AI-based histologic scoring enables automated and reproducible assessment of enrollment criteria and endpoints in NASH clinical trials.

Clinical trials in nonalcoholic steatohepatitis (NASH) require histologic scoring for assessment of inclusion criteria and endpoints. However, guidelines for scoring key features have led to variability in interpretation, impacting clinical trial outcomes. We developed an artificial intelligence (AI)-based measurement (AIM) tool for scoring NASH histology (AIM-NASH). AIM-NASH predictions for NASH Clinical Research Network (CRN) grades of necroinflammation and stages of fibrosis aligned with expert consensus scores and were reproducible. Continuous scores produced by AIM-NASH for key histological features of NASH correlated with mean pathologist scores and with noninvasive biomarkers and strongly predicted patient outcomes. In a retrospective analysis of the ATLAS trial, previously unmet pathological endpoints were met when scored by the AIM-NASH algorithm alone. Overall, these results suggest that AIM-NASH may assist pathologists in histologic review of NASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient therapeutic response.

Artificial Intelligence Enables Quantitative Assessment of Ulcerative Colitis Histology.

Ulcerative colitis is a chronic inflammatory bowel disease that is characterized by a relapsing and remitting course. Assessment of disease activity critically informs treatment decisions. In addition to endoscopic remission, histologic remission is emerging as a treatment target and a key factor in the evaluation of disease activity and therapeutic efficacy. However, manual pathologist evaluation is semiquantitative and limited in granularity. Machine learning approaches are increasingly being developed to aid pathologists in accurate and reproducible scoring of histology, enabling precise quantitation of clinically relevant features. Here, we report the development and validation of convolutional neural network models that quantify histologic features pertinent to ulcerative colitis disease activity, directly from hematoxylin and eosin-stained whole slide images. Tissue and cell model predictions were used to generate quantitative human-interpretable features to fully characterize the histology samples. Tissue and cell predictions showed comparable agreement to pathologist annotations, and the extracted slide-level human-interpretable features demonstrated strong correlations with disease severity and pathologist-assigned Nancy histological index scores. Moreover, using a random forest classifier based on 13 human-interpretable features derived from the tissue and cell models, we were able to accurately predict Nancy histological index scores, with a weighted kappa (κ = 0.91) and Spearman correlation (⍴ = 0.89, P < .001) when compared with pathologist consensus Nancy histological index scores. We were also able to predict histologic remission, based on the absence of neutrophil extravasation, with a high accuracy of 0.97. This work demonstrates the potential of computer vision to enable a standardized and robust assessment of ulcerative colitis histopathology for translational research and improved evaluation of disease activity and prognosis.

Can remote endarterectomy expand access to kidney transplantation in patients with severe iliac calcification?

Severe iliac artery calcification in patients with end-stage renal disease is a common barrier to listing for kidney transplant. While few surgical solutions to iliac calcification have been reported, improving treatment may thus improve access to transplant care. Here we present two cases of a novel application of remote endarterectomy of the external iliac artery to facilitate listing for renal transplant. Both patients were listed following remote endarterectomy, followed by successful renal transplants using the treated vessels.

Wound Closure with Transcutaneous Absorbable Polyglactin Sutures after Hidradenitis Suppurativa Excision.

OBJECTIVE: Wide surgical excision is the standard treatment for severe hidradenitis suppurativa (HS). Because of the nature of HS, these wounds are often nonsterile, located in moist intertriginous regions, and closed under tension, increasing the risk for surgical site complications. Although uncommon, absorbable sutures may confer benefits over nonabsorbable material for skin closure. Accordingly, the authors evaluated the use of absorbable, braided, transcutaneous polyglactin sutures after wide surgical excision of HS. METHODS: The authors performed a retrospective chart review for all consecutive patients who underwent wide surgical excision of HS at a tertiary university hospital between January 2009 and March 2020. RESULTS: Sixty consecutive patients with 174 operative sites were included in the study. The surgical site complication rate was 17.8%. Postoperative complications included wound dehiscence (n = 18), surgical site infection (n = 2), and scar contracture (n = 1). Sutures were removed from 12 (6.9%) operative sites. Factors influencing complications were Hurley grade and area of excision. Complications did not differ significantly among disease locations (P = .6417). CONCLUSIONS: The results support the growing evidence that absorbable sutures are an appropriate option after wide surgical excision of HS.

