collaboration.

BACKGROUND: While student-run free clinics (SRFCs) play an important role in care for underserved populations, few mechanisms exist to promote collaboration among regional SRFCs. AIMS: To address this gap, the Chicagoland Free Clinics Consortium (CFCC) was formed to (1) facilitate collaboration between Chicagoland SRFCs, (2) provide innovation grant funding, and (3) host an annual conference. SETTING AND PARTICIPANTS: In 2018, students from the Pritzker School of Medicine founded the CFCC and partnered with peers from area schools to implement programming. PROGRAM DESCRIPTION: Between 2018 and 2022, CFCC engaged 23 SRFCs representing all 6 Chicagoland schools, held 4 annual conferences, and distributed $15,423 in grants to 19 projects at 14 SRFC sites. PROGRAM EVALUATION: A total of 176 students from 5 schools attended the 4 conferences. In 2022, 82 unique participants were surveyed, and 66% (54/82) responded. Eighty percent (43/54) reported they were "more likely to collaborate with other Chicagoland free clinics." In 2022, all grant sites were surveyed and 84% (16/19) responded. Most (87%,14/16) agreed the grant "allowed them to implement a project that would not have otherwise been accomplished" and 21% (4/19) were inter-institutional collaborations. DISCUSSION: To our knowledge, CFCC is the first student-led organization to promote sustained collaboration across SRFCs in a metropolitan area.

Step-Economic Total Synthesis of Melosatin A from Eugenol.

An efficient and straightforward route toward the isatin-type natural product melosatin A is reported, employing a trisubstituted aniline as a key intermediate. The latter was synthesized in 4 steps and 60% overall yield from eugenol, through its regioselective nitration, sequentially followed by a Williamson methylation, an olefin cross-metathesis with 4-phenyl-1-butene and the simultaneous reduction of olefin and nitro groups. The final step, a Martinet cyclocondensation of the key aniline with diethyl 2-ketomalonate, provided the natural product with 68% yield.

Spanish Adaptation and Evaluation of Clinical Discussion Guides: Communicating the External Beam Radiotherapy Experience (CEBRE) en Español.

PURPOSE: Cancer is the leading cause of death for the Hispanic/Latinx United States (US) community, which comprises 64% of the US population with limited English proficiency. Despite the common use of radiation therapy for cancer treatment, there is a dearth of radiation therapy educational materials-at appropriate reading levels-available in Spanish. To address the gap in patient-centered educational resources for communicating with Spanish-speaking patients about radiation therapy, we sought to linguistically and culturally adapt the Communicating the External Beam Radiotherapy Experience (CEBRE) clinical discussion guide series into Spanish. METHODS AND MATERIALS: From January to December 2021, we developed and applied a stepwise methodology for Spanish adaptation of the discussion guides involving (1) professional translation; (2) interprofessional review for linguistic and cultural appropriateness and medical accuracy; (3) design review; and (4) evaluation for readability, understandability, and actionability using validated tools. We applied 4 indices for readability evaluation: Gilliam-Peña-Mountain, Läsbarhetsindex, Rate Index, and the Spanish Simple Measure of Gobbledygook. Two trained reviewers assessed understandability and actionability using the Patient Education Materials Assessment Tool. RESULTS: After 2 revision rounds, 4 CEBRE en español discussion guides were produced through an interprofessional, iterative translation and linguistic/cultural adaptation process. Readability scores across the 4 guides ranged from 4.3 to 7.3 grade-level equivalents, thereby meeting the American Medical Association's 8th-grade standard. Patient Education Materials Assessment Tool analysis yielded near-perfect scores along understandability and actionability domains. CONCLUSIONS: The stepwise linguistic/cultural adaptation process yielded a patient-centered guide that is appropriately readable, understandable, and actionable for Spanish-speaking patients receiving radiation therapy in the US. Future work should include an external evaluation of CEBRE en español by clinicians and patients. The methodology described can be applied to adapting resources for patient-centered communication in other fields of medicine and into other languages as part of an interprofessional approach to delivering equitable health care for all.

Communicating the Gynecologic Brachytherapy Experience (CoGBE): Clinician perceived benefits of a graphic narrative discussion guide.

