bluuebunny/crossref_metadata_2025 huggingface dataset:
The Importance of Pathogenesis: A Molecular Investigation on A Solitary Choriocarcinoma Lung Lesion with No Primary Lesion
Authors: luu L , LUU L
Published: October 2024

Introduction/Objective

We present an exceedingly rare case of metastatic choriocarcinoma to the lung with no primary lesion. Notably, this is the only case where STR molecular studies have been conducted.

Methods/Case Report

A 43-year-old G1P1001 female with no past medical history presents with severe shortness of breath, left-sided back, and chest pain for severe shortness of breath, left sided back and chest pain. Patients pregnancy test was positive with a B-hCG of 17944 u/L. Transvaginal ultrasound was negative for IUP. CTAP showed no masses in the uterine cavity or ovaries. D-dimer was elevated at 623 ng/ml. However, CTA chest was negative for pulmonary emboli but revealed a RLL mass measuring 2.6 x 2.5 cm x 2.9 cm with lobulated areas suspicious for vascular structures and connection to the right pulmonary vein.

Patient was treated with a complete right lower lobectomy. An endometrial biopsy was performed and was negative for malignancy with no significant findings.

Grossly, the mass was well-circumscribe, hemorrhagic, and necrotic, measuring 3.5 cm. Microscopically, the malignant cells had highly pleomorphic and hyperchromatic nuclei. There were also multiple multinucleated cells and mitotic figures present. Some of the cells had nested architecture leading to us to suspect a pleomorphic lung adenocarcinoma with choriocarcinomatous differentiation. We performed IHC staining that demonstrated strong positivity of AE1/AE3, CK7, hCG and a high Ki-67 index. The neoplastic cells also had focal p63 and p40 positivity. Furthermore, TTF1 and SALL4 were both negative. This staining pattern as well as patient’s clinical history of no gynecological lesion, lead us to favor lung adenocarcinoma with choriocarcinomatous differentiation. However, due to the abundance of syncytiotrophoblastic and trophoblastic cells, metastatic choriocarcinoma could not be ruled out.

Therefore, the case was sent out for external consultation and Short Tandem Repeat (STR) molecular testing. Surprisingly, the STR testing results showed some STR of paternal origin indicating a metastatic gestational choriocarcinoma.

The patient’s surgery was highly successful and lead to a down trending of b-hCG from 17944 to 1768 after removal.

Results (if a Case Study enter NA)

NA

Conclusion

Performing STR testing was pivotal in this case as it revealed the presence of DNA of paternal origin, providing crucial evidence that the tumor was of gestational origin, guiding the diagnosis towards metastatic gestational choriocarcinoma.
Identification and Validation of a novel Circulating miRNA Predictive Biomarkers for acquired Bortezomib Resistance in Multiple Myeloma patients at Southeast Medical Center
Authors: Bamfield-Cummings S , Silva J
Published: October 2024

Introduction/Objective

Bortezomib is used to treat multiple myeloma but some patients become resistant to it. MiRNAs, small non-coding RNAs that regulate gene expression, may serve as biomarkers for drug resistance in cancer. Dysregulation of miRNA expression is common in cancer development. We investigated whether plasma miRNAs can serve as clinical indicators for bortezomib resistance in multiple myeloma. We hypothesize that there is a significant difference in miRNA signature between sensitive and resistant Bortezomib multiple myeloma samples derived from African American male patients.

Methods/Case Report

Specific Aim 1: Discovery: To identify miRNAs using five BTZ-resistant and five sensitive African American male bone marrow samples using RNA sequencing technology. Using log2fold change ≥ 1.3, p ≤ 0.05, and known function as screening criteria of statistically significant upregulated miRNAs.

Specific Aim 2: Analytical validation: Quantitative reverse-transcription PCR (qRT-PCR) technology using bone African American Male Bone Marrow samples to confirm the differential expression of candidate miRNAs identified in Aim 1. Using log2fold change ≥ 1.3, p ≤ 0.05, and Two-tailed student T-Test known function as screening criteria of statistically significant upregulated miRNAs.

Specific Aim 3: Clinical Validation: To be performed using patients’ serum and qRT-PCR technology. Using log2fold change ≥ 1.3, p ≤ 0.05, known function, and Two-tailed student T-Test as the screening criteria of statistically significant upregulated miRNAs.

Results (if a Case Study enter NA)

We identified upregulated and downregulated miRNAs from African American males with MM in 5-BTZ-resistant and 5-BTZ-sensitive bone marrow samples using RNA sequencing. Four statistically significant upregulated miRNAs were identified and validated using RT-qPCR and bioinformatic target prediction (has-miR-18a-3p, has-miR-18a-5p, has-miR-20a-5p, has-mir-664a-5p). Using log2fold change ≥ 1.3, p ≤ 0.05, and Two-tailed student T-Test, and known function as screening criteria, has-miR-18a-5p and has-miR-20a-5p were validated as statistically significant upregulated miRNAs among the BTZ-resistant bone marrow samples. These miRNAs will now undergo clinical validation.