Spontaneous Thrombosis of an Isolated Internal Iliac Artery Aneurysm.

BACKGROUND: Isolated internal iliac artery aneurysms (IIAAs) are uncommon but potentially morbid lesions that are a challenge to monitor and treat. However, given the small numbers of reported cases and high rates of incidentally discovered lesions, the natural history of isolated IIAAs is not well characterized. This case describes an atypical and previously unreported spontaneous thrombosis of an isolated IIAA, a lesion typically thought to progressively enlarge and rupture. METHODS: Medical records and imaging studies were retrospectively reviewed with the approval of our Institutional Review Board. A single patient underwent fluoroscopic angiography followed by computed tomography (CT) angiography, with no subsequent operative intervention. RESULTS: An isolated 5.5 cm left IIAA was discovered incidentally on CT scan and subsequently seen with fluoroscopic pelvic angiography. Three weeks following initial angiography, repeat pelvic angiography and CT scan demonstrated spontaneous thrombosis of the aneurysm. CONCLUSIONS: Isolated IIAAs are conditions for which the natural history remains uncertain despite their potential risk for rupture and mortality. Spontaneous thrombosis of these lesions is possible, suggesting that the natural history as previously described warrants further consideration.

Salvage of autogenous dialysis access with balloon-assisted thrombin injection.

Arteriovenous fistulas are known to be one of the most enduring and safe hemodialysis access modalities. However, access preservation can be challenging in the setting of degeneration, including the development of complex pseudoaneurysms. Prolonged compression or thrombin injection can risk thrombosis of the fistula, and covered stent use can predispose the access to infection and other stent complications. We present a case in which endovascular balloon occlusion was used to facilitate the use of ultrasound-guided thrombin injection to resolve a dialysis access pseudoaneurysm by transiently reducing flow and preventing thromboembolism. This method is a safe, effective, and minimally invasive technique that should be considered for salvage of autogenous access compromised by pseudoaneurysm development.

Type B Aortic Dissection Complicated by Intimo-Intimal Intussusception and Extensive Intimal Denuding: Case Report with Long-term Follow-up.

BACKGROUND: Acute aortic dissection rarely results in circumferential dissections of the aortic intima that may lead to intimo-intimal intussusception (IIS) with complete separation from the aortic wall. Circumferential dissection may then result in distal embolization of the involved intima and media, adding considerable complexity to the management of such cases. Despite the severity of this complication, the natural history of aortic disease following extensive intimal denuding and IIS is not well documented in the literature. Here we present a case with long-term follow-up of type B aortic dissection (TBAD) complicated by IIS and embolization of the intima into the distal aorta following thoracic endovascular aortic repair. METHODS: Medical records and imaging studies were retrospectively reviewed with the approval of the Institutional Review Board. A single patient underwent repair of a TBAD that was complicated by IIS, with follow-up for 6 years. Aortic recovery was monitored with serial computerized tomography scans. RESULTS: During endovascular stent deployment, the patient's dissection progressed circumferentially, leading to distal embolization of the intima and aortic occlusion. An open transabdominal aortic exploration was performed to extract the embolized intima. Despite this severe aortic structural disruption, the patient recovered well postoperatively and exhibited favorable aortic remodeling over long-term follow-up. The denuded aorta did not rupture or develop progressive worsening aneurysmal dilation and the diameter of the involved aortic segment remained stable during follow-up. CONCLUSIONS: Acute TBADs can progress to circumferential intimal separation and IIS when managed with endovascular stenting and balloon dilation. Continued endovascular management once IIS has occurred may lead to further intimal damage, resulting in distal embolization of the intima and aortic occlusion. Thus, IIS may require conversion to open repair. However, in the event that loss of the aortic intima does occur following IIS, it is possible for the denuded aorta to recover well and remain stable with favorable remodeling over long-term follow-up.

