Improved Access to Potent Anticancer Tubulysins and Linker-Functionalized Payloads Via an All-On-Resin Strategy.

Tubulysins are among the most recent antimitotic compounds to enter into antibody/peptide-drug conjugate (ADC/PDC) development. Thus far, the design of the most promising tubulysin payloads relied on simplifying their structures, e. g., by using small tertiary amide N-substituents (Me, Et, Pr) on the tubuvaline residue. Cumbersome solution-phase approaches are typically used for both syntheses and functionalization with cleavable linkers. p-Aminobenzyl quaternary ammonium (PABQ) linkers were a remarkable advancement for targeted delivery, but the procedures to incorporate them into tubulysins are only of moderate efficiency. Here we describe a novel all-on-resin strategy permitting a loss-free resin linkage and an improved access to super potent tubulysin analogs showing close resemblance to the natural compounds. For the first time, a protocol enables the integration of on-resin tubulysin derivatization with, e. g., a maleimido-Val-Cit-PABQ linker, which is a notable progress for the payload-PABQ-linker technology. The strategy also allows tubulysin diversification of the internal amide N-substituent, thus enabling to screen a tubulysin library for the discovery of new potent analogs. This work provides ADC/PDC developers with new tools for both rapid access to new derivatives and easier linker-attachment and functionalization.

Surgical management of Rathke cleft cysts in pediatric patients: a single institution experience.

OBJECTIVE: Rathke cleft cysts (RCCs) are benign, epithelial-lined sellar lesions that arise from remnants of the craniopharyngeal duct. Due to their rarity in the pediatric population, data are limited regarding the natural history and optimal management of growing or symptomatic RCCs. We present our institutional experience with the surgical management of RCCs. METHODS: We performed a retrospective study of consecutive RCC patients ≤ 18 years old treated surgically at our institution between 2006 and 2022. RESULTS: Overall, 567 patients with a diagnosis of pituitary mass or cyst were identified. Of these, 31 had a histopathological diagnosis of RCC, 58% female and 42% male. The mean age was 13.2 ± 4.2 years. Presenting symptoms included headache (58%), visual changes (32%), and endocrinopathies or growth delay (26%); 13% were identified incidentally and subsequently demonstrated growth on serial imaging. Six percent presented with symptomatic intralesional hemorrhage. Surgical approach was transsphenoidal for 90% of patients and orbitozygomatic for 10%. Preoperative headaches resolved in 61% of patients and preoperative visual deficits improvement in 55% after surgery. New pituitary axis deficits were seen in 9.7% of patients. Only two complications occurred from a first-time surgery: one cerebrospinal fluid leak requiring lumbar drain placement, and one case of epistaxis requiring cauterization. No patients experienced new visual or neurological deficits. Patients were followed postoperatively with serial imaging at a mean follow-up was 62.9 ± 58.4 months. Recurrence requiring reoperation occurred in 32% of patients. Five-year progression-free survival was 47.9%. Except for one patient with multiple neurological deficits from a concurrent tectal glioma, all patients had a modified Rankin Scale score of 0 or 1 (good outcome) at last follow-up. CONCLUSION: Due to their secretory epithelium, pediatric RCCs may demonstrate rapid growth and can cause symptoms due to local mass effect. Surgical management of symptomatic or growing pediatric RCCs via cyst fenestration or partial resection of the cyst wall can be performed safely, with good neurologic outcomes. There is a nontrivial risk of endocrinologic injury, and long-term follow up is needed due to high recurrence rates.

Treatment of pediatric intracranial aneurysms: institutional case series and systematic literature review.

