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Background: Breast cancer-related lymphoedema (BCRL) is a growing concern with the increased survival rate following breast cancer (Smith et al, 2011). However, limited data is available on prospective management designed to reduce the morbidity of BCRL. Aims: To evaluate the impact of the development of a BCRL programme on the management of women with breast cancer. Methods: In 2004, a BCRL programme was developed at William Beaumont Hospital (WBH) to increase awareness regarding BCRL and to have more patients evaluated by a BCRL expert prospectively. Indications for patient referral and therapies recommended were evaluated and compared during a five-year time period. Results: At inception, the majority of cases seen in the clinic focused on existing BCRL (86%), with no patients seen electively (91% of all patients presented with clinically evident lymphoedema). Five years after inception, 25% of all new breast cancers diagnosed at WBH were seen electively in the clinic and significantly more were seen for elective evaluation (18.9% v. 0%, p<0.001). Conclusions: Five years following the inception of a BCRL clinic, significant increases in elective BCRL visits were seen. Declaration of interest: None. [ABSTRACT FROM AUTHOR]

Acquired cerebellar tonsillar herniation and syringomyelia associated with posterior fossa mass lesions is an exception rather than the rule. In the present article, we describe the neuroimaging findings in a case of 28-year-old female patient presented with a history of paraesthesia involving right upper limb of 8-month duration. Magnetic resonance imaging showed a giant retrocerebellar arachnoid causing tonsillar herniation with cervical syringomyelia. The findings in the present case supports that the one of the primary mechanism for the development of syringomyelia may be the obstruction to the flow of cerebrospinal fl uid causing alterations in the passage of extracellular fluid in the spinal cord and leading to syringomyelia. [ABSTRACT FROM AUTHOR]

Background: Aortic stenosis (AS) is frequently identified at an advanced stage after clinical symptoms appear. The aim of this systematic review and meta-analysis is to evaluate the diagnostic accuracy of artificial intelligence (AI) algorithms for AS screening. Methods: We conducted a thorough search of six databases. Several evaluation parameters, such as sensitivity, specificity, diagnostic odds ratio (DOR), negative likelihood ratio (NLR), positive likelihood ratio (PLR), and area under the curve (AUC) value were employed in the diagnostic meta-analysis of AI-based algorithms for AS screening. The AI algorithms utilized diverse data sources including electrocardiograms (ECG), chest radiographs, auscultation audio files, electronic stethoscope recordings, and cardio-mechanical signals from non-invasive wearable inertial sensors. Results: Of the 295 articles identified, 10 studies met the inclusion criteria. The pooled estimates for AI-based algorithms in diagnosing AS were as follows: sensitivity 0.83 (95% CI: 0.81-0.85), specificity 0.81 (95% CI: 0.79-0.84), PLR 4.78 (95% CI: 3.12-7.32), NLR 0.20 (95% CI: 0.13-0.28), and DOR 27.11 (95% CI: 14.40-51.05). The AUC value was 0.909 (95% CI: 0.889-0.929), indicating outstanding diagnostic accuracy. Subgroup and meta-regression analyses showed that continent, type of AS, data source, and type of AI-based method constituted sources of heterogeneity. Furthermore, we demonstrated proof of publication bias for DOR values analyzed using Egger's regression test (P = 0.002) and a funnel plot. Conclusion: Deep learning approaches represent highly sensitive, feasible, and scalable strategies to identify patients with moderate or severe AS. [ABSTRACT FROM AUTHOR]