Autogenous Femoral Vein for Secondary Repair of Subclavian Arteries: A Salvage Solution for Complex Clinical Scenarios.

BACKGROUND: Endovascular stent and prosthetic graft placement are commonplace techniques for correction of subclavian artery (SCA) lesions. However, when initial surgical repair of the SCA becomes complicated by subsequent infection or thrombosis of the repair site, stents and prosthetic grafts are no longer suitable for secondary repair due to the risk of recurrent failure and limited longevity. Autogenous tissue is more resistant to infection and has improved long-term patency, and thus may be a better option for secondary reconstruction in these complex clinical scenarios. The most commonly used autogenous conduit for SCA reconstruction is the great saphenous vein; however, the significant size mismatch makes this unsuitable in many circumstances. The autogenous femoral vein is a promising alternative conduit for SCA repair. Here we present 3 successful cases of its use as a salvage technique following iatrogenic complications of prior surgical repair. METHODS: From 2015 to 2019, 3 patients underwent harvest of the femoral vein for use in SCA repair, with 2 carotid-axillary bypasses and 1 carotid-subclavian bypass. Indications included a mycotic pseudoaneurysm secondary to an infected SCA stent, an SCA avulsion secondary to an infected carotid-subclavian bypass graft, and an occluded SCA stent in a young patient. Postoperative graft patency was monitored via clinical resolution of symptoms and maintenance of perfusion, intact pulses, and arterial duplex or computed tomography (CT) scan. RESULTS: All these patients had a good outcome following their procedures. Each had intact radial pulses immediately postoperatively and maintained normal perfusion to the upper extremity for the duration of follow-up, with bypass patency confirmed via CT scan or arterial duplex. The SCA repair also allowed for salvage of the upper extremity and symptomatic relief in all patients. None of the patients developed deep vein thrombosis in the donor extremity, and neither of the infected patients developed recurrent infection of the repair site. CONCLUSIONS: The success of these cases demonstrates that the autogenous femoral vein is an effective and safe option for SCA reconstruction. It is particularly useful for secondary salvage when prior surgical repair via standard techniques is complicated by infection or thrombosis, and when target vessel size precludes the use of the great saphenous vein. This is an excellent choice of conduit that vascular surgeons should consider for use in complex SCA repairs.

Five-Year Outcomes of a Phase 1 Dose-Escalation Study Using Stereotactic Body Radiosurgery for Patients With Low-Risk and Intermediate-Risk Prostate Cancer.

PURPOSE: To report toxicity outcomes, prostate-specific antigen (PSA) relapse, and cumulative incidence posttreatment biopsy results among patients treated on a prospective dose escalation study using ultra-hypofractionated stereotactic body radiation therapy (SBRT) for patients with low- and intermediate-risk prostate cancer. METHODS AND MATERIALS: A total of 136 patients were enrolled in a phase 1 dose-escalation study to determine the tolerance of escalating radiation dose levels of SBRT for the treatment of localized prostate cancer. The initial dose level was 32.5 Gy in 5 fractions, and doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy. Eligibility criteria included only patients with low and intermediate risk, and the maximum prostate volume was 60 cm3. Patients treated with neoadjuvant androgen deprivation were excluded. The median follow-up in survivors for the 4 dose levels was 5.9, 5.4, 4.1, and 3.5 years, respectively. RESULTS: The incidence of acute grade 2 rectal toxicities for dose levels 1 to 4 were 0%, 2.9%, 2.8%, and 11.4% respectively. No grade 3 or 4 acute rectal toxicities were observed. The incidence of acute grade 2 urinary toxicities for dose levels 1 to 4 were 16.7%, 22.9%, 8.3%, and 17.1%, respectively. No grade 3 or 4 acute urinary toxicities were observed. No grade 2 or higher rectal toxicities were observed. The incidence of late grade 2 urinary toxicities for dose levels 1 to 4 was 23.3%, 25.7%, 27.8%, and 31.4%, respectively. Only 1 late grade 3 urinary toxicity (urethral stricture) developed in the 40-Gy dose arm; the stricture was corrected with transurethral resection. No grade 4 late urinary toxicity was observed. The 5-year cumulative incidence of prostate-specific antigen failure for dose levels 1 to 4 was 15%, 6%, 0%, and 0%. The incidence of a 2-year positive posttreatment biopsy was 47.6%, 19.2%, 16.7%, and 7.7%, respectively for the 4 dose arms (P = .013). CONCLUSIONS: SBRT doses ranging from 32.5 to 40 Gy in 5 fractions were well tolerated without severe urinary or rectal toxicities. Biopsy outcomes suggest improved rates of tumor clearance observed with higher doses.