Conclusion

According to the qRT-PCR analysis, significant differential expression was observed between the Bortezomib-sensitive and Bortezomib-resistant groups was has-miR-18a-5p (p ≤ 0.02) and has-miR-20a-5p (p ≤ 0.04) as statistically significant differential expressed miRNAs and are associated with promoting carcinogenesis.
Novel human PDX1 Asn196Thr variant causes pancreas agenesis and reduces the generation of duodenal enteroendocrine cells
Authors: Yang X , Ishibashi J , Haemmerle M W , Stoffers D A , Schiaffini R , Rapini N , Miraglia del Giudice E , Cristina Digilio M , Mucciolo M , Cianfarani S , Barbetti F , Zanfardino A , Piscopo A , Iafusco D , Iorio R
Published: October 2024

Introduction/Objective

Pancreatic and duodenal homeobox 1 (PDX1) is a well-studied transcription factor required for pancreas organogenesis. PDX1 mutations are associated with the development of diabetes. An 8-month-old female patient with previously uncharacterized compound heterogeneous PDX1 missense mutations (Thr151Met and Asn196Thr) was identified in this study. The patient has permanent neonatal diabetes, pancreas hypoplasia, and a malformed gallbladder.

Methods/Case Report

PDX1 Thr151Met and Asn196Thr variants in the patient were identified by next-generation sequencing gene panel and confirmed by Sanger sequencing. To examine how the mutations affect PDX1 functions in vitro, we expressed mouse Pdx1 Thr152Met and Asn197Thr, homologous to human PDX1 Thr151Met and Asn196Thr, respectively, in mouse insulinoma MIN6 cells and human embryonic kidney 293T cells and examined protein localization, protein stability, DNA binding, and protein-protein interaction. We also generated embryonic day 18 mouse embryos carrying Pdx1 Asn197Thr missense mutation using CRISPR/Cas9 to examine its roles in the development of the pancreas and other digestive organs in vivo.

Results (if a Case Study enter NA)

We found that the Pdx1 Asn197Thr variant, but not Thr152Met, altered its nuclear localization and disrupted PDX1-Onecut 1 interaction. Neither variant significantly affected PDX1 protein stability, but both reduced PDX1 binding to the Pdx1 gene promoter. Importantly, we found that the Pdx1 Asn197Thr variant caused pancreas agenesis and a reduction in the generation of enteroendocrine cells in the proximal duodenum in mouse models.

Conclusion

Our data indicated that the PDX1 Asn196Thr variant impairs its DNA binding and protein-protein interaction, causing pancreas agenesis and a reduction in the generation of duodenal enteroendocrine cells.
Uncovering factors predicting BRAF mutation in cutaneous melanoma
Authors: Dudin O , Mintser O , Sulaieva O
Published: October 2024

Introduction/Objective

BRAF mutations are considered to be the most common genetic alteration in cutaneous melanoma (CM). Patient management relies on assessing molecular biomarkers enabling the personalization of patients’ treatment. The goal of this study was to develop the tools for predicting BRAF mutation using routine clinical and histological features.

Methods/Case Report

A total of 2041 CM cases were enrolled in the study to identify factors associated with BRAF mutation. Variables included sex, age, primary location, stage, histological type, ulceration, mitosis, Clark level, Breslow thickness, lymphocytes, lymphovascular invasion (LVI), perineural invasion (PNI), regression, microsatellite, association with nevus.

Results (if a Case Study enter NA)

The Ukrainian population demonstrated a high rate of BRAF mutation in CM, associated with the younger age and location at non-sun-expose skin. This study also revealed gender-specific differences in CM anatomic distribution and BRAF mutation subtype prevalence.

By using the genetic selection method, the minimal set of variables related to BRAF mutations was defined and included age, primary tumor location, histological type, ulceration, LVI, and association with nevus. To encounter non- linear links, the non-linear neural network modeling was applied. For this aim multilayer perceptron (MLP) with one hidden layer was used. The hidden layer architecture included 4 neurons with a logistic activating function. The AUROCMLP6 of the model was 0.79 (0.74 – 0.84). When applying the optimal threshold, the following characteristics of the model were reached: sensitivity - 89.4% (84.5 – 93.1%); specificity - 50.7% (42.2% – 59.1%); positive predictive value (PPV) - 73.1% (69.6% – 76.3%) and NPV - 76.0% (67.6% – 82.8%) respectively. The developed MLP model allows the prediction of BRAF status in CM, facilitating decisions concerning further patient management.

Conclusion

The developed MLP model, relying on 6 variables analysis allows the prediction of BRAF status in melanoma, facilitating decisions concerning further patient management.
Validation of Neutrophil gelatinase-associated lipocalin (NGAL) for Diabetes-associated Acute Kidney Injury
Authors: Bufkin K B , Karim Z , Silva J
Published: October 2024

Introduction/Objective

This study aimed to evaluate the analytical and clinical performance of the BioPorto NGAL Test on the Beckman Coulter AU480 to correlate plasma neutrophil gelatinase-associated lipocalin levels (pNGAL) with clinical progression and severity of diabetes-associated acute kidney injury (AKI) with hospitalized patients at an East Central Georgia Medical Center

Methods/Case Report

Analytical validation of the BioPorto NGAL Test was carried out on the AU480 and was based on imprecision, limit of blank, limit of detection, functional sensitivity, carryover, and specificity. Clinical validation studies included 45 patients hospitalized between January and November 2023 with and without diabetes at risk for developing AKI. All patients’ pNGAL levels were measured at admission until 96 hours post admission. Receiver operating characteristics and likelihood ratio methods were used to determine optimal sensitivity, specificity, cutoff value, and the discriminatory power of pNGAL.

