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Methotrexate (MTX), an antifolate, is administered at high doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high-dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life-threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 SDs above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of laboratory results that do not directly correspond to the algorithm prove to be a limitation of its use. The goal of our study was to develop a clinical decision support tool to optimize the administration of glucarpidase for patients receiving HD MTX. Here, we describe the development of a novel 3-compartment MTX population pharmacokinetic (PK) model using 31,672 MTX plasma concentrations from 772 pediatric patients receiving HD MTX for the treatment of acute lymphoblastic leukemia and its integration into the online clinical decision support tool, MTXPK.org. This web-based tool has the functionality to utilize individualized demographics, serum creatinine, and real-time drug concentrations to predict the elimination profile and facilitate model-informed administration of glucarpidase.

Vision loss following surgery for pituitary adenoma is poorly described in the literature and cannot be reliably predicted with current prognostic models. Detailed characterization of this population is warranted to further understand the factors that predispose a minority of patients to post-operative vision loss.The medical records of 587 patients who underwent endoscopic transsphenoidal surgery at the Mount Sinai Medical Centre between January 2013 and August 2018 were reviewed. Patients who experienced post-operative vision deterioration, defined by reduced visual acuity, worsened VFDs, or new onset of blurry vision, were identified and analysed.Eleven out of 587 patients who received endoscopic surgery for pituitary adenoma exhibited post-operative vision deterioration. All eleven patients presented with preoperative visual impairment (average duration of 13.1 months) and pre-operative optic chiasm compression. Seven patients experienced visual deterioration within 24 h of surgery. The remaining four patients experienced delayed vision loss within one month of surgery. Six patients had complete blindness in at least one eye, one patient had complete bilateral blindness. Four patients had reduced visual acuity compared with preoperative testing, and four patients reported new-onset blurriness that was not present before surgery. High rates of graft placement (10/11 patients) and opening of the diaphragma sellae (9/11 patients) were found in this series. Four patients had hematomas and four patients had another significant post-operative complication.While most patients with pituitary adenoma experience favourable ophthalmological outcomes following endoscopic transsphenoidal surgery, a subset of patients exhibit post-operative vision deterioration. The present study reports surgical and disease features of this population to further our understanding of factors that may underlie vision loss following pituitary adenoma surgery. Graft placement and opening of the diaphragma sellae may be important risk factors in vision loss following ETS and should be an area of future investigation.

Introduction Dopamine-agonist (DA) resistant prolactinomas are characterized by failure to achieve normal prolactin levels or reduce tumor size by at least 50% on maximal conventional DA dosages. This occurs in about 10% of patients on cabergoline and is more common in larger macroadenomas, and in men compared with women. The underlying cause of resistance may be a lack of D2 receptor (D2R) tumor expression. As high dose DA therapy may have serious cardiac side effects, it is important to determine the D2R expression. Further, the sexual dimorphism observed in resistant prolactinomas may be due to estrogen receptor alpha (ERα) expression in female tumors, as ERα signaling has been shown to enhance sensitivity to DAs. We investigated the possibility that androgen receptor (AR) signaling in males promotes resistance via induction of transmembrane serine protease 2 (TMPRSS2), a cell surface serine protease, a known promoter of tumor progression in prostate and lung cancer. Methods This is a retrospective, single-center study conducted at an academic quaternary-care center. Immunohistochemical (IHC) analysis was performed on 16 specimens from surgically removed lactotroph cell type tumors, including D2R, growth hormone (GH), prolactin (PRL), TMPRSS2, ERα, AR, and the stem cell marker, CD133. We simultaneously conducted a chart review of the Electronic Medical Record to determine age at diagnosis, tumor size, initial PRL level, medical treatment, and reason for surgical resection. Results A total of 14 patients were included in our study. Two patients had multiple surgeries for resistant prolactinomas such that the sample size included 16 specimens- 7 resistant prolactinomas and 9 controls (resected for another reason other than treatment resistance). There were 2 men and 3 women in the resistant group, and 5 women and 4 men in the control group. Baseline prolactin level was higher in the resistant group (2413ng/mL) than the control group (676.4ng/mL) and tumor size was larger—2.05cm vs. 1.57cm in the largest diameter in the resistant vs. control groups, respectively. D2R expression was positive in 8 out of 9 controls vs. 1 out of 7 in resistant tumors. ERα positivity did not correlate with DA resistance. AR expression was negative in all specimens although the majority of tumors in both groups did express TMPRSS2. CD133 was negative in all but one of the resistant tumors. Conclusion We found that 80% of specimens from patients with DA-resistant prolactinomas had negative D2R expression. The one resistant tumor that had positive D2R and negative TMPRSS2 expression was from an 11 year old girl who also had negative ERα expression that may explain the lack of response to dopamine agonist therapy. D2R IHC can identify lack of D2R expression in DA-resistant tumors and provide a rationale for discontinuation of high dose DA therapy to avoid toxicity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Geometric morphometric analysis with Procrustes superimposition is an advanced computational tool that can be used to quantify dynamic changes in complex three-dimensional structures. The present study couples high resolution CT imaging with a Geometric Morphometric approach in order to further understand the complex dysmorphology that occurs in unilateral coronal synostosis (UCS).Forty-one UCS patients and 41 age- and sex-matched controls received high-resolution CT imaging. Thirty-one anatomical landmarks were identified on each imaging set. A geometric morphometric workflow was used to perform a Procrustes superimposition to register landmarks into a common space. Procrustes-aligned landmarks were used to derive angle calculations, lengths, and other anatomical measurements. Three-dimensional coordinates were also used to perform a principal components analysis (PCA).Unilateral coronal synostosis patients exhibited significant angular deviation at the levels of the inferior skull base, mid-posterior fossa, and vertex. Both left- and right-sided UCS patients showed increased lengthening in the transverse (left-right) dimension, exhibiting increased length between the left and right EAC (P = 0.047). Conversely, UCS patients revealed shortening in the midline AP dimension as evidenced by the decreased Nasal root-Lambda (P 0.0001) and Nasal root-superior dorsum sellae (P = 0.01) distances compared with controls. PCA revealed that 25.26% of variation in shape among the patients sampled to be driven by flattening of the skull and that18.93% of variation was driven by right-sided deformity and mediolateral expansion.Significant dysmorphology between UCS patients and controls was quantified using Geometric Morphometric approach, which may be useful in further characterizing the dynamic craniofacial changes in UCS.