PURPOSE: Many current radiotherapy patient education materials are not patient-centered. An interprofessional team developed Communicating the Gynecologic Brachytherapy Experience (CoGBE), a graphic narrative discussion guide for cylinder, intracavitary, and interstitial high-dose-rate (HDR) gynecologic brachytherapy. This study assesses perceived clinical benefits, usability, and anxiety-reduction of CoGBE. METHODS AND MATERIALS: An electronic survey was sent to members of the American Brachytherapy Society. Participants were assigned to assess one of the three modality-specific CoGBE versions using a modified Systems Usability Scale (SUS), modified state-trait anxiety index (mSTAI), and Likert-type questions. Free response data was analyzed using modified grounded theory. RESULTS: Median modified SUS score was 76.3 (interquartile range [IQR], 71.3-82.5) and there were no significant differences between guide types. Median mSTAI was 40 (IQR, 40-43.3) for all guides collectively. The cylinder guide had a significantly higher median mSTAI than the intracavitary and interstitial guides (41.6 vs. 40.0 and 40.0; p = 0.04) suggesting the cylinder guide may have less impact on reducing anxiety. Most respondents reported that CoGBE was helpful (72%), would improve patient understanding (77%) and consultation memorability (82%), and was at least moderately likely to be incorporated into their practice (80%). Qualitative analysis themes included personalization and relatability (positive); generalizability (negative); illustrations (both). CONCLUSIONS: Clinicians rate CoGBE as usable with potential to reduce patient anxiety, especially with more invasive treatment modalities including intracavitary or interstitial high-dose-rate. CoGBE has the potential to improve patient-clinician communication for a wider range of patients due to its accessible, adaptable, and patient-centered design.

The Association Between USMLE Step 2 Clinical Knowledge Scores and Residency Performance: A Systematic Review and Meta-Analysis.

PURPOSE: With the change in Step 1 score reporting, Step 2 Clinical Knowledge (CK) may become a pivotal factor in resident selection. This systematic review and meta-analysis seeks to synthesize existing observational studies that assess the relationship between Step 2 CK scores and measures of resident performance. METHOD: The authors searched MEDLINE, Web of Science, and Scopus databases using terms related to Step 2 CK in 2021. Two researchers identified studies investigating the association between Step 2 CK and measures of resident performance and included studies if they contained a bivariate analysis examining Step 2 CK scores' association with an outcome of interest: in-training examination (ITE) scores, board certification examination scores, select Accreditation Council for Graduate Medical Education core competency assessments, overall resident performance evaluations, or other subjective measures of performance. For outcomes that were investigated by 3 or more studies, pooled effect sizes were estimated with random-effects models. RESULTS: Among 1,355 potential studies, 68 met inclusion criteria and 43 were able to be pooled. There was a moderate positive correlation between Step 2 CK and ITE scores (0.52, 95% CI 0.45-0.59, P < .01). There was a moderate positive correlation between Step 2 CK and ITE scores for both nonsurgical (0.59, 95% CI 0.51-0.66, P < .01) and surgical specialties (0.41, 95% CI 0.33-0.48, P < .01). There was a very weak positive correlation between Step 2 CK scores and subjective measures of resident performance (0.19, 95% CI 0.13-0.25, P < .01). CONCLUSIONS: This study found Step 2 CK scores have a statistically significant moderate positive association with future examination scores and a statistically significant weak positive correlation with subjective measures of resident performance. These findings are increasingly relevant as Step 2 CK scores will likely become more important in resident selection.

Patient-Reported Quality of Communication Skills in the Clinical Workplace for Clinicians Learning Medical Spanish.