Background: Breast-conserving surgery with synchronous 50-kV X-ray intraoperative radiation therapy (TARGIT-IORT) is a convenient form of partial breast irradiation; however, the existing literature supports a wide range of local control rates. Objectives: We investigated the treatment effectiveness and toxic effects of TARGIT-IORT in a patient cohort aged 64 years or older with low-risk breast cancer. Design: Retrospective analysis. Methods: Patients who received breast-conserving surgery with synchronous TARGIT-IORT at a single institution from 2016 to 2019 were reviewed. Additional whole breast irradiation was recommended at the discretion of the treating radiation oncologist. Baseline patient demographics and treatment details were recorded. Acute and chronic toxicities, measured using the Common Terminology Criteria for Adverse Events version 3.0 or 4.0 and breast cosmetic outcomes, using the Harvard Cosmesis score, were recorded. Locoregional recurrence, distant metastasis, and overall survival were recorded, and 5-year rates were estimated using the Kaplan-Meier method. Results: 61 patients were included with a median follow-up of 3.5 years and median age of 72 years. Eight (13%) patients received additional whole breast irradiation, and fifty-four (89%) received adjuvant hormone therapy. There were no local, regional, or distance recurrences. One patient died of complications from COVID-19 infection. Grade 2 + acute and chronic toxicities were observed in 6 (12%) and 7 (14%) patients, respectively. One patient experienced a grade 3 acute toxicity. Cosmetic outcome was "excellent" or "good" in 45 (92%) patients. Conclusions: Breast TARGIT-IORT was well tolerated and conferred excellent disease control in this cohort of patients with low-risk breast cancer. While continued follow-up is required, TARGIT-IORT may be an appropriate treatment option for this population. [ABSTRACT FROM AUTHOR]

• Open bicondylar tibial plateau fractures have a high rate of complications with a high incidence of Gustilo-Anderson type IIIB and C injuries. • Time to flap coverage greater than 7 days was associated with higher rates of deep infection and unplanned reoperation in this cohort. • Complication rates did not differ significantly after acute ORIF compared to staged management in the appropriately selected fracture. Complete articular tibial plateau fractures are typically high-energy injuries associated with significant soft tissue trauma. The primary aim of this study was to evaluate the incidence of wound complications and need for soft tissue coverage after open, complete articular tibial plateau fractures. The secondary aim was to study the effect of timing of fixation and timing of flap coverage on deep infection rates in these injuries. This was a retrospective cohort study of consecutive patients > 18 years undergoing ORIF of a Bicondylar Tibial Plateau (BTP) fracture between 2001 and 2018. Surgical data were recorded for open fractures including number of debridements, timing of definitive ORIF and soft tissue coverage relative to injury. Primary outcomes included rates of deep infection and unplanned reoperation. 508 AO/OTA 41C BTP fractures were identified, with 51 open fractures included in 50 patients with a mean (SD) age 45.7 (12.3) years and a mean (SD) follow up of 4.3 (3.8) years. There were 20 cases of deep infection, unplanned reoperation occurred in 26 cases. The majority of cases (28 fractures) had initial external fixation placed, while 24 had ORIF at the initial debridement. Twelve patients had a planned flap for definitive closure on average of 6.4 days (SD 3.9) after injury, 14 required a flap for wound complications. Among patients with IIB and C injuries, rates of deep infection (5/6 vs 1/6, p = 0.02) and reoperation (5/7 vs 2/6, p = 0.08) were higher in patients treated with flap coverage >7 days from injury compared to early flap coverage. There were no differences in complication rates between early (<24hrs) and delayed fixation. Complete articular, open tibial plateau fractures are associated with high rates of complications. Time to flap coverage of seven days or more was a significant predictor of deep infection and unplanned reoperation in this cohort. Patients should be counseled about the high rate of unplanned reoperation and definitive soft tissue coverage should be accomplished within a week of injury whenever possible. [ABSTRACT FROM AUTHOR]

Background: The Current National Comprehensive Cancer Network guidelines recommend modified radical mastectomy (MRM) as the surgical treatment of choice for nonmetastatic inflammatory breast cancer (IBC). Limited studies have looked into the outcomes of breast conserving surgery (BCS) vs. MRM for IBC. Methods: National Cancer Database (NCDB) data from 2004 to 2014 were retrospectively analyzed. Patients' demographics, tumor characteristics, and overall survival (OS) trends were compared for BCS and MRM cases of nonmetastatic IBC. Univariate and multivariate analyses were performed. Results: A total of 413 (3.89%) BCS and 10,197 (96.11%) MRM cases were identified. Median follow‐up was 58.45 months. Compared to MRM, BCS patients were more likely to be older, be African American, have Medicare/Medicaid or be uninsured, live in lower education ZIP codes, and live in a metropolitan area (all p < 0.05). BCS rates significantly decreased from 5.84% in 2004 to 3.19% in 2014 (p < 0.001). BCS patients also were more likely to have less than 50% of the breast involved (51.57% vs. 43.88%; p = 0.0081) and were less likely to receive trimodal therapy (50.85% vs. 74.62%; p = <0.0001). The OS was significantly higher in the mastectomy group over 9 years at 62.02% vs. 54.47% in the BCS group. Additionally, in the adjusted multivariate model, BCS cases were associated with 23% higher hazards of overall mortality (p = 0.0091). Conclusion: BCS was performed in a limited number of cases, which decreased over the study period. The analysis identified both demographic predictors of receiving BCS and significantly lower OS for IBC patients undergoing a BCS. [ABSTRACT FROM AUTHOR]