Methotrexate (MTX), an anti-folate, is administered at high-doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high-dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life-threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 standard deviations above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of lab results that do not directly correspond to the algorithm prove to be a limitation of its use.The goal of our study was to develop a clinical decision support tool to optimize the administration of glucarpidase for patients receiving HD MTX. Here, we describe the development of a novel three-compartment MTX population PK model using 31,672 MTX plasma concentrations from 772 pediatric patients receiving HD MTX for the treatment of acute lymphoblastic leukemia and its integration into the online clinical decision support tool, MTXPK.org. This web-based tool has the functionality to utilize individualized demographics, serum creatinine, and real-time drug concentrations to predict the elimination profile and facilitate model-informed administration of glucarpidase.

Background: Parents of children newly diagnosed with cancer are confronted with multiple stressors that place them at risk for significant psychological distress. One strategy that has been shown to help reduce uncertainty is the provision of basic information; however, families of newly diagnosed cancer patients are often bombarded with educational material. Technology has the potential to help families manage their informational needs and move towards normalization. Objective: The aim of this study was to create a mobile app that pulls together data from both the electronic health record (EHR) and vetted external information resources to provide tailored information to parents of newly diagnosed children as one method to reduce the uncertainty around their child’s illness. This app was developed to be used by families in a National Institutes of Health (NIH)-funded randomized controlled trial (RCT) aimed at decreasing uncertainty and the subsequent psychological distress. Methods: A 2-phase qualitative study was conducted to elicit the features and content of the mobile app based on the needs and experience of parents of children newly diagnosed with cancer and their providers. Example functions include the ability to view laboratory results, look up appointments, and to access educational material. Educational material was obtained from databases maintained by the National Cancer Institute (NCI) as well as from groups like the Children’s Oncology Group (COG) and care teams within Cincinnati Children’s Hospital Medical Center (CCHMC). The use of EHR-based Web services was explored to allow data like laboratory results to be retrieved in real-time. Results: The ethnographic design process resulted in a framework that divided the content of the mobile app into the following 4 sections: (1) information about the patient’s current treatment and other data from the EHR; (2) educational background material; (3) a calendar to view upcoming appointments at their medical center; and (4) a section where participants in the RCT document the study data. Integration with the NCI databases was straightforward; however, accessing the EHR Web services posed a challenge, though the roadblocks were not technical in nature. The lack of a formal, end-to-end institutional process for requesting Web service access and a mechanism to shepherd the request through all stages of implementation proved to be the biggest barrier. Conclusions: We successfully deployed a mobile app with a custom user interface that can integrate with the EHR to retrieve laboratory results and appointment information using vendor-provided Web services. Developers should expect to face hurdles when integrating with the EHR, but many of them can be addressed with frequent communication and thorough documentation. Executive sponsorship is also a key factor for success. Trial Registration: ClinicalTrials.gov NCT02505165; https://clinicaltrials.gov/ct2/show/NCT02505165 (Archived by WebCite at http://www.Webcitation.org/6r9ZSUgoT) [JMIR Res Protoc 2017;6(6):e122]