Association of Rapid Molecular Testing With Duration of Respiratory Isolation for Patients With Possible Tuberculosis in a US Hospital.

Importance: New guidelines recommend that molecular testing replace sputum-smear microscopy to guide discontinuation of respiratory isolation in patients undergoing evaluation for active tuberculosis (TB) in health care settings. Objective: To evaluate the implementation and impact of a molecular testing strategy to guide discontinuation of isolation. Design, Setting, and Participants: Prospective cohort study with a pragmatic, before-and-after-implementation design of 621 consecutive patients hospitalized at Zuckerberg San Francisco General Hospital and Trauma Center who were undergoing sputum examination for evaluation for active pulmonary TB from January 2014 to January 2016. Interventions: Implementation of a sputum molecular testing algorithm using GeneXpert MTB/RIF (Xpert; Cepheid) to guide discontinuation of isolation. Main Outcomes and Measures: We measured the proportion of patients with molecular testing ordered and completed; the accuracy of the molecular testing algorithm in reference to mycobacterial culture; the duration of each component of the testing and isolation processes; length of stay; mean days in isolation and in hospital; and mean cost. We extracted data from hospital records and compared measures before and after implementation. Results: Clinicians ordered sputum testing for TB for 621 patients at ZSFG during the 2-year study period. Of 301 patients in the preimplementation period with at least 1 sputum microscopy and culture ordered, clinicians completed the rapid TB testing evaluation process for 233 (77%).Among 320 patients evaluated in the postimplementation period, clinicians ordered molecular testing for 234 (73%) patients and received results for 295 of 302 (98%) tests ordered. Median age was 54 years (interquartile range, 44-63 years), and 161 (26%) were women. The molecular testing algorithm accurately diagnosed all 7 patients with culture-confirmed TB and excluded TB in all 251 patients with Mycobacterium tuberculosis (MTB) culture-negative results. Compared with the preimplementation period, there were significant decreases in median times to final rapid test result (39.1 vs 22.4 hours, P < .001), discontinuation of isolation (2.9 vs 2.5 days, P = .001), and hospital discharge (6.0 vs 4.9 days, P = .003), on average saving $13 347 per isolated TB-negative patient. Conclusions and Relevance: A sputum molecular testing algorithm to guide discontinuation of respiratory isolation for patients undergoing evaluation for active TB was safe, feasible, widely and sustainably adopted, and provided substantial clinical and economic benefits. Molecular testing may facilitate more efficient, patient-centered evaluation for possible TB in US hospitals.

The dynamic Atg13-free conformation of the Atg1 EAT domain is required for phagophore expansion.