Pilocytic astrocytoma (PA) is a subset of gliomas characterized by a benign course with an excellent prognosis and rarely metastasizing or spreading along the neuraxis. We report a case of a 56-year female with intraventricular dissemination of pilocytic astrocytoma in an adult and discuss the clinical significance diagnosis and management including the peculiar pattern of dissemination of the pilocytic astrocytoma. The course of the disseminated disease may not be as good as that of patients with localized recurrence or totally resected primary disease and can vary from rapid progression to prolonged stabilization. [ABSTRACT FROM AUTHOR]

Importance: Privately insured patients who receive care from in-network physicians may receive unexpected out-of-network bills ("surprise bills") from out-of-network clinicians they did not choose. In elective surgery, this can occur if patients choose in-network surgeons and hospitals but receive out-of-network bills from other involved clinicians.Objective: To evaluate out-of-network billing across common elective operations performed with in-network primary surgeons and facilities.Design, Setting, and Participants: Retrospective analysis of claims data from a large US commercial insurer, representing 347 356 patients who had undergone 1 of 7 common elective operations (arthroscopic meniscal repair [116 749]; laparoscopic cholecystectomy [82 372]; hysterectomy [67 452]; total knee replacement [42 313]; breast lumpectomy [18 018]; colectomy [14 074]; coronary artery bypass graft surgery [6378]) by an in-network primary surgeon at an in-network facility between January 1, 2012, and September 30, 2017. Follow-up ended November 8, 2017.Exposure: Patient, clinician, and insurance factors potentially related to out-of-network bills.Main Outcomes and Measures: The primary outcome was the proportion of episodes with out-of-network bills. The secondary outcome was the estimated potential balance bill associated with out-of-network bills from each surgical procedure, calculated as total out-of-network charges less the typical in-network price for the same service.Results: Among 347 356 patients (mean age, 48 [SD, 11] years; 66% women) who underwent surgery with in-network primary surgeons and facilities, 20.5% of episodes (95% CI, 19.4%-21.7%) had an out-of-network bill. In these episodes, the mean potential balance bill per episode was $2011 (95% CI, $1866-$2157) when present. Out-of-network bills were associated with surgical assistants in 37% of these episodes; when present, the mean potential balance bill was $3633 (95% CI, $3384-$3883). Out-of-network bills were associated with anesthesiologists in 37% of episodes; when present, the mean potential balance bill was $1219 (95% CI, $1049-$1388). Membership in health insurance exchange plans, compared with nonexchange plans, was associated with a significantly higher risk of out-of-network bills (27% vs 20%, respectively; risk difference, 6% [95% CI, 3.9%-8.9%]; P < .001). Surgical complications were associated with a significantly higher risk of out-of-network bills, compared with episodes with no complications (28% vs 20%, respectively; risk difference, 7% [95% CI, 5.8%-8.8%]; P < .001). Among 83 021 procedures performed at ambulatory surgery centers with in-network primary surgeons, 6.7% (95% CI, 5.8%-7.7%) included an out-of-network facility bill and 17.2% (95% CI, 15.7%-18.8%) included an out-of-network professional bill.Conclusions and Relevance: In this retrospective analysis of commercially insured patients who had undergone elective surgery at in-network facilities with in-network primary surgeons, a substantial proportion of operations were associated with out-of-network bills. [ABSTRACT FROM AUTHOR]

The article focuses on a study on the correlation between response to neoadjuvant chemotherapy and molecular classification groups. The molecular classification group such as luminal-A, luminal-B and HER 2-variant was determined in several breast cancer patients who received neoadjuvant treatment using immunohistochemistry. The study concludes that molecular classification system is useful for identifying carcinoma patients who are most likely and those who are least likely to achieve a complete pathologic response.