Introduction Patient-clinician communication is a key factor in patient satisfaction with care. Clinicians take medical language courses to improve communication with linguistically diverse populations, yet little is known about how patients perceive clinicians' skills. Methods We designed a prospective, comparative survey study of patient perception of clinician communication using a convenience sampling of health professionals enrolled in an interprofessional medical Spanish course. We analyzed the patient-reported quality of communication skills from 214 clinical encounters and self-evaluations of 18 clinicians with Spanish- and English-speaking patients. Results Communication scores were lower for Spanish vs. English encounters as reported by both patients and clinicians (p<0.001). Clinician-reported scores were lower than patient-reported scores in Spanish encounters (9.05±0.23 vs. 8.05±0.23; p<0.001), whereas there was no difference in English encounters (11.17±0.15 vs. 11.35±0.19; p=0.914). The effect of language remained significant (p<0.001) when controlling for medical setting and complexity. Conclusion Spanish-speaking patients report lower-quality communication from clinicians learning Spanish than do English-speaking patients. Incorporating and further evaluating patient perceptions of clinician Spanish communication skills may improve language-appropriate healthcare and clinician education.

Impact of Fiducial Marker Placement Before Stereotactic Body Radiation Therapy on Clinical Outcomes in Patients With Pancreatic Cancer.

PURPOSE: Localized pancreatic cancer is commonly treated with stereotactic body radiation therapy (SBRT), which often requires the placement of fiducial markers. We compared the clinical outcomes of patients with and without fiducial markers. METHODS AND MATERIALS: We retrospectively collected data on patients with pancreatic cancer treated with neoadjuvant SBRT at a single institution. Patients were divided into 2 groups based on the placement of a fiducial marker. Local recurrence was the primary outcome. Time to event endpoints were analyzed using COX regression. RESULTS: We included 96 patients with unresectable pancreatic cancer: 46 patients (47.9%) did not have a fiducial marker, and 50 patients (52.1%) had a fiducial placed. Patients in the fiducial group were older and had more locally advanced pancreatic cancer compared with those who did not have a fiducial placed. Most patients in both groups (92.7%) received chemotherapy before SBRT treatment. SBRT was delivered to a median of 36 Gy over 5 fractions in the no-fiducial group, and 38 Gy over 5 fractions in the fiducial group. At a median follow-up of 20 months, local recurrence was similar irrespective of fiducial placement (adjusted hazard ratio [aHR] 0.6, 95% CI 0.3-1.3, P = .59). Furthermore, no difference in overall survival was noted between the 2 groups (aHR 0.8, 95% CI 0.3-1.9, P = .65). In patients who eventually underwent surgery post-SBRT, no difference in surgical margins (P = .40) or lymphovascular invasion (P = .76) was noted between the 2 groups. No patient developed acute pancreatitis after fiducial placement. CONCLUSIONS: Our data suggest that the use of fiducial markers does not negatively affect clinical outcomes in patients with localized pancreatic cancer. Prospective confirmation of our results is still needed.

Radiation-Associated Lymphopenia and Outcomes of Patients with Unresectable Hepatocellular Carcinoma Treated with Radiotherapy.

BACKGROUND: The immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan-Meier method. Univariable and multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy. RESULTS: Of 143 patients identified, the median age was 66 (range, 19-90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13-25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/µL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk. CONCLUSION: Grade 3 or higher lymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.

Pathologic Response and Postoperative Complications After Short-course Radiation Therapy and Chemotherapy for Patients With Rectal Adenocarcinoma.

BACKGROUND: The role of neoadjuvant short-course radiation therapy (SCRT) in treating rectal adenocarcinoma is a topic of ongoing debate. Growing interest in total neoadjuvant therapy has spurred discussion on the optimal sequence of preoperative SCRT and chemotherapy. PATIENTS AND METHODS: All patients receiving SCRT (5 Gy × 5 fractions) were identified. Details about preoperative treatments, radiation toxicities, and postoperative complications were collected. Patients were divided into 2 groups: those who underwent surgery within 14 days of completing SCRT and those with a longer delay. Outcomes compared included extent of pathologic response, margin-negative resection rate, acute radiation toxicities, and postoperative complications. RESULTS: Fifty-seven patients with locally advanced or metastatic rectal cancer received SCRT between 2008 and 2018. Thirty-nine of 57 patients underwent definitive pelvic surgery with total mesorectal excision. There were no significant differences in tumor downstaging, radial margin status, or percent tumor viability between patients with immediate surgery versus delayed surgery. The delay group had higher rates of nodal downstaging (64.7% vs. 18.2%; P = .003). There were no differences in total or grade 3+ gastrointestinal radiation toxicity, postoperative complications, reoperation, readmission, and mortality between the 2 groups. CONCLUSIONS: Though not yet common in the United States, SCRT has compared favorably with long course chemoradiation in multiple trials. Moreover, it is associated with greater efficiency and less disruption to chemotherapy. Our data show similar response and toxicity outcomes between the immediate and delay groups, suggesting SCRT is well-tolerated regardless of treatment sequence. Recently completed prospective trials may reveal the optimal preoperative treatment sequence.