Yeast macroautophagy begins with the de novo formation of a double-membrane phagophore at the preautophagosomal structure/phagophore assembly site (PAS), followed by its expansion into the autophagosome responsible for cargo engulfment. The kinase Atg1 is recruited to the PAS by Atg13 through interactions between the EAT domain of the former and the tMIM motif of the latter. Mass-spectrometry data have shown that, in the absence of Atg13, the EAT domain structure is strikingly dynamic, but the function of this Atg13-free dynamic state has been unclear. We used structure-based mutational analysis and quantitative and superresolution microscopy to show that Atg1 is present on autophagic puncta at, on average, twice the stoichiometry of Atg13. Moreover, Atg1 colocalizes with the expanding autophagosome in a manner dependent on Atg8 but not Atg13. We used isothermal titration calorimetry and crystal structure information to design an EAT domain mutant allele ATG1DD that selectively perturbs the function of the Atg13-free state. Atg1DD shows reduced PAS formation and does not support phagophore expansion, showing that the EAT domain has an essential function that is separate from its Atg13-dependent role in autophagy initiation.

Unveiling the role of VPS34 kinase domain dynamics in regulation of the autophagic PI3K complex.

The class III PI 3-kinase, VPS34 forms distinct complexes essential for cargo sorting and membrane trafficking in endocytosis as well as for autophagosome nucleation and maturation. We used integrative structural biology approach to provide insights into the conformational dynamics of the complex and mechanisms that regulate VPS34 activity at the membrane.

Scaffolding the cup-shaped double membrane in autophagy.

Autophagy is a physiological process for the recycling and degradation of cellular materials. Forming the autophagosome from the phagophore, a cup-shaped double-membrane vesicle, is a critical step in autophagy. The origin of the cup shape of the phagophore is poorly understood. In yeast, fusion of a small number of Atg9-containing vesicles is considered a key step in autophagosome biogenesis, aided by Atg1 complexes (ULK1 in mammals) localized at the preautophagosomal structure (PAS). In particular, the S-shaped Atg17-Atg31-Atg29 subcomplex of Atg1 is critical for phagophore nucleation at the PAS. To study this process, we simulated membrane remodeling processes in the presence and absence of membrane associated Atg17. We show that at least three vesicles need to fuse to induce the phagophore shape, consistent with experimental observations. However, fusion alone is not sufficient. Interactions with 34-nm long, S-shaped Atg17 complexes are required to overcome a substantial kinetic barrier in the transition to the cup-shaped phagophore. Our finding rationalizes the recruitment of Atg17 complexes to the yeast PAS, and their unusual shape. In control simulations without Atg17, with weakly binding Atg17, or with straight instead of S-shaped Atg17, the membrane shape transition did not occur. We confirm the critical role of Atg17-membrane interactions experimentally by showing that mutations of putative membrane interaction sites result in reduction or loss of autophagic activity in yeast. Fusion of a small number of vesicles followed by Atg17-guided membrane shape-remodeling thus emerges as a viable route to phagophore formation.

Vps34 Kinase Domain Dynamics Regulate the Autophagic PI 3-Kinase Complex.

The class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) is required for the initiation of essentially all macroautophagic processes. PI3KC3-C1 consists of the lipid kinase catalytic subunit VPS34, the VPS15 scaffold, and the regulatory BECN1 and ATG14 subunits. The VPS34 catalytic domain and BECN1:ATG14 subcomplex do not touch, and it is unclear how allosteric signals are transmitted to VPS34. We used EM and crosslinking mass spectrometry to dissect five conformational substates of the complex, including one in which the VPS34 catalytic domain is dislodged from the complex but remains tethered by an intrinsically disordered linker. A "leashed" construct prevented dislodging without interfering with the other conformations, blocked enzyme activity in vitro, and blocked autophagy induction in yeast cells. This pinpoints the dislodging and tethering of the VPS34 catalytic domain, and its regulation by VPS15, as a master allosteric switch in autophagy induction.

Salvage brachytherapy for recurrent prostate cancer after definitive radiation therapy: A comparison of low-dose-rate and high-dose-rate brachytherapy and the importance of prostate-specific antigen doubling time.