A case study of a 74-year-old White female who was incidentally found to have a prominent mass, is presented. Topics include ultrasound-guided core needle biopsy of the mass was performed which showed a fragment of myxoid tissue but did not identify lymphoid tissue or breast tissue; and benign breast masses found in young individuals with no prior history of breast surgery and found as benign masses in the breast on routine imaging or palpable mass on physical examination.

Purpose/objective(s): There is a paucity of data regarding the use of whole breast irradiation (WBI) as part of breast conserving therapy (BCT) in women diagnosed with breast cancer who had undergone prior breast implant-based augmentation. In this population, we investigated various factors that impact radiation related toxicities, including the need for additional cosmetic surgery.Materials/methods: A retrospective review was performed for a single institution, with queries done on health-system medical records, radiation therapy medical records, radiology mammography studies, and internal radiation therapy and toxicity databases. We included patients with a prior history of breast implant-based augmentation who subsequently underwent BCT and WBI. Patient and treatment characteristics were collected and reported, and univariate analyses comparing factors correlating with toxicity endpoints were performed. Long-term cosmesis was assessed by the patient's radiation oncologist during routine follow-up visits via the Harvard grading criteria.Results: 35 patients treated at our institution between 2006 and 2020 were included in our analyses, with a median follow up time of 2.4 years. Of these, 28 were treated with conventionally fractionated WBI (1.8-2 Gy/Fx) and 7 were treated with hypofractionated WBI (2.66 Gy/Fx). Good/excellent long-term cosmesis was observed in 94% of all patients. 44% of patients ultimately needed additional cosmetic surgery at some point after radiation. Indications for additional surgery included capsular contracture (10), wound complications (2), implant rupture (1), volume loss (1), and asymmetry (1). Fourteen patients (50%) treated with conventionally fractionated WBI and one patient (14%) patient treated with hypofractionated WBI required additional surgery, but this difference was not significant on UVA (P = 0.12). Other factors found not to be significantly associated with rates of additional surgery included BMI, stage, the volume of the breast receiving 105% or 110% of the prescription dose, and presence or absence of bolus during treatment. No patients experienced local or regional recurrence.Conclusion: Patients with a prior history of breast implantation often experience good long-term cosmesis with a moderate risk of needing additional future surgery. The use of hypofractionated WBI was not associated with worse cosmetic outcome or an increase in need for additional cosmetic surgery. [ABSTRACT FROM AUTHOR]

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by hemolytic anemia, renal failure, and thrombocytopenia. While the typical form of HUS is often associated with Shiga toxin-producing Escherichia coli (STEC) infections, atypical hemolytic uremic syndrome (aHUS) is caused by uncontrolled complement system activation, leading to endothelial damage, microthrombi formation, and other complications. Although aHUS is commonly linked to genetic mutations and infections, emerging evidence suggests that certain substances, particularly illicit drugs like heroin, cocaine, and ecstasy, can also trigger this condition, adding complexity to its diagnosis and management. This narrative review examines the mechanisms by which substance use can lead to aHUS, discusses its clinical presentation, and highlights the diagnostic challenges in distinguishing it from other thrombotic microangiopathies, such as thrombotic thrombocytopenic purpura (TTP) and STEC-HUS. A thorough literature search identified relevant case reports, case series, and observational studies, underscoring the need for genetic testing and complement assays to confirm aHUS in substance users. The review also explores the role of complement inhibitors, such as eculizumab and ravulizumab, which target the underlying pathophysiology and have shown promise in improving patient outcomes. However, the management of substance-induced aHUS remains challenging due to limited data, varying clinical presentations, and the need to optimize treatment protocols. Early recognition and tailored therapy are crucial for effective management. Further research is needed to refine diagnostic criteria, develop new therapeutic approaches, and improve care for patients with this under-recognized condition., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Akbariansaravi et al.)