Results (if a Case Study enter NA)

The intra-assay and inter-assay imprecision percent relative standard deviation was between 0.8 (2.7%) and 3.7 (4.2%). The limit of blank and limit of detection of Bioporto NGAL was 2.2 ng/mL and 15.4 ng/mL, respectively. An analytical coefficient of variation of 20% corresponded to a pNGAL value of 9.9 ng/mL. The optimal cutoff value for pNGAL to predict AKI for patients with DM was 293 ng/mL, with a sensitivity of 80% and specificity of 87%; AUC: 0.85, p < 0.001. In a multivariate logistic regression model, pNGAL levels at 48 hours post admission were a risk factor for diabetes-associated AKI (OR 1.012, 95% CI:1.000 – 1.023; p = 0.051).

Conclusion

These results show that pNGAL levels at 48h are an independent risk factor for diabetes-associated AKI, and the optimal cutoff for this condition is 293 ng/mL. The optimal cutoff values for AKI for early diagnosis and risk stratification, along with its association with comorbidities, are important to improve patient outcomes and diagnosis accuracy.
Keeping The Stock Alive, A Dilemma of Hemovigilance
Authors: Haque A , Agaronov M , Talabong D , NGICHABE J , Yakut E , Rana-Gupta T , Gabutan E , Kang S
Published: October 2024

Introduction/Objective

Being well-prepared for emergent blood transfusions is crucial in level 1 trauma centers. As advocates of hemovigilance, we follow protocols that encourage the appropriate use of group O, D- (O-) pRBCs.

Moreover, by prioritizing using red blood cells with shorter shelf lives, we can better ensure that these valuable resources are not wasted.

Methods/Case Report

The number of O short-dated RBC units transfused in a level 1 trauma hospital in December 2023 was evaluated for type-specific distribution and utilization in bleeding patients and massive transfusion protocol. This study defines short-dated units as units expiring ≤7 days during transfusion.

Results (if a Case Study enter NA)

Of the 320 pRBCs evaluated, 59 were identified as short-dated units and 46(78%) were of the O- blood type. Interestingly, most O- units used for transfusion during this month (69%, 46/66) were short- dated; in comparison, only 5% (13/254) of group O, D+ (O+) units were transfused with a shorter shelf life. O- units were administered to 10 O- patients (17%), 27 O+ patients (46%), and 9 non-O blood type patients (15%). All short- dated O+ units were given to O+ patients, with 31% (4/13) used in massive transfusion protocols (MTP). None of the short-dated O- units were used in MTP, but over half (52%, 24/46) were utilized in patients experiencing bleeding.

Conclusion

Approximately 95% of individuals of African American descent have a blood type of D+. Given that this is the primary demographic we serve, it is unsurprising that our institution sees a relatively higher usage of O+ blood units, resulting in fewer short-dated O+ units being transfused. The cause of increased usage of short-dated O- is likely multifactorial, one of which is maintaining an adequate O- in our inventory for trauma patients. Balancing our preparedness for massive hemorrhage situations and hemovigilance for this blood type can be challenging for institutions like ours.
Serologic investigation and management of an antibody screen negative para-Bombay phenotype during pregnancy
Authors: Jamal Y A , Nicholas J A , Wang T , Abdelmonem M , Pandey S , Virk M S
Published: October 2024

Introduction/Objective

Individuals with the Bombay and para-Bombay red blood cell (RBC) phenotypes express anti- H antibodies associated with acute hemolytic transfusion reactions. The rarity of compatible donor units creates unique logistical challenges. However, para-Bombay individuals have been shown to tolerate transfusion of non- Bombay RBCs without acute hemolysis. Therefore, accurate serologic identification and judicious management of blood products are crucial when planning to transfuse patients with anti-H. This is especially true during pregnancy, as early onset of labor and fetal distress can occur without warning.

Methods/Case Report

A 24-year-old gravida 2 para 1 (G2P1) at approximately 38 weeks gestation with the fetus in breech position was transferred to our hospital after anti-H antibodies were detected. Although our in-house antibody screen was negative on automated solid-phase red cell adherence (SPRCA) testing, manual tube testing revealed the presence of anti-H antibodies, and forward typing with Ulex europaeus lectin confirmed the absence of H-antigen.

Further, Lewis B phenotyping and saliva neutralization demonstrated the presence of H-antigen in secretions, consistent with the O-para-Bombay phenotype. Finally, differential adsorption ruled out other clinically significant allo- antibodies.

An external cephalic version (ECV) was initially planned since vaginal delivery carries lower bleeding risk than cesarean section (CS). Three frozen Bombay RBC units were obtained, with one possibly compromised before arrival. Four pre-warmed, cross-match compatible units of O-positive RBCs (non-Bombay) were also prepared.

Acknowledging the unpredictability of ECV, the challenge of timing thawed frozen units, and the possibilities of massive hemorrhage versus wasting rare donor blood, our transfusion service ultimately recommended an elective CS with only one Bombay unit deglycerolized. The patient underwent an uneventful procedure without transfusion.