INTRODUCTION: Pediatric intracranial aneurysms (IAs) are rare and have distinct clinical profiles compared to adult IAs. They differ in location, size, morphology, presentation, and treatment strategies. We present our experience with pediatric IAs over an 18-year period using surgical and endovascular treatments and review the literature to identify commonalities in epidemiology, treatment, and outcomes. METHODS: We identified all patients < 20 years old who underwent treatment for IAs at our institution between 2005 and 2020. Medical records and imaging were examined for demographic, clinical, and operative data. A systematic review was performed to identify studies reporting primary outcomes of surgical and endovascular treatment of pediatric IAs. Demographic information, aneurysm characteristics, treatment strategies, and outcomes were collected. RESULTS: Thirty-three patients underwent treatment for 37 aneurysms over 18 years. The mean age was 11.4 years, ranging from one month to 19 years. There were 21 males (63.6%) and 12 females (36.4%), yielding a male: female ratio of 1.75:1. Twenty-six (70.3%) aneurysms arose from the anterior circulation and 11 (29.7%) arose from the posterior circulation. Aneurysmal rupture occurred in 19 (57.5%) patients, of which 8 (24.2%) were categorized as Hunt-Hess grades IV or V. Aneurysm recurrence or rerupture occurred in five (15.2%) patients, and 5 patients (15.2%) died due to sequelae of their aneurysms. Twenty-one patients (63.6%) had a good outcome (modified Rankin Scale score 0-2) on last follow up. The systematic literature review yielded 48 studies which included 1,482 total aneurysms (611 with endovascular treatment; 656 treated surgically; 215 treated conservatively). Mean aneurysm recurrence rates in the literature were 12.7% and 3.9% for endovascular and surgical treatment, respectively. CONCLUSIONS: Our study provides data on the natural history and longitudinal outcomes for children treated for IAs at a single institution, in addition to our treatment strategies for various aneurysmal morphologies. Despite the high proportion of patients presenting with rupture, good functional outcomes can be achieved for most patients.

Preservation of cranial nerve function in large and giant trigeminal schwannoma resection: a case series.

BACKGROUND: Trigeminal schwannomas (TSs) are intracranial tumors that can cause significant brainstem compression. TS resection can be challenging because of the risk of new neurologic and cranial nerve deficits, especially with large (≥ 3 cm) or giant (≥ 4 cm) TSs. As prior surgical series include TSs of all sizes, we herein present our clinical experience treating large and giant TSs via microsurgical resection. METHODS: This was a retrospective, single-surgeon case series of adult patients with large or giant TSs treated with microsurgery in 2012-2023. RESULTS: Seven patients underwent microsurgical resection for TSs (1 large, 6 giant; 4 males; mean age 39 ± 14 years). Tumors were classified as type M (middle fossa in the interdural space; 1 case, 14%), type ME (middle fossa with extracranial extension; 3 cases, 43%), type MP (middle and posterior fossae; 2 cases, 29%), or type MPE (middle/posterior fossae and extracranial space; 1 case, 14%). Six patients were treated with a frontotemporal approach (combined with transmastoid craniotomy in the same sitting in one patient and a delayed transmaxillary approach in another), and one patient was treated using an orbitofrontotemporal approach. Gross total resection was achieved in 5 cases (2 near-total resections). Five patients had preoperative facial numbness, and 6 had immediate postoperative facial numbness, including two with worsened or new symptoms. Two patients (28%) demonstrated new non-trigeminal cranial nerve deficits over mean follow-up of 22 months. Overall, 80% of patients with preoperative facial numbness and 83% with facial numbness at any point experienced improvement or resolution during their postoperative course. All patients with preoperative or new postoperative non-trigeminal tumor-related cranial nerve deficits (4/4) experienced improvement or resolution on follow-up. One patient experienced tumor recurrence that has been managed conservatively. CONCLUSIONS: Microsurgical resection of large or giant TSs can be performed with low morbidity and excellent long-term cranial nerve function.

A cost analysis of MR-guided laser interstitial thermal therapy for adult refractory epilepsy.

OBJECTIVE: MR-guided laser interstitial thermal therapy (LITT) is used increasingly for refractory epilepsy. The goal of this investigation is to directly compare cost and short-term adverse outcomes for adult refractory epilepsy treated with temporal lobectomy and LITT, as well as to identify risk factors for increased costs and adverse outcomes. METHODS: The National Inpatient Sample (NIS) was queried for patients who received LITT between 2012 and 2019. Patients with adult refractory epilepsy were identified. Multivariable mixed-effects models were used to analyze predictors of cost, length of stay (LOS), and complications. RESULTS: LITT was associated with reduced LOS and overall cost relative to temporal lobectomy, with a statistical trend toward lower incidence of postoperative complications. High-volume surgical epilepsy centers had lower LOS overall. Longer LOS was a significant driver of increased cost for LITT, and higher comorbidity was associated with non-routine discharge. SIGNIFICANCE: LITT is an affordable alternative to temporal lobectomy for adult refractory epilepsy with an insignificant reduction in inpatient complications. Patients may benefit from expanded access to this treatment modality for both its reduced LOS and lower cost.

Going the distance in acoustic neuroma resection: microsurgical outcomes at high-volume centers of excellence.

