Faculty Bibliography

Alexander von Humboldt's early nineteenth-century explorations of the Andes established foundational methods in biogeography and environmental science, emphasizing measurement, spatial integration, and the interdependence of natural systems. Nearly two centuries later, southern Ecuador became the site of a landmark discovery in endocrine genetics: a population with growth hormone receptor deficiency (Laron syndrome) characterized by severe insulin-like growth factor-1 (IGF-1) deficiency. This article examines the historical and scientific continuity of observation in the Ecuadorian Andes, linking Humboldt's integrative natural philosophy with modern approaches to human molecular physiology. While no direct historical connection exists between Humboldt's writings and the later identification of this endocrine condition, the shared geographic setting underscores the enduring scientific value of place-based investigation.

BACKGROUND:In vivo assessment of the embryonic mouse placenta and vasculature is challenging, and ultrasound remains the most commonly used imaging modality. However, even with contrast agents, conventional preclinical ultrasound lacks the temporal resolution required to resolve complex vascular networks. Ultrafast Doppler methods offer a contrast-agent-free approach for visualizing embryonic placental and vascular flow. METHODS:A 15-MHz linear array was used to acquire 0.5 sec of ultrafast ultrasound data at mouse embryonic day 13.5 (E13.5) using a semi-invasive, non-destructive preparation in which a single embryo within the uterine horn was imaged in vivo. Adjacent image planes were acquired at 0.25-mm spacing to generate a 3D dataset. The data were post-processed to produce power Doppler, color Doppler, and Doppler waveforms. Image data were also segmented to facilitate visualization of distinct organ systems, including the feto-placental vascular tree. RESULTS:Ultrafast Doppler ultrasound provided greater detail of vascular flow than a 30-MHz preclinical ultrasound system. Power Doppler maps delineated the feto-placental vascular tree and the umbilical, vitelline, and yolk sac circulations. Color Doppler enabled visualization of pulsatile flow over nearly two cardiac cycles in vessels such as the vitelline artery. Following segmentation, flow within the aorta, heart, placental labyrinth, and umbilical vessels could be clearly distinguished. CONCLUSION/CONCLUSIONS:Ultrafast Doppler ultrasound enables in vivo contrast-agent-free visualization of embryonic feto-placental circulation in the mouse. The method provides high-resolution vascular structural and dynamic flow information across the placenta, embryo, and uterus. This approach is well suited for longitudinal studies of embryonic and placental development.

BACKGROUND:Primary erythromelalgia (PE) is a rare, hereditary disorder characterized by chronic burning pain in the extremities and commonly linked to mutations in the SCN9A gene. The management of erythromelalgia-associated pain remains challenging, since there are currently no standardized guidelines for the treatment thereof due to the rare and refractory nature of the disorder. CASE REPORT/METHODS:A 17-year-old boy with SCN9A-related PE presented with intractable bilateral lower extremity pain complicated by ulcerations and osteomyelitis. After not responding to multiple medications and interventions, he experienced significant relief upon receiving a popliteal sciatic nerve block effected with lidocaine and triamcinolone. Afterward, peripheral nerve stimulation (PNS) was implanted, leading to lasting pain relief, improved functionality, and wound healing for the patient. CONCLUSION/CONCLUSIONS:PNS offers a promising treatment for refractory PE, warranting further investigation to establish the role of this technique in managing this challenging condition.

Many individuals hospitalized due to severe viral infections develop mental and physical sequelae, which could potentially be prevented by targeted interventions for those at risk. Our goal was to develop and externally validate an algorithm for predicting mental and physical symptoms after SARS-CoV-2 hospitalization utilizing routinely collected clinical data. Participants were included from two independent samples of the German National Pandemic Cohort Network (NAPKON): a model development sample (SUEP; N = 451; mean age: 55.6 ± 15.3; 36.2% female) and an external validation sample (HAP: N = 158; mean age: 55.1 ± 12.1; 39.9% female). Machine learning models leveraging demographic, clinical and biological variables collected at the time of admission were employed to predict Patient-Reported Outcomes Measurement Information System scores (PROMIS) across 7 domains (physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities, and pain) three months after SARS-CoV-2 hospitalization. Shapley Additive exPlanation values were used to provide interpretable information about key predictive factors. Approximately 15-20% of participants reported moderate to severe impairment in at least one PROMIS domain three months after hospitalization. For the mental health composite score, the best-performing model achieved RMSE = 1.833 ± 0.341 and R² = 0.927 ± 0.031 in SUEP and RMSE = 3.131 and R² = 0.893 in HAP. For the physical health composite, the best-performing model achieved RMSE = 2.908 ± 0.703 and R² = 0.824 ± 0.052 in SUEP and RMSE = 3.019 and R² = 0.850 in HAP. Furthermore, the models achieved high predictive performance across all individual PROMIS domain scores in both samples. We provide an externally validated methodology for accurately predicting mental and physical symptomatology following hospitalization due to a severe viral infection. This approach may facilitate the development of a brief risk stratification tool at the point of hospitalization, enabling early identification of at-risk patients, improving the prediction accuracy of subsequent psychological and physical sequelae, and supporting timely preventive interventions.