Strokes are a major cause of morbidity and mortality across the globe. An ischemic stroke of thalamic origin should be considered if a patient presents with a set of non-localizing symptoms such as speech issues, sensory abnormalities, chorea-like movements, ataxia and confusion that cannot be explained by a single lesion. A 78-year-old female with a past medical history of hypertension and smoking developed right-hand numbness and ataxia that progressively worsened to numbness of the entire right side of the body and right-arm hemiballismus. Magnetic resonance imaging (MRI) confirmed an acute left thalamic ischemic stroke as the cause of her symptoms. Our case report highlights the rare clinical presentation of thalamic strokes that can aid in the diagnosis and localization of such pathologies. Further research regarding the best therapy for these post-stroke movement pathologies is needed., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, King et al.)

Dyshormonogenetic goiter (DG) is a rare cause of congenital hypothyroidism (CH) occurring due to the lack of enzymes necessary for thyroid hormone synthesis. If left untreated, it impairs hormone production leading to developmental and metabolic complications. Morphologically, it is characterized by architectural and cellular pleomorphism that may mimic thyroid malignancy causing difficulties in diagnosis. Thus, accurate histopathological evaluation is crucial in distinguishing DG from malignancy. We report a case of a 13-year-old female diagnosed with hypothyroidism at the age of six. Over time, she exhibited slow development of a multinodular goiter and began experiencing dyspnea in the supine position. Ultrasonography confirmed an enlarged thyroid gland with solid hypoechoic nodules devoid of calcifications, so a total thyroidectomy was performed. Gross examination revealed that the gland was notably enlarged with a grey-tan nodular appearance with few cystic hemorrhagic areas and had a firm rubbery texture. Microscopy identified microfollicular cells with significant hyperplasia and cytologic atypia along with scant colloid, indicative of DG. Histopathological literature has been essential to prevent overdiagnosis of malignancy. Additionally, the authors suggest that it is crucial to include DG in the differential diagnosis when evaluating potential causes of CH., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Dekhne et al.)

Patients with cancer are at risk for thrombotic complications due to a hypercoagulable state. However, the benefit of prophylactic anticoagulation is unclear in many subsets of these patients. For the first episode of acute thromboembolic disease (VTE) in patients with active cancer, anticoagulant therapy is administered for at least three to six months. Herein, we present a 31-year-old female with active, recurrent stage IIIa classical Hodgkin lymphoma (CHL) (nodular sclerosis), previously treated for proximal upper extremity deep vein thrombosis (DVT), presenting for evaluation of shortness of breath and eventually diagnosed with bilateral pulmonary embolism (PE) secondary to a right atrial thrombus. The patient was successfully treated with surgical resection of the thrombus. With this case report, we hope to encourage physicians to use prophylactic indefinite anticoagulation in patients with active cancer and previous DVT, including patients with upper extremity DVT., Competing Interests: Conflict of interest: No conflict of interest., (© 2024 Greater Baltimore Medical Center.)

Neuralgia is characterized by chronic pain resulting from damage or diseases in the somatosensory system, including nerves responsible for transmitting sensory information. Current treatments for neuropathic pain, which is a type of neuralgia, have limited success rates and can cause unwanted side effects. Since 1989, botulinum toxin-A (BTX-A), derived from the potent neurotoxin Clostridium botulinum , has been used to treat neuropathic pain in humans. BTX-A has shown analgesic effects by inhibiting the release of neurotransmitters involved in pain transmission. This review aims to evaluate the effectiveness of BTX-A in various types of neuralgia. The research question guiding this review is whether BTX-A is safe and effective in reducing pain in different types of neuralgias. To conduct this review, a literature search was performed using the PubMed, Medline, and PubMed Central databases. The search strategy included relevant keywords related to BTX-A, neuralgia, and neuropathic pain. After screening titles, abstracts, and full texts, a total of 30 articles were included in the review. These studies examined the efficacy of BTX-A in various conditions such as postherpetic neuralgia (PHN), auriculotemporal neuralgia (ATN), occipital neuralgia (ON), leprosy-induced neuropathic pain (LIN), focal painful neuropathies, complex regional pain syndrome (CRPS), trigeminal neuralgia (TN), and neuropathic pain associated with spinal cord injury. However, further research is needed to enhance our understanding of the optimal use of BTX-A in specific neuralgias. It is important to acknowledge the limitations of the included studies. Nevertheless, BTX-A might be considered a viable treatment option for neuralgia., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Dekhne et al.)