PURPOSE: High-volume hospitals are associated with improved surgical outcomes for acoustic neuromas (ANs). Due to the benign and slow-growing nature of ANs, many patients travel to geographically distant cities, states, or countries for their treatment. However, the impact of travel burden to high-volume centers, as well as its relative benefit are poorly understood. We compared post-operative outcomes between AN patients that underwent treatment at local, low-volume hospitals with those that traveled long distances to high-volume hospitals. METHODS: The National Cancer Database was used to analyze AN patients that underwent surgery (2004-2015). Patients in the lowest quartile of travel distance and volume (Short-travel/Low-Volume: STLV) were compared to patients in the highest quartile of travel distance and volume (Long-travel/High-Volume: LTHV). Only STLV and LTHV cases were included for analysis. RESULTS: Of 13,370 cases, 2,408 met inclusion criteria. STLV patients (n = 1,305) traveled a median of 6 miles (Interquartile range [IQR] 3-9) to low-volume centers (median 2, IQR 1-3 annual cases) and LTHV patients (n = 1,103) traveled a median of 143 miles [IQR 103-230, maximum 4,797] to high-volume centers (median 34, IQR 28-42 annual cases). LTHV patients had lower Charlson/Deyo scores (p = 0.001), mostly received care at academic centers (81.7% vs. 39.4%, p < 0.001), and were less likely to be minorities (7.0% vs. 24.2%, p < 0.001) or underinsured (4.2% vs. 13.8%, p < 0.001). There was no difference in average tumor size. On multivariable analysis, LTHV predicted increased likelihood of gross total resection (odds ratio [OR] 5.6, 95% confidence interval [CI] 3.8-8.4, p < 0.001), longer duration between diagnosis and surgery (OR 1.3, 95% CI 1.0-1.6, p = 0.040), decreased length of hospital stay (OR 0.5, 95% CI 0.4-0.7, p < 0.001), and greater overall survival (Hazard Ratio [HR] 0.6, 95% CI 0.4-0.95, p = 0.029). There was no significant difference in 30-day readmission on adjusted analysis. CONCLUSION: Although traveling farther to high-volume centers was associated with greater time between diagnosis and treatment for AN patients, they experienced superior postoperative outcomes compared to patients who received treatment locally at low-volume centers. Enabling access and travel to high-volume centers may improve AN patient outcomes.

Purpurascenines A-C, Azepino-Indole Alkaloids from Cortinarius purpurascens: Isolation, Biosynthesis, and Activity Studies on the 5-HT2A Receptor.

Three previously undescribed azepino-indole alkaloids, named purpurascenines A-C (1-3), together with the new-to-nature 7-hydroxytryptophan (4) as well as two known compounds, adenosine (5) and riboflavin (6), were isolated from fruiting bodies of Cortinarius purpurascens Fr. (Cortinariaceae). The structures of 1-3 were elucidated based on spectroscopic analyses and ECD calculations. Furthermore, the biosynthesis of purpurascenine A (1) was investigated by in vivo experiments using 13C-labeled sodium pyruvate, alanine, and sodium acetate incubated with fruiting bodies of C. purpurascens. The incorporation of 13C into 1 was analyzed using 1D NMR and HRESIMS methods. With [3-13C]-pyruvate, a dramatic enrichment of 13C was observed, and hence a biosynthetic route via a direct Pictet-Spengler reaction between α-keto acids and 7-hydroxytryptophan (4) is suggested for the biosynthesis of purpurascenines A-C (1-3). Compound 1 exhibits no antiproliferative or cytotoxic effects against human prostate (PC-3), colorectal (HCT-116), and breast (MCF-7) cancer cells. An in silico docking study confirmed the hypothesis that purpurascenine A (1) could bind to the 5-HT2A serotonin receptor's active site. A new functional 5-HT2A receptor activation assay showed no functional agonistic but some antagonistic effects of 1 against the 5-HT-dependent 5-HT2A activation and likely antagonistic effects on putative constitutive activity of the 5-HT2A receptor.

Cilostazol for the management of moyamoya disease: a systematic review of the early evidence, efficacy, safety, and future directions.