Results (if a Case Study enter NA)

NA

Conclusion

Overall, this case highlights key diagnostic and management considerations for patients with Bombay and para-Bombay phenotypes. First, automated SPRCA testing may provide false negative results for anti-H antibodies. Second, backup transfusion strategies for para-Bombay patients may include non-Bombay RBCs. Finally, the procurement, preparation, and use of rare donor blood products requires multidisciplinary clinical decision-making to optimize patient outcomes, especially for high-risk labor when unexpected acute bleeding events can occur.
One size does NOT fit all – factoring weight into current stem cell transplant guidelines in multiple myeloma patients
Authors: Jebackumar Travis , Marques Marisa , Singh Nirupama , Costa Luciano
Published: October 2024

Autologous hematopoietic stem cell (HPSC) transplantation serves as the standard of care treatment for multiple myeloma patients. The standard ASCT procedures for multiple myeloma (MM) patients often includes induction therapy, stem cell collection via apheresis and autologous hematopoietic cell transplantation (HCT) for eligible patients. The current guideline for HPSC collection for multiple myeloma established that 3x106 cells/kg of actual body weight (ABW) by the 1997 study of stem cell transplants in breast cancer. Recent research indicates that ideal body weight (IBW) utilization is a stronger predictor of post-autotransplantation neutrophil recovery than calculations based on ABW. Reducing the cost of HPSC collection and cryopreservation is critical to mitigate the cost incurred by the transplant center and the patient. This study evaluates whether using a patient’s IBW or Adjusted Ideal Body Weight (AIBW) would be satisfactory in determining the amount of stem cells required for transfusion when compared to ABW.

After institutional review board approval, a retrospective chart review study analyzed a cohort of 224 deceased MM patients, who received HCT at the UAB Medicine Hospital within the fiscal years of 2017 to 2019. The ABW for each patient was used to calculate their IBW and AIBW using the formulas shown below. The target CD34+ cell amount for patients was calculated using each body weight parameter. The platelet count and absolute neutrophil count (ANC) defined a successful platelet and neutrophil engraftment. The engraftment date was determined as the day the platelet value exceeded 20 and ANC exceeded 0.5 for three consecutive days (without any transfusion within a seven day window) and a statistical analysis was utilized to determine whether the IBW and AIBW parameters were adequate to achieve successful engraftment and HCT.

This study finds that the cohort of multiple myeloma patients are significantly more overweight than the prior study that established the current guidelines for autologous hematopoietic cell transplantation. The results for CD34+/kg cell targets for ideal and adjusted ideal body weight suggests that there are minimal differences in platelet and neutrophil engraftment and number of platelet transfusions when compared to CD34+/kg targets using actual body weight. Some methods to reduce excessive stem cell collection include decreasing target cell dosage from previous standards of 6.0 x 106 cells/kg or calculating total cell dosage with IBW or AIBW instead of ABW. Future studies should evaluate the efficacy of cell dosage decrease to lowered targets and total cell calculations using IBW or AIBW instead of ABW.

Equation 1. ABW to IBW Conversion (H = height over 5 ft. in inches)

IBW(males) = 50 kg + (2.3 kg x H)

IBW(females) = 45.5 kg + (2.3 kg x H)

Equation 2. ABW to AIBW Conversion

AIBW = IBW + 0.5(ABW-IBW)
Critical appraisal of the utility of 13 discriminant formulas for distinguishing beta thalassemia trait from iron deficiency in patients with microcytic anemia and the introduction of a new formula in a USA population
Authors: Weli Homayemem , Hernandez Patricia , Frater John
Published: October 2024

Iron deficiency anemia (IDA) and beta thalassemia trait (ß-TT) are two frequent causes of microcytic anemia that often pose a diagnostic dilemma with implications for management. Many discriminant formulas have been proposed for distinguishing these two conditions. However, there is a need for independent verifications of these formulas to determine their applicability to other populations, particularly more diverse populations, as seen in the United States. To date, no study has been performed in the United States to evaluate the utility of these formulas in distinguishing both conditions. The study objective was to evaluate the utility and predictive values of 13 discriminant indices and formulas for distinguishing ß-TT from IDA in a US population. We investigated 13 formulas comprising only hematologic parameters available on all analyzers. The investigational population consisted of 238 patients with microcytic anemia; 165 with a hemoglobin electrophoresis diagnosis of ß-TT and 73 diagnosed with IDA by clinician review or iron studies. The study population comprised 55% black or African American, 35% White, 5% Asian, 1.2% Native American, and 2.5% unidentified. Receiver operating characteristic curves were employed to evaluate the diagnostic performances of the formulas. All investigated formulas had poor sensitivities but high specificities. The three best-performing indices or formulas from those previously proposed for distinguishing ß-TT from IDA were the RBC (sensitivity 62.2%, specificity 87.1%), Green and King (MCV2×RDW/100 hemoglobin, Hb) with a sensitivity of 65.4% and specificity of 82.6%, and Wongprachum et al. (MCV×RDW/RBC) – 10 Hb) with a sensitivity of 63.6% and specificity of 82.6%. Areas under the curve (AUCs) were 0.68 for the RBC and, 0.67 for both Green and King and Wongprachum formulas. The Youden indices were 0.49, 0.48, and 0.46, respectively. The Mentzer index had a sensitivity of 63.4%, specificity of 81.7% and Youden index of 0.45. We introduced a new formula comprising the sum of three of the most readily obtained red cell parameters (RBC + Hb + MCV). It had a Youden index of 0.95, sensitivity of 96.8, specificity of 98.0, and AUC of 0.97, significantly outperforming other formulas in our study population (p=0.00). This is the first study in the USA evaluating the utility of multiple indices for distinguishing ß-TT from iron deficiency anemia. The best performing formulas in other studies did not perform well in our population. This necessitated an introduction of a new formula that demonstrates excellent potential to address the unique diversity of the US population.
Reemergence of Hemoglobin Yukuhashi
Authors: Dar Abdul Jabbar , Malik Anum , Campbell Sean , Mulvey Joseph Justin
Published: October 2024