BACKGROUND:Some centres advocate preoperative radiotherapy in patients with pancreatic cancer and arterial involvement despite a lack of Level 1 evidence on survival benefit. Although it has been suggested that preoperative radiotherapy may increase the risk of postpancreatectomy haemorrhage (PPH) and morbidity, evidence is again lacking. This study investigated the association between preoperative radiotherapy and both PPH and major morbidity following arterial divestment/resection during pancreatic adenocarcinoma resection after chemotherapy. METHODS:Consecutive patients diagnosed with pancreatic adenocarcinoma and > 180° arterial involvement who were treated with preoperative chemotherapy with or without radiotherapy followed by pancreatic resection with arterial divestment/resection were included in the study. Logistic regression analyses including propensity score-based overlap weighting were performed to investigate associations between radiotherapy and in-hospital PPH grade B/C and major morbidity, expressed as adjusted risk differences (aRDs). RESULTS:Overall, 246 patients undergoing pancreatic resection with arterial resection (169, 69%) or divestment (77, 31%) were included. Radiotherapy was not associated with PPH (aRD 6%; 95% confidence interval (c.i.) -3 to 14), regardless of arterial divestment (aRD 3%; 95% c.i. -5 to 11) or arterial resection (aRD 12%; 95% c.i. 1 to 23; Pinteraction = 0.189). Radiotherapy was associated with a 14% (95% c.i. 2 to 25) higher risk of major morbidity, especially after arterial resection (aRD 27%; 95% c.i. 11 to 43) compared with arterial divestment (aRD -12%; 95% c.i. -35 to 11; Pinteraction = 0.006) and after external beam radiotherapy (aRD 21%; 95% c.i. 8 to 32) compared with stereotactic body radiotherapy (aRD -12%; 95% c.i. -27 to 6; Pinteraction = 0.0001). Ninety-day mortality was increased, albeit not significantly, after preoperative radiotherapy (10 (8%) versus 3 (3%) deaths with versus without preoperative radiotherapy, respectively; P = 0.067). CONCLUSIONS:Radiotherapy before resection of pancreatic cancer with > 180° arterial involvement was associated with an increased risk of postoperative major morbidity when arterial resection, but not arterial divestment, was performed. This risk should be taken into account when considering preoperative radiotherapy in patients who may require arterial resection.

BACKGROUND:Alpha-emitting radionuclides enable precise cancer therapy through high linear energy transfer and limited tissue penetration, damaging tumor cells while sparing healthy tissue. Diffusing Alpha-emitters Radiation Therapy (Alpha DaRT) features Ra-224 sources that are implanted directly into the tumor and emit alpha particles during radioactive decay. Alpha DaRT has demonstrated efficacy and safety in preclinical and early clinical trials across multiple tumor types, including skin, head and neck, and pancreatic cancers. PURPOSE/OBJECTIVE:Reliable and efficient methods for verifying Alpha DaRT source activity prior to treatment can help support accurate and consistent radiation delivery. The direct measurement of alpha particles from sources within an Alpha DaRT applicator is impractical due to their short range; however, gamma emissions from the Ra-224 sources can be used to infer radioactivity. This study established a protocol for verifying the source activity within Ra-224 Alpha DaRT applicators using a reentrant well-type ionization chamber, providing users with a practical method for detecting errors in source manufacturing or certificate paperwork without compromising applicator sterility. METHODS:Ra-224 Alpha DaRT sources in sterile packaging (Flex and Needle applicators with 1-4 sources) were assessed. Source energy spectra and activities were verified using a high-purity germanium (HPGe) radiation detector. Calibration factors (kBq/pA) were established using an IVB1000 well-type ionization chamber with measurements conducted by placing single applicator sterile packages into the chamber with sources centered in the chamber's sweet spot and corrected for temperature, pressure, and leakage current. Quality assurance was performed on 26 Flex applicators using the established calibrations before the first clinical procedure. RESULTS:HPGe measurements agreed with vendor-stated activities. The average calibration coefficient using the IVB1000 chamber was 233 ± 3 kBq/pA for Flex and 597 ± 7 kBq/pA for Needle applicators. Calibration coefficients were consistent across two IVB1000 chambers. Source number dependence was observed, with calibration factors increasing by 1.7% ± 0.7% per source (Needle) and 2.7% ± 0.6% per source (Flex). Measurement repeatability was 3.3%. Applying the calibration to 26 Flex applicators before the first patient treatment yielded a 1.1 ± 5.8% (range: -7.5% to 11.4%) difference relative to the vendor's stated activity. CONCLUSION/CONCLUSIONS:A reentrant well-type ionization chamber is suitable for pre-treatment quality assurance of Ra-224 Alpha DaRT applicators, enabling verification of the vendor-stated activity while maintaining sterility within sealed packaging.

Localized treatment of oligometastatic liver disease can improve both local control and survival. The liver is a frequent site of metastases from colorectal, breast, and lung cancers, but most patients are not eligible for surgical resection due to lesion number, location, or comorbidities. For these patients, non-surgical ablative methods such as radiofrequency ablation (RFA) and stereotactic body radiotherapy (SBRT) and increasingly microwave ablation (MWA) are used. RFA was used as the primary comparator in this review because it represents the most historically established and widely reported ablative modality in the comparative radiotherapy literature. While RFA has been the traditional approach, SBRT is emerging as a promising alternative, offering precise, non-invasive treatment. SBRT may be especially useful for larger lesions or tumors in locations where RFA is difficult to perform. However, high-quality evidence and large-scale trials are still needed to confirm its efficacy and define its role. This review compares the strengths and limitations of both methods and provides practical guidance for clinical decision-making in the treatment of patients with inoperable liver metastases.