Surgical revascularization remains the standard treatment for symptomatic moyamoya disease (MMD). As with any major surgical treatment, revascularization is associated with risks and limitations, denoting the need for noninvasive treatments to improve ischemic symptoms and prevent strokes. Cilostazol is a selective phosphodiesterase III inhibitor with antiplatelet, antithrombotic, and vasodilatory effects commonly used in peripheral vascular disease. Clinical studies assessing the efficacy of cilostazol in the management of stroke and MMD were recently reported, although a comprehensive assessment of the overall evidence is lacking. A systematic scoping review was conducted to assess the early evidence on cilostazol administration in patients with MMD. The inclusion criteria encompassed original human studies primarily focused on cilostazol's safety, efficacy, or utilization in managing MMD patients. A search of the PubMed database was conducted in June 2023, yielding 5 peer-reviewed publications that satisfied the inclusion criteria and were subjected to narrative synthesis. Risk of bias assessment was not applicable due to the scoping nature of this review. East Asian studies demonstrate increasing rates of cilostazol prescriptions for patients with MMD. In a large population-based study, cilostazol was compared to other antiplatelet medications and yielded the largest decrease in mortality among patients with newly diagnosed MMD. Other studies reported significant improvements in cerebral blood flow and cognitive function, which were deemed to be independent of one another. There are limited data on the safety profile of cilostazol in the MMD population, although the evidence derived from various studies performed in the general stroke population can likely provide insights into its potential utility in MMD patients. Cilostazol targets several critical pathways involved in the pathophysiology of MMD. The evidence corroborates the potential benefits of cilostazol for the management of MMD, although these findings should be interpreted with caution due to the small number of studies and lack of randomized trials. Subgroups of patients need to be identified who can safely undergo medical management in lieu of revascularization surgery or to improve surgical outcomes. Additional studies are needed to assess the efficacy and safety of cilostazol therapy, especially in Western populations.

Multiple approaches to a spheno-orbital and deep face meningioma: how I do it.

BACKGROUND: The integration of multiple approaches is sometimes needed for the safe resection of complex multicompartment skull base tumors. METHOD: We present the case of a spheno-orbital and deep face meningioma that required a staged resection strategy using transnasal, transoral, transfacial, and transcranial approaches for airway protection and maximal safe tumor removal. CONCLUSION: Limitations in individual skull base approaches for complex tumors can be anticipated and overcome by combining approaches.

Combined retrosigmoid and middle fossa approach for a small, superiorly located petroclival meningioma: how I do it.

BACKGROUND: Petroclival meningiomas pose significant surgical challenges because of their deep location and complex surrounding neurovasculature. The use of multiple surgical approaches can optimize safe tumor removal from multiple anatomic compartments. METHOD: We describe a patient with a growing superior petroclival meningioma centered at the posterior clinoid with extension into Meckel's cave that was successfully removed with a combined retrosigmoid and subtemporal middle fossa approach. This strategy avoided the need for anterior petrous bone drilling and tentorial splitting. CONCLUSION: A combined retrosigmoid and subtemporal middle fossa approach can provide safe access to tumors spanning the supra- and infratentorial compartments.

Far lateral craniotomy for disconnection of vertebral dural arteriovenous fistula: how I do it.

BACKGROUND: Craniocervical junction (CCJ) vascular abnormalities can be challenging to treat because of the surrounding density of critical neurovascular anatomy. Although most dural arteriovenous fistulas (dAVFs) are now treated with endovascular surgery, dAVFs near the CCJ are often better suited for microsurgical obliteration with precise vascular control. METHODS: We describe our microsurgical approach to treating dAVFs at the CCJ. This includes a far-lateral approach with a small incision centered over the transverse process of the atlas and circumferential skeletonization of the vertebral artery in addition to clipping the fistula to limit lesion recurrence. CONCLUSIONS: Definitive microsurgical treatment of CCJ dAVFs can be accomplished using a minimally invasive approach.

Closure of small skull base defects with muscle plug napkin ring technique: how I do it.

BACKGROUND: Defects through the skull base into the paranasal sinuses can occur during anterior skull base procedures, risking cerebrospinal fluid leak and infection if not repaired. METHODS: We describe a muscle plug napkin ring technique for closure of small skull base defects, wherein a free muscle graft slightly bigger than the defect is packed tightly in the defect, half extracranially and half intracranially and sealed with fibrin glue. The technique is illustrated in the case of a 58-year-old woman with a large left medial sphenoid wing/clinoidal meningioma. CONCLUSIONS: The muscle plug napkin ring technique is a simple solution to small skull base defects.

In-out-in technique for petrosal sinus dural arteriovenous fistula obliteration: How I Do It.

BACKGROUND: Dural arteriovenous fistulas (dAVFs) at the superior petrosal sinus are a rare but important subtype that pose a high risk of mortality and morbidity. Treatment for these lesions can be challenging with stand-alone endovascular methods. METHODS: We describe our "in-out-in" technique for disconnecting dAVFs at the superior petrosal sinus, which includes definitive sacrifice of the superior petrosal sinus and the transverse sigmoid sinus, if involved. This method achieves complete fistula obliteration and minimizes recurrence risk with new arterial feeders. CONCLUSIONS: The in-out-in technique is a safe and effective approach for the treatment of dAVFs involving the superior petrosal sinus.