BACKGROUND: Salvage brachytherapy is a treatment option for patients with locally recurrent prostate cancer after primary radiation therapy. We reviewed our experience using low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy to compare the outcome and toxicity profiles of each approach in the salvage brachytherapy setting. METHODS AND MATERIALS: Ninety-eight patients with biopsy-proven locally recurrent prostate cancer who underwent salvage brachytherapy (LDR = 37; HDR = 61) following an initial course of definitive radiotherapy between 4/2003 and 4/2015 were retrospectively reviewed. All patients underwent salvage brachytherapy using LDR or HDR. Androgen deprivation therapy was used in 45% of the patients. Prostate-specific antigen (PSA) failure was determined using the Phoenix (nadir+2) definition. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4 and patient-reported questionnaires. RESULTS: Median followup was 31 months. The 3-year PSA relapse-free survival (RFS) was 60.1% (95% CI, 49.6-72.5%). There was no difference between LDR and HDR brachytherapy in terms of PSA RFS (p = 0.84 by log-rank test). On multivariate analysis, only prostate-specific antigen doubling time (PSADT) <12 months was significantly associated with PSA relapse. The 3-year PSA RFS for patients with a PSADT <12 months was 39% compared with 73% for PSADT ≥12 months (p = 0.002 by long-rank test). There were no statistically significant differences in toxicity between LDR and HDR brachytherapy. There was a higher peak in urinary symptoms in LDR patients; however by 24-36 months, most patients in both groups returned to baseline. CONCLUSIONS: Both LDR and HDR salvage brachytherapy are an excellent treatment options for appropriately selected patients with comparable outcome and toxicity. Patients with a PSADT < 12 months seem to have worse outcomes.

Structure and function of the ULK1 complex in autophagy.

The ULK1 complex initiates autophagosome formation, linking cellular nutrient status to downstream events in autophagy. Recent work suggests that the ULK1 complex might also be activated in selective autophagy independent of nutrient or energy status. In this review we will discuss our current understanding of how the ULK1 complex is regulated by different signals, as well as how this complex then regulates other components of the autophagy machinery. Recently obtained structural data both on ULK1 and the orthologous yeast Atg1 complex are beginning to shed light on the higher-order organization of ULK1 complex. Ultimately, these insights might make it possible to understand how cargo organization and structure recruits and regulates ULK1 in selective autophagy initiation.

Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites.

The primary cilium is a microtubule-based organelle that functions in sensory and signalling pathways. Defects in ciliogenesis can lead to a group of genetic syndromes known as ciliopathies. However, the regulatory mechanisms of primary ciliogenesis in normal and cancer cells are incompletely understood. Here we demonstrate that autophagic degradation of a ciliopathy protein, OFD1 (oral-facial-digital syndrome 1), at centriolar satellites promotes primary cilium biogenesis. Autophagy is a catabolic pathway in which cytosol, damaged organelles and protein aggregates are engulfed in autophagosomes and delivered to lysosomes for destruction. We show that the population of OFD1 at the centriolar satellites is rapidly degraded by autophagy upon serum starvation. In autophagy-deficient Atg5 or Atg3 null mouse embryonic fibroblasts, OFD1 accumulates at centriolar satellites, leading to fewer and shorter primary cilia and a defective recruitment of BBS4 (Bardet-Biedl syndrome 4) to cilia. These defects are fully rescued by OFD1 partial knockdown that reduces the population of OFD1 at centriolar satellites. More strikingly, OFD1 depletion at centriolar satellites promotes cilia formation in both cycling cells and transformed breast cancer MCF7 cells that normally do not form cilia. This work reveals that removal of OFD1 by autophagy at centriolar satellites represents a general mechanism to promote ciliogenesis in mammalian cells. These findings define a newly recognized role of autophagy in organelle biogenesis.

Interaction between small GTPase Rab7 and PI3KC3 links autophagy and endocytosis: A new Rab7 effector protein sheds light on membrane trafficking pathways.