Background: Accurate assessment of aortic annulus size (AoA) is critical for insuring successful transcatheter aortic valve replacement (TAVR) as well as to minimize para-valvular regurgitation. However, the AoA is occasionally difficult to assess due to challenges caused by annular calcification, motion artifact and improper CT gating. Proper TAVR valve size and sealing is dependent more than just AoA, but rather multiple other measurements including the left ventricular outflow tract (LVOT) diameters and sinuses of Valsalva. We hypothesized that the measurement of sinuses of Valsalva and LVOT by cardiac computed tomographic angiography (CCTA) imaging are important adjunctive measurements in determining the ideal valve size for TAVR. Methods: Consecutive patients evaluated for TAVR underwent single phase, prospective ECG gated CCTA with contrast to evaluate the aortic valve anatomy. Measurements of annular, coronary height, left ventricular outflow tract diameters and areas were performed. Findings were analyzed using ANOVA and regression models. Results: CCTA was performed on 87 patients being evaluated for TAVR. Increasing body surface area (BSA) is weakly associated with AoA and somewhat correlated with sinotubular junction measurements. Sinuses of Valsalva and LVOT are strongly predictive of AoA and the ideal valve size (r 2 =0.66, r 2 =0.86, respectively). Sinuses of Valsalva and LVOT are helpful predictive adjuncts along with AoA in determining the ideal valve size for TAVR, specifically in those with the smallest and largest annular areas (figure 1). Coronary heights were not associated with AoA or BSA. Conclusion: There is a strong association between the annulus size and sinuses of Valsalva diameter and LVOT measured by CCTA. This finding is particularly useful in determining the appropriate valve size in those borderline cases or when accurate aortic annulus dimensions are difficult to obtain.

To the Editor: —I can heartily endorse Fletcher's assertion with reference to the value of quinin in malaria, reviewed in the editorial on the resistance of malaria to quinin (The Journal, April 5). In 1922-1923 while I was director of internal medicine in the American University of Bierut, Syria, eighty-nine hospitalized patients were treated with quinin for malaria. The types recognized by the parasite in the blood were tertian, sixty-three; quotidian, nineteen, and quartian, seven. All were arrested; by arrest is meant a cessation of chills and fever and a disappearance of the plasmodium from the peripheral blood. The quinin was administered, to the average patient, by mouth, 15 grains (1 gm.) in the early morning on an "empty stomach"; and 15 grains at 10 p. m. Usually three or four days was a sufficient length of time to secure an arrest. The earlier the infection was recognized and proper

Renal irritation, indicated by albumin, casts and red and white blood cells in the urine, and "focal infection" I have witnessed a number of times; but the case reported here offered the first opportunity to observe an acute renal irritation of such severity, secondary to suppurative otitis media, complicated by mastoiditis and lateral sinusitis, caused by the streptococcus micro-organism, from onset to recovery. The child was examined, Dec. 2. 1919. About this time a very helpful article by Dr. Lewis Webb Hill 1 appeared inThe Journal, in which were mentioned four cases of nephritis secondary to otitis media. This case is reported as corroborative evidence of the material presented in that article, and for the aid it may give to those encountering the same or similar pathologic conditions. It emphasizes the fact that renal disturbance is a secondary rather than a primary disturbance. Report OF CASE A girl (Record

Seldom is the opportunity given to check up on one's colleagues as closely and accurately as this case affords. The case is worth while reporting because of the lesion, the radical operation performed seventeen years prior to death, and the ease with which all facts pertaining were assembled. A man, aged 52, admitted in May, 1925, complained of loss of weight as a result of inability to take and assimilate food. From then until his death, November 23, repeated and detailed examinations failed to diagnose more than gastric malignancy. His history stated that part of the stomach was cut away and a new opening made by Dr. William Mayo, sixteen years previously. The patient had fair health until eight months before coming to the hospital. The roentgenogram showed a functioning gastro-enterostomy; about one third of the stomach, the cardiac end, could be seen. Hydrochloric acid was absent. Occult blood was

Loss of voice is a rare condition when it is caused by pressure of the thyroid gland. R. C. Coffey 1 does not remember having had a case of aphonia which was relieved by the removal of a goiter. G. W. Crile 1 says: "About 4 per cent of our cases show a unilateral paralysis and often present some difficulty in speech but usually are thoroughly compensated. With the exception of malignant cases I have never had a case with complete loss of voice. The functional side of such a case must of course, be considered. A laryngoscopic examination would clear up this point." E. S. Judd 1 cannot recall a case of this sort except one or two in which there was a hysterical aphonia which was relieved by operation; these, however, showed no definite paralysis of the cords on laryngoscopic examination. REPORT OF CASE A white man, aged