The abnormal hemoglobin, Hb Yukuhashi, identified in Japan in 1963, exhibits slower migration compared to Hb A and is associated with target cells on peripheral smear. A similar hemoglobin, Hb Dhofar, is found in an Omani tribesman and is defined as a substitution of arginine for proline at the 58th amino acid position of the beta-globin chain. Despite both Yukuhashi and Dhofar seemingly arising from the same exonic point mutation, variations in expression were clarified through beta-globin gene amplification. Hb Dhofar, unlike Yukuhashi, was linked to a splice-site mutation at codon 29, explaining its reduced expression. Despite these hemoglobins’ structural alterations, their functional properties on a molecular level, including oxygen affinity and heme-heme interaction, remained largely unaffected. While mutations at codon 58 have been observed alongside other mutations in Hb Dhofar and Hb C-Ziguinchor, this case represents the first sequencing and report of a beta-globin gene mutation solely at codon 58, as only Yukuhashi’s protein coding region had been sequenced, not the whole gene. “Hemoglobin D” was detected on newborn screening of a male child with no other significant medical history or physical abnormalities. Capillary Electrophoresis and Cation-Exchange HPLC showed abnormal hemoglobin fractions, with 20.1% in the S Zone and 25.7% in the D-window, respectively. This led to a presumptive diagnosis of Hemoglobin Dhofar trait; however, discrepancies in hematologic parameters and relative hemoglobin levels were noted. Genetic testing of the Beta Globin gene confirmed a C to G substitution at codon 58 but lacked the characteristic codon 29 mutations associated with Hemoglobin Dhofar. The patient, was discovered to possess a mutation at codon 58 on the beta globin gene, a mutation not previously reported in isolation. In contrast to previous studies on Hb Dhofar, where variant Hb levels were lower and accompanied by abnormal RBC indices indicative of beta thalassemia trait, this case exhibited higher variant Hb levels with normal RBC indices, suggestive of a typical beta globin variant. The mutation at codon 58 did not significantly alter intermolecular interactions of the globin which may mean the variant is clinically asymptomatic in nature. Continued follow-up is necessary to confirm this suspicion, although initial assessments at 3 and 6 months of age showed normal RBC parameters. This case represents the first instance of an isolated mutation at codon 58 of the beta globin gene, emphasizing the need to consider this mutation in interpreting hemoglobinopathy screening results.
Differences Between Serum and Plasma: An Indirect Approach to Derive a Combined Reference Interval for Total Protein, Albumin, and Globulin
Authors: Militello Leah , El-Khoury Joe , Durant Thomas
Published: October 2024

The objective of our study is to derive reference intervals (RI) for total protein (TP), albumin and globulin that are appropriate for both plasma and serum samples by applying statistical analyses to retrospective patient data. Both plasma and serum are acceptable matrices for these tests at our institution, with a single RI that applies to all specimens. The widespread shortage of lithium heparin (LH) tubes that occurred as a consequence of the pandemic prompted our lab to switch the primary tube type for comprehensive metabolic panels (CMPs) from LH to serum separator tubes (SST) in October 2021. The primary tube type reverted to LH in October 2023, and no adjustments were made to RIs at either time. To determine how well our RIs align with the accepted matrices, we used R Statistical Programing version 4.3.1 to apply an indirect, nonparametric statistical approach to data extracted from the laboratory information system (LIS) between July 2018 and December 2023. All orders for TP, albumin and globulin were queried to include the following components in the analysis: TP, albumin, globulin, serum TP, serum albumin and serum globulin. The records were divided into 3 epochs based on the primary tube type for CMP on the order date, with epochs 1 and 3 reflecting LH and epoch 2 reflecting SST. We attempted to identify a subset of serum and plasma samples in healthy individuals by applying exclusion criteria based on inpatient status, age, and draw station at which the specimen was collected. For each component, a resampling bootstrap method was used to calculate the RIs and corresponding 95% confidence intervals by epoch. Our results show that the RI of TP, albumin and globulin changed significantly between the epochs, reflecting the difference in primary matrix. The components serum TP, serum albumin, and serum globulin did not see a significant change in values over the epochs. A verification study looking at plasma and serum samples in 20 healthy individuals support these results. Based on these findings, our reference intervals were updated from 6.6-8.7 g/dL to 5.9-8.3 g/dL for TP, from 3.6-4.9 g/dL to 3.6-5.1 g/dL for albumin and from 2.3-3.5 g/dL to 1.5-3.9 g/dL for globulin. We show that there are statistically and potentially clinically significant differences in the reference intervals of TP, albumin and globulin in serum compared to plasma. This study demonstrates a big data analytics approach to derivation of RIs and emphasizes the importance of RI assessment and adjustment for patient population and acceptable specimen type.
Mind the Gap: Influence of Monoclonal Immunoglobulin on Anion Gap in Multiple Myeloma
Authors: Chen Lechuang , Meng Qing H
Published: October 2024

Background

Multiple myeloma (MM) is a plasma cell disorder in which anion gap and sodium measurement are critically influenced by the presence of abnormal protein concentrations. This study investigates the relationship between anion gap, pseudohyponatremia, and monoclonal immunoglobulin levels (IgG, IgA, IgM), particularly the common IgG. Focusing on the clinical implications of these laboratory results.

Methods

We retrospectively analyzed data from 136 patients diagnosed with MM, focusing on anion gap values, monoclonal immunoglobulin levels, and sodium levels. The patients were categorized based on their anion gap values (<8) into five groups (anion gap=3, 4, 5, 6, and 7). Monoclonal immunoglobulin levels were standardized to the same units as the anion gap for direct comparison. Additionally, we investigated the pseudohyponatremia by examining sodium levels in these patients.