Endocytosis and autophagy are both membrane trafficking pathways vital for cell survival. Endocytosis, the primary means by which cells internalize material such as cell-surface receptors and their protein ligands, is essential for proper cell growth and communication. Autophagy is a catabolic process that degrades cargo ranging from organelles to protein aggregates to bacteria, and it is important for maintaining cellular homeostasis. Defects in both endosome and autophagosome maturation lead to an array of human diseases, including cancer; however, the molecular mechanisms underlying endosome and autophagosome maturation are not well characterized. In the case of endocytosis, small GTPases, key players in membrane organization, are required for endosome maturation. Specifically, activation of the small GTPase Rab7 is required for the initiation of the early-to-late endosome transition, although how this is regulated is largely unknown. Now recent findings from our laboratory show that Rubicon, a component of the PI3KC3 complex, inhibits endosome maturation by preventing activation of Rab7. Not only do our results clarify the molecular link between PI3KC3 and Rab7 function in endosome maturation, they lead us to propose new models for PI3KC3 involvement in membrane trafficking, particularly at the convergence between the endosome and autophagosome pathways.

FGF signaling through FGFR1 is required for olfactory bulb morphogenesis.

During development, the embryonic telencephalon is patterned into different areas that give rise to distinct adult brain structures. Several secreted signaling molecules are expressed at putative signaling centers in the early telencephalon. In particular, Fgf8 is expressed at the anterior end of the telencephalon and is hypothesized to pattern it along the anteroposterior (AP) axis. Using a CRE/loxP genetic approach to disrupt genes in the telencephalon, we address the role of FGF signaling directly in vivo by abolishing expression of the FGF receptor Fgfr1. In the Fgfr1-deficient telencephalon, AP patterning is largely normal. However, morphological defects are observed at the anterior end of the telencephalon. Most notably, the olfactory bulbs do not form normally. Examination of the proliferation state of anterior telencephalic cells supports a model for olfactory bulb formation in which an FGF-dependent decrease in proliferation is required for initial bulb evagination. Together the results demonstrate an essential role for Fgfr1 in patterning and morphogenesis of the telencephalon.

Lymphangiogram-assisted lymph node target delineation for patients with gynecologic malignancies.

PURPOSE: Intensity-modulated radiotherapy for gynecologic malignancies requires proper knowledge of the volumes to be irradiated and accurate delineation of these volumes on a three-dimensional projection. In this study, assisted by lymphangiography (LAG), we derived guidelines for delineating nodal target volumes on CT. METHODS AND MATERIALS: Sixteen patients with cervical cancer who underwent radiotherapy between 1995 and 1999 at the Mallinckrodt Institute of Radiology were enrolled in the study. The initial 6 patients underwent bipedal LAG as part of the staging workup. Cross-sectional CT images were acquired and analyzed, and lymph node locations were described relative to the aorta, vena cava, common iliac, external iliac, and femoral vessels. The greatest distance from lymph node to vessel wall and pelvic sidewall was determined for each nodal group. This served as a guideline from which the clinical target volume (CTV) definitions were developed. This proposed CTV was then applied to CT scans of 10 patients to determine the amounts of normal tissues encompassed. RESULTS: Nodal CTV guidelines were derived to cover 100% of LAG-avid lymph nodes. This CTV definition encompassed an average of 58.1 +/- 22.8 cm(3) (6.8% +/- 2.8% of total volume) small bowel, 28.4 +/- 19.2 cm(3) (4.2% +/- 3.2%) large bowel, 8.6 +/- 8.6 cm(3) (3.2% +/- 2.6%) bladder, and 1.6 +/- 3.1 cm(3) (1.0% +/- 1.7%) rectum. The absolute volume and fraction of normal tissues encompassed by CTV plus 1- or 2-cm margins were calculated. CONCLUSION: This study presents the first time that three-dimensional lymph node mapping with the aid of LAG has been used to generate a nodal CTV guideline. This information may assist radiation oncologists in properly determining nodal target volumes and selecting a margin around the CTV for intensity-modulated radiotherapy.