Objectives This study aimed to analyze the impact of the United States Medical Licensing Examination (USMLE) Step 1 transition to a pass/fail scoring system in 2022 on the performance of first-time test takers in three distinct groups: Doctor of Osteopathy (DO) and Doctor of Medicine (MD) examinees from US/Canadian schools and examinees from non-US/Canadian schools. The analysis spans a decade-long period from 2012 to 2022, offering insights into the implications of this pivotal change in medical education. Methods We analyzed the performance of first-time USMLE Step 1 examinees from US/Canadian MD and DO programs and non-US/Canadian schools from 2012 to 2022, including the transition year to a pass/fail scoring system. Data were obtained from USMLE performance data reports and organized into annual contingency tables. Descriptive statistics and comparative analysis were used to identify trends and differences in performance across the groups. Data visualization techniques were employed to illustrate these findings, and the results were contextualized within the broader changes in medical education. Results In 2021, first-time takers from US/Canadian MD and DO Degree programs had pass rates of 96% and 94%, respectively, while non-US/Canadian schools had a pass rate of 82%. However, in 2022, these rates dropped to 93%, 89%, and 74%, respectively. The most significant relative decline was observed among non-US/Canadian Schools' first-time takers, with an 8% decrease. Repeaters consistently had lower pass rates across all groups. Conclusion The study reveals a notable decline in pass rates following the transition to pass/fail scoring, although this is based on just one year of data. This underscores the importance of students not rushing into the exam and dedicating sufficient time for preparation. The potential impact of this research could be transformative for medical education, but more years of data post-transition will be needed to confirm these initial findings. These findings serve as a reminder that the change in scoring does not diminish the rigor of the exam, prompting students to approach their studies with diligence and patience and potentially paving the way for systemic improvements in medical education and healthcare delivery worldwide., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Yadav et al.)

We previously showed that classical 6-substituted pyrrolo[2,3-d]pyrimidine antifolates bind to folate receptor (FR) α and the target purine biosynthetic enzyme glycinamide ribonucleotide formyltransferase (GARFTase) with different cis and trans conformations. In this study, we designed novel analogs of this series with an amide moiety in the bridge region that can adopt both the cis and trans lowest energy conformations. This provides entropic benefit, by restricting the number of side-chain conformations of the unbound ligand to those most likely to promote binding to FRα and the target enzyme required for antitumor activity. NMR of the most active compound 7 showed both cis and trans amide bridge conformations in ~1:1 ratio. The bridge amide group in the best docked poses of 7 in the crystal structures of FRα and GARFTase adopted both cis and trans conformations, with the lowest energy conformations predicted by Maestro and evidenced by NMR within 1 kcal/mol. Compound 7 showed ~3-fold increased inhibition of FRα-expressing cells over its non-restricted parent analog 1 and was selectively internalized by FRα over the reduced folate carrier (RFC), resulting in significant in vitro antitumor activity toward FRα-expressing KB human tumor cells. Antitumor activity of 7 was abolished by treating cells with adenosine but was incompletely protected by 5-aminoimidazole-4-carboxamide (AICA) at higher drug concentrations, suggesting GARFTase and AICA ribonucleotide formyltransferase (AICARFTase) in de novo purine biosynthesis as the likely intracellular targets. GARFTase inhibition by compound 7 was confirmed by an in situ cell-based activity assay. Our results identify a "first-in-class" classical antifolate with a novel amide linkage between the scaffold and the side chain aryl L-glutamate that affords exclusive selectivity for transport via FRα over RFC and antitumor activity resulting from inhibition of GARFTase and likely AICARFTase. Compound 7 offers significant advantages over clinically used inhibitors of this class that are transported by the ubiquitous RFC, resulting in dose-limiting toxicities., (Copyright © 2019 Elsevier Ltd. All rights reserved.)