Results

Among the 136 MM patients, 70 patients’ anion gap were lower than 8. A negative correlation between MM monoclonal immunoglobulins and anion gap values were observed. The anion gap decreased from 7 to 3 as the IgG average levels ranged increasing from 1755 mg/dL to 2655 mg/dL (RI 610-1616 mg/dL). Similarly, the anion gap decreased from 6 to 3 as the IgM average levels ranged increasing from 1170 mg/dL to 2880 mg/dL (RI 35-242 mg/dL). Additionally, a number of low sodium levels (<136 mmol/L) was observed in each group.

Conclusion

Our study highlights the negative impact of MM monoclonal immunoglobulins, particularly IgG and IgM, on the anion gap. Both laboratory and clinical personnel should be aware of these phenomena, might prevent unnecessary diagnosis, streamlining patient management and avoiding potential mismanagement.
Evaluation of autoimmune neurology testing clinical utility and stewardship initiatives
Authors: Kroner Grace , Kunchok Amy
Published: October 2024

Testing for neural autoantibodies associated with autoimmune neurological diseases has an important role in clinical care. However, as they are niche tests for relatively rare diseases, they often have longer turn-around-times and more expensive costs than many other laboratory tests. In addition, due to the low yield of positive results, they often appear as attractive stewardship targets. Our objective was to review current utilization and ordering patterns and evaluate the impact of ongoing stewardship efforts to inform next steps regarding stewardship of these tests. Methods: Data on utilization and ordering patterns of autoimmune and paraneoplastic neural autoantibody panels from January 1 to December 31, 2023, was obtained from reference laboratory and electronic medical record (EMR) data. Additional data on best practice advisories from the most recent six months was obtained from the EMR. Results: Overall, we observed that providers tested 2270 patients both from our defined test menu (five total tests, ~89% of total orders) and through the miscellaneous route (12 total tests, ~11% of total orders), which allows providers to place orders for tests not currently on our menu. Just under one third of the orders were in cerebrospinal fluid (CSF) (n=725), while the remaining were for serum (n=1545). The percent positivity was generally higher in serum specimens, ranging from 0 to 50% per test (n=227 total positive specimens). The percent positivity in CSF specimens ranged from 0 to 40% per test (n=29 total positive specimens), which is generally consistent with previously published literature. Most of the orders were placed by neurology providers (56%). The best practice advisories (BPAs) currently in use are soft stops that target repeat tests in the same specimen type within thirty days of a previous order. Of note, these BPAs can only catch orders placed through the defined process. In six months, the BPA for repeat serum orders fired 104 times for 42 unique patients; the BPA for repeat CSF orders fired 96 times for 38 unique patients. The serum BPA resulted in elimination of the repeat order for 43% of patients (n=18), while the CSF BPA resulted in elimination of the repeat order for 24% of patients (n=9). We observed some situations in which the BPA appeared to be firing when previous orders were incorrectly collected and so not able to be sent out. Conclusion: Based on these data, we plan three main steps to continue to refine autoimmune neurology testing: 1) update our test menu to offer the most clinically useful orders through the defined route, 2) pilot review of tests ordered through the miscellaneous route, and 3) optimize BPAs to target situations with inappropriate utilization rather than technical issues.
Transcriptome analysis reveals selectively high expression of beige adipocyte marker genes in mouse perinephric fat
Authors: Misawa Yoshinori , Takahashi Yu , Sasaki Takashi , Sato Ryuichiro , Yamauchi Yoshio
Published: October 2024

To reveal the differences in the properties of visceral adipose tissue in healthy unstimulated mice, we performed transcriptome analysis using RNA sequencing. Among visceral adipose tissues, perinephric adipose tissue was found to exclusively express beige adipocyte markers while expressing white adipocyte markers. These results imply potential specific roles of perinephric adipose tissue in both physiological and pathological conditions.
Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder
Authors: Seaby Eleanor G , Godwin Annie , Meyer-Dilhet Géraldine , Clerc Valentine , Grand Xavier , Fletcher Tia , Monteiro Laloe , Kerkhofs Martijn , Carelli Valerio , Palombo Flavia , Seri Marco , Olivucci Giulia , Grippa Mina , Ciaccio Claudia , D’Arrigo Stefano , Iascone Maria , Bermudez Marion , Fischer Jan , Di Donato Nataliya , Goesswein Sophie , Leung Marco L , Koboldt Daniel C , Myers Cortlandt , Arnadottir Gudny Anna , Stefansson Kari , Sulem Patrick , Goldberg Ethan M , Bruel Ange-Line , Tran-Mau-Them Frederic , Willems Marjolaine , Bjornsson Hans Tomas , Hognason Hakon Bjorn , Thorolfsdottir Eirny Tholl , Agolini Emanuele , Novelli Antonio , Zampino Giuseppe , Onesimo Roberta , Lachlan Katherine , Baralle Diana , Rehm Heidi L , O’Donnell-Luria Anne , Courchet Julien , Guille Matt , Bourgeois Cyril F , Ennis Sarah
Published: October 2024

DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we compiled a case series of 11 patients with neurodevelopmental phenotypes harbouring de novo monoallelic variants in DDX17. All 11 patients in our case series had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated.