Radiation dose escalation for locally advanced unresectable intrahepatic and extrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC) remain challenging diseases to treat. The majority of patients present with advanced disease, and the tumors often cause life-threatening biliary obstruction and vascular compromise of the liver. Local control (LC) of these tumors has the potential to prolong life for patients. While escalated-dose radiation therapy (EDRT) has been demonstrated to be an effective, safe option to achieve LC of IHCC, data for EHCC suggest that EDRT with current techniques has limitations, often due to dose-limiting bowel structures in close proximity to the extrahepatic biliary system. Here we review the results of EDRT for IHCC and EHCC and point to potential directions to combine radiotherapy with novel agents. The molecular characterization of cholangiocarcinoma has particularly opened new avenues for clinical investigations of targeted therapies with EDRT and may point to ways to achieve both systemic and LC benefits for patients.

Computed Tomography-Based Biomarker Outcomes in a Prospective Trial of Preoperative FOLFIRINOX and Chemoradiation for Borderline Resectable Pancreatic Cancer.

PURPOSE: Effective preoperative regimens and biomarkers for pancreatic ductal adenocarcinoma (PDAC) are lacking. We prospectively evaluated fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX)-based treatment and imaging-based biomarkers for borderline resectable PDAC. METHODS: Eligible patients had treatment-naïve, histology-confirmed PDAC and one or more high-risk features: mesenteric vessel involvement, CA 19-9 level of 500 mg/dL or greater, and indeterminate metastatic lesions. Patients received modified FOLFIRINOX and chemoradiation before anticipated pancreatectomy. Tumors were classified on baseline computed tomography as high delta (well-defined interface with parenchyma) or low delta (ill-defined interface). We designated computed tomography interface response after therapy as type I (remained or became well defined) or type II (became ill defined). The study had 80% power to differentiate a 60% from 40% resection rate (α = .10). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and subgroups were compared using log-rank tests. RESULTS: Thirty-three patients initiated therapy; 45% underwent pancreatectomy. The median OS was 24 months (95% CI, 16.2 to 29.6 months). For patients who did and did not undergo pancreatectomy, the median OS was 42 months (95% CI, 17.7 months to not estimable) and 14 months (95% CI, 9.0 to 24.8 months), respectively. Patients with high-delta tumors had lower 3-year PFS (4% v 40%) and 3-year OS rates (20% v 60%) than those with low-delta tumors (both P < .05). Patients with type II interface responses had lower 3-year PFS (0% v 29%) and 3-year OS rates (16% v 47%) than those with type I responses (both P < .001). CONCLUSION: Preoperative FOLFIRINOX followed by chemoradiation for high-risk borderline resectable PDAC was associated with a resection rate of 45% and median OS of approximately 2 years. Our imaging-based biomarker validation indicates that personalized treatment may be achieved using these biomarkers at baseline and post-treatment.

Total Synthesis of Waltherione F, a Nonrutaceous 3-Methoxy-4-quinolone, Isolated from Waltheria indica L. F.

Waltherione F was totally synthesized in seven steps and 31% overall yield from 2-nitro-3-methylanisole without the use of protecting groups. Key steps in the sequence were a Suzuki-Miyaura coupling to attach the n-octyl chain and a microwave-promoted cyclization of an acetonyl anthranilate to give the heterocyclic core whose 3-OH was O-methylated.

Antiviral effect of compounds derived from the seeds of Mammea americana and Tabernaemontana cymosa on Dengue and Chikungunya virus infections.