We performed in utero cortical electroporation in the brain of developing mice, assessing axon complexity and outgrowth of electroporated neurons, comparing wild-type and Ddx17 knockdown. We then undertook ex vivo cortical electroporation on neuronal progenitors to quantitatively assess axonal development at a single cell resolution. Mosaic ddx17 crispants and heterozygous knockouts in Xenopus tropicalis were generated for assessment of morphology, behavioural assays and neuronal outgrowth measurements. We further undertook transcriptomic analysis of neuroblastoma SH-SY5Y cells, to identify differentially expressed genes in DDX17-KD cells compared to controls.

Knockdown of Ddx17 in electroporated mouse neurons in vivo showed delayed neuronal migration as well as decreased cortical axon complexity. Mouse primary cortical neurons revealed reduced axon outgrowth upon knockdown of Ddx17 in vitro. The axon outgrowth phenotype was replicated in crispant ddx17 tadpoles and in heterozygotes. Heterozygous tadpoles had clear neurodevelopmental defects and showed an impaired neurobehavioral phenotype. Transcriptomic analysis identified a statistically significant number of differentially expressed genes involved in neurodevelopmental processes in DDX17-KD cells compared to control cells.

We have identified potential neurodevelopment disease-causing variants in a gene not previously associated with genetic disease, DDX17. We provide evidence for the role of the gene in neurodevelopment in both mammalian and non-mammalian species and in controlling the expression of key neurodevelopment genes.
Nontuberculous Mycobacterial Pulmonary Disease: Patients, Principles, and Prospects
Authors: Nguyen Minh-Vu H , Haas Michelle K , Kasperbauer Shannon H , Calado Nogueira de Moura Vinicius , Eddy Jared J , Mitchell John D , Khare Reeti , Griffith David E , Chan Edward D , Daley Charles L
Published: October 2024

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in incidence globally and challenging to manage. The 2020 multisociety treatment guideline and the 2022 consensus recommendations provide comprehensive evidence-based guides to manage pulmonary diseases caused by the most common NTM. However, with >190 different NTM species that may require different multidrug regimens for treatment, the breadth and complexity of NTM-PD remain daunting for both patients and clinicians. In this narrative review, we aim to distill this broad, complex field into principles applicable to most NTM species and highlight important nuances, specifically elaborating on the presentation, diagnosis, principles of patient-centered care, principles of pathogen-directed therapy, and prospects of NTM-PD.
MULTIMODAL (5-ALA, TRACTOGRAPHY AND ULTRASOUND GUIDED) AWAKE CRANIOTOMY FOR GLIOBLASTOMA: MAXIMISING SAFE SURGICAL RESECTION
Authors: Honeyman Dr Susan , Martin Mr Sean , Stacey Mr Richard , Apostolopoulos Mr Vasileios , Plaha Prof Puneet
Published: October 2024

AIMS

Maximising the extent of surgical resection of glioblastoma is a key prognostic factor for survival. This must be balanced against avoiding neurological deﬁcit, which may delay or preclude adjuvant treatments. This is a particular challenge in eloquent tumours. Optimal surgical adjuncts to enable maximal resection of glioblastomas in eloquent brain regions, remain unclear. We present the ﬁrst series assessing the safety and eﬃcacy of multimodality image-guided, awake resection of IDH-wildtype glioblastoma, combining 5-aminolevulinic acid (5-ALA), diffusion tractography (DTI) and intraoperative ultrasound (USS).

METHOD

We present a single centre retrospective series of 175 patients undergoing awake craniotomy for primary resection of glioblastomas, between January 2014 and January 2023. Awake craniotomy was considered if tumours were in or adjacent to eloquent areas. Key outcomes assessed included post-operative neurological complications (classiﬁed into transient, if persisting <3 months and completely resolved, or permanent if persisting >3 months), extent of resection (EOR) and overall survival (OS).

RESULTS

175 patients (103M:72F) were included, with a mean age of 58.2 years. All cases used neuronavigation, whilst 5- ALA and DTI were used in 98.9% and 97.1% of patients respectively. Intraoperative USS was used 88/175 (50.3%). Gross total resection (>98%) was achieved in 101/175 patients (64.7%). 83/175 patients (47.4%) experienced a post-operative neurological deﬁcit, which was temporary in 84.3% (70/83) of cases. When transient deﬁcits occurred, these were most often speech related (49/70). Subgroup analysis found left temporal tumours were highest risk for transient dysphasia (59.2%), followed by left frontal (21.7%) and left parietal (16.0%). The median percentage EOR with USS was 100%, whilst without USS was 97.8% (Wilcox, p=0.0004).

CONCLUSION

Patients should be counselled about the high risk of transient neurological complications following awake surgery, particularly speech deﬁcit. Multimodal image-guided surgery can maximise the extent of safe resection for glioblastoma.
EVALUATION OF AN ALLIED HEALTH PROFESSIONAL PREHABILITATION SERVICE IN NEURO-ONCOLOGY
Authors: Humphreys Ms Rosie , Farrow Ms Madeleine , Moran Ms Charlotte
Published: October 2024

AIMS

The evidence base for the beneﬁts of prehabilitation in the cancer population is increasing. So far, the focus has been on colorectal, breast and lung cancer sites with no current research into the effects in patients with primary or secondary brain tumours. It is hypothesised that patients with brain cancer would beneﬁt from prehabilitation as current evidence demonstrates the positive effects of exercise, cognitive and language rehabilitation in this patient group. The aim of this project is to demonstrate the feasibility and impact of a two-year prehabilitation pilot service. The service comprises physiotherapy, occupational therapy and speech and language therapy for patients with brain cancer in the pre-operative phase.

METHOD

A pilot study was carried out at a tertiary UK neurosurgery centre. Patients over the age of 17 with a diagnosis of primary or secondary brain tumour awaiting surgery were eligible for the prehabilitation service. The impact was measured through Length of Stay, Quality of Life (EQ-5D-5L), emergency department attendances and admission rates 90 days post-surgery.

RESULTS

128 patients were seen in prehabilitation from 01/11/2022 to 31/01/2024. Length of hospital stay post-surgery was lower for the prehabilitation group (0.9 days with 95% conﬁdence interval) compared to control group. A mean improvement in the EQ-5D-5L Index from pre-operative assessment to post-surgery follow up was demonstrated

CONCLUSION

This study reveals data demonstrating the beneﬁts of prehabilitaiton for patients with brain tumours. Prehabilitation for this patient group appears to improve clinical outcomes alongside patients’ quality of life. Future directions for the service will focus on expanding the provision to patients with spinal and benign tumours, where this is also a possibility of therapeutic need in the pre and post-operative phase.
INTEGRATING ALLIED HEALTH PROFESSIONALS DURING THE ONCOLOGICAL TREATMENT PHASE FOR GLIOBLASTOMA PATIENTS: A CASE STUDY AT A UK CANCER CENTRE
Authors: Wyatt Mrs Toni , Peat Mrs Nicola
Published: October 2024

AIMS

Primary brain tumour patients should be offered neurological rehabilitation assessment at diagnosis and every stage of follow With only 5% of glioblastoma patients surviving more than 5 years, specialist management that spans across all phases of the Dietz rehabilitation model is required to optimise function, treatment tolerance and Quality-of-life. At Guy’s cancer centre an Allied health multi-disciplinary team (Physiotherapy, Occupational therapy and Speech and language therapy) work alongside the oncologist-led clinic to support this patient group.

METHOD

Case history A 54-year-old, male, was diagnosed with right parietal Glioblastoma, WHO grade 4, IDH wildtype, MGMT 5.47% methylated (August 2023) on biopsy only. He underwent chemo/radiotherapy - 60gy/90 fractions with Temozolmide (TMZ) on 3/11/2023 Currently C4 of adjuvant TMZ. Dexamethazone 2mg was discontinued on 29/11/2023, he continues with Keppra 500mg twice daily.

RESULTS

Dietz Intervention approach in phases:

PREVENTATIVE

Fatigue management was introduced prior to radiotherapy including a physical activity review, advice on pacing, sleep hygiene and relaxation techniques. Given the patient’s history of shift work and altered sleep patterns, managing risks of treatment-related fatigue was of particular importance. Restorative & Supportive: A targeted and periodised exercise programme was initiated, comprising 1:1 gym based physiotherapy sessions. The aims included enhancing exercise conﬁdence, improve balance, endurance, maintain strength, pain management and weight maintenance during chemo/radiotherapy and adjuvant TMZ. Education was deployed on adjusting activity levels based on chemotherapy cycle and day to day side effects, alongside ongoing fatigue management advice around pacing and sleep hygiene.

CONCLUSION

Learning and Recommendations Implementing tailored rehabilitation interventions early in the patient’s treatment pathway, enables proactive management to mitigate the impact of treatment-related side effects on their QOL. Based on our experience, early engagement with a dedicated therapy team is recommended to foster strong rapport with both the patient and their caregivers. This facilitates timely rehabilitation planning for optimal outcomes.
ROR1 MRNA EXPRESSION IN GLIOMA - A NOVEL PROGNOSTIC BIOMARKER
Authors: Madani Dr Daniel , Satgunaseelan Dr Laveniya , El-Hayek Ms Jessica , Shivalingam Prof Brindha , Ford Prof Caroline
Published: October 2024

AIMS

Glioblastoma is the most common and aggressive primary brain tumour in adults. Despite maximal surgical resection followed by concomitant chemo-/radiotherapy, the three-year survival remains less than 5%. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) overexpression is associated with poor prognosis in several cancers. ROR1 therapeutics are in Phase I/II clinical trials making it an exciting novel target with translational potential to explore for glioblastoma treatment. The aim of this study was to examine the association between ROR1 mRNA expression and overall survival (OS), by applying the WHO 2021 classiﬁcation of transcriptomic glioma datasets.

METHOD

Clinical, histological, and molecular data were extracted from four independent glioma datasets (TCGA, CGGA, Rembrandt, and Gravendeel) via the GlioVis portal and analysed using the WHO 2021 classiﬁcation. Only conﬁrmed cases of astrocytoma, oligodendroglioma, or glioblastoma, and ROR1 mRNA expression data were included (2,216 cases). Kaplan-Meier survival curves were produced for OS with low/high grade glioma versus ROR1 mRNA expression. Log-rank (Mantel-Cox) multivariate regression was applied to analyse the effect of selected covariates on OS and ROR1 mRNA expression.

RESULTS

We observed a signiﬁcant decrease in median OS in patients with high-ROR1 mRNA expression when compared to the low-ROR1 mRNA expression cohort (20 and 70 months, respectively). High-grade gliomas represented the highest ROR1 mRNA expression across the consortium, resulting in a poor median OS of 16 months.

CONCLUSION

This study represents the ﬁrst report of an association between OS and the oncogenic role of ROR1 in glioma, a targetable cell surface marker for novel putative treatment in glioblastoma.