BACKGROUND: The transmission of Dengue virus (DENV) and Chikungunya virus (CHIKV) has increased worldwide, due in part to the lack of a specific antiviral treatment. For this reason, the search for compounds with antiviral potential, either as licensed drugs or in natural products, is a research priority. The objective of this study was to identify some of the compounds that are present in Mammea americana (M. americana) and Tabernaemontana cymosa (T. cymosa) plants and, subsequently, to evaluate their cytotoxicity in VERO cells and their potential antiviral effects on DENV and CHIKV infections in those same cells. METHODS: Dry ethanolic extracts of M. americana and T. cymosa seeds were subjected to open column chromatographic fractionation, leading to the identification of four compounds: two coumarins, derived from M. americana; and lupeol acetate and voacangine derived from T. cymosa.. The cytotoxicity of each compound was subsequently assessed by the MTT method (at concentrations from 400 to 6.25 µg/mL). Pre- and post-treatment antiviral assays were performed at non-toxic concentrations; the resulting DENV inhibition was evaluated by Real-Time PCR, and the CHIKV inhibition was tested by the plating method. The results were analyzed by means of statistical analysis. RESULTS: The compounds showed low toxicity at concentrations ≤ 200 µg/mL. The compounds coumarin A and coumarin B, which are derived from the M. americana plant, significantly inhibited infection with both viruses during the implementation of the two experimental strategies employed here (post-treatment with inhibition percentages greater than 50%, p < 0.01; and pre-treatment with percentages of inhibition greater than 40%, p < 0.01). However, the lupeol acetate and voacangine compounds, which were derived from the T. cymosa plant, only significantly inhibited the DENV infection during the post-treatment strategy (at inhibition percentages greater than 70%, p < 0.01). CONCLUSION: In vitro, the coumarins are capable of inhibiting infection by DENV and CHIKV (with inhibition percentages above 50% in different experimental strategies), which could indicate that these two compounds are potential antivirals for treating Dengue and Chikungunya fever. Additionally, lupeol acetate and voacangine efficiently inhibit infection with DENV, also turning them into promising antivirals for Dengue fever.

Deep sequencing: becoming a critical tool in clinical virology.

Population (Sanger) sequencing has been the standard method in basic and clinical DNA sequencing for almost 40 years; however, next-generation (deep) sequencing methodologies are now revolutionizing the field of genomics, and clinical virology is no exception. Deep sequencing is highly efficient, producing an enormous amount of information at low cost in a relatively short period of time. High-throughput sequencing techniques have enabled significant contributions to multiples areas in virology, including virus discovery and metagenomics (viromes), molecular epidemiology, pathogenesis, and studies of how viruses to escape the host immune system and antiviral pressures. In addition, new and more affordable deep sequencing-based assays are now being implemented in clinical laboratories. Here, we review the use of the current deep sequencing platforms in virology, focusing on three of the most studied viruses: human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza virus.

Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response.

Human lymphocyte antigen (HLA)-restricted CD8(+) cytotoxic T lymphocytes (CTL) target and kill HIV-infected cells expressing cognate viral epitopes. This response selects for escape mutations within CTL epitopes that can diminish viral replication fitness. Here, we assess the fitness impact of escape mutations emerging in seven CTL epitopes in the gp120 Env and p24 Gag coding regions of an individual followed longitudinally from the time of acute HIV-1 infection, as well as some of these same epitopes recognized in other HIV-1-infected individuals. Nine dominant mutations appeared in five gp120 epitopes within the first year of infection, whereas all four mutations found in two p24 epitopes emerged after nearly two years of infection. These mutations were introduced individually into the autologous gene found in acute infection and then placed into a full-length, infectious viral genome. When competed against virus expressing the parental protein, fitness loss was observed with only one of the nine gp120 mutations, whereas four had no effect and three conferred a slight increase in fitness. In contrast, mutations conferring CTL escape in the p24 epitopes significantly decreased viral fitness. One particular escape mutation within a p24 epitope was associated with reduced peptide recognition and high viral fitness costs but was replaced by a fitness-neutral mutation. This mutation appeared to alter epitope processing concomitant with a reduced CTL response. In conclusion, CTL escape mutations in HIV-1 Gag p24 were associated with significant fitness costs, whereas most escape mutations in the Env gene were fitness neutral, suggesting a balance between immunologic escape and replicative fitness costs.