Combined and staged retrosigmoid, extended middle fossa, and endoscopic transnasal approach to a petroclival chondrosarcoma: how I do it.

BACKGROUND: Tumors of the petroclival region with multicompartment extension can be difficult to address with a single surgical approach. METHOD: We present the case of a patient with a large chondrosarcoma centered at the right petroclival fissure with extension into the cavernous sinus, the region beneath the cavernous sinus, cerebellopontine angle with deformation of the pons, and prevertebral space. A staged complete resection was performed using a stage 1 single-incision combined right retrosigmoid craniotomy and extended middle fossa craniotomy, followed by a stage 2 endoscopic transnasal approach. CONCLUSION: A combined approach to selected petroclival tumors can maximize safe resection.

Unstable ventricular tachycardia requiring defibrillation from rapid ventricular pacing during basilar apex aneurysm clipping.

BACKGROUND: Controlled hypotension is an important tool in the open treatment of complex intracranial aneurysms. Of the available methodologies, rapid ventricular pacing (RVP) provides titratable, sustained hypotension with a relatively safe profile. METHOD: We report the case of a 63-year-old woman who underwent a combined subfrontal and subtemporal approach for clipping of anterior communicating artery and basilar apex aneurysms. RVP was used during initial dissection of the basilar apex aneurysm and perforators but caused uncontrolled ventricular tachycardia requiring synchronized defibrillation. After restoration of hemodynamic stability, the aneurysm was uneventfully clipped. CONCLUSION: Preparation for unstable cardiac arrhythmias is needed with RVP.

Combined direct and indirect superficial temporal artery-to-middle cerebral artery bypass with a hinged bone flap: how I do it.

BACKGROUND: Superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass is a critical treatment for moyamoya disease and steno-occlusive cerebrovascular disease. Combined bypass (direct + indirect) optimizes the chance of durable flow augmentation but can complicate wound closure from tissue disruption. METHODS: We describe our technique for combined direct and indirect (encephaloduromyosynangiosis; EDAMS) STA-MCA bypass using a hinged bone flap. In addition to a direct bypass, EDAMS provides multiple sources for indirect revascularization. The hinged bone flap gently approximates the muscle and pia for secondary vascular ingrowth. CONCLUSIONS: Combined STA-MCA bypass with a hinged bone flap safely maximizes revascularization potential.

Basilar decompression via a far lateral transcondylar approach: technical note.

BACKGROUND: Treatments for symptomatic or unstable basilar invagination (BI) include posterior decompression, distraction/fusion, trans-nasal or trans-oral anterior decompression, and combined techniques, with the need for occipitocervical fusion based on the degree of craniocervical instability. Variations of the far lateral transcondylar approach are described in limited case series for BI, but have not been widely applied. METHODS: A single-institution, retrospective review of consecutive patients undergoing a far lateral transcondylar approach for odontoidectomy (± resection of the inferior clivus) followed by occipitocervical fusion over a 6-year period (1/1/2016 to 12/31/2021) is performed. Detailed technical notes are combined with images from cadaveric dissections and patient surgeries to illustrate our technique using a lateral retroauricular incision. RESULTS: Nine patients were identified (3 males, 6 females; mean age 40.2 ± 19.6 years). All patients had congenital or acquired BI causing neurologic deficits. There were no major neurologic or wound-healing complications. 9/9 patients (100%) experienced improvement in preoperative symptoms. CONCLUSIONS: The far lateral transcondylar approach provides a direct corridor for ventral brainstem decompression in patients with symptomatic BI. A comprehensive knowledge of craniovertebral junction anatomy is critical to the safe performance of this surgery, especially when using a lateral retroauricular incision.

Bioactive Phenolic Compounds from Peperomia obtusifolia.

Peperomia obtusifolia (L.) A. Dietr., native to Middle America, is an ornamental plant also traditionally used for its mild antimicrobial properties. Chemical investigation on the leaves of P. obtusifolia resulted in the isolation of two previously undescribed compounds, named peperomic ester (1) and peperoside (2), together with five known compounds, viz. N-[2-(3,4-dihydroxyphenyl)ethyl]-3,4-dihydroxybenzamide (3), becatamide (4), peperobtusin A (5), peperomin B (6), and arabinothalictoside (7). The structures of these compounds were elucidated by 1D and 2D NMR techniques and HREIMS analyses. Compounds 1-7 were evaluated for their anthelmintic (against Caenorhabditis elegans), antifungal (against Botrytis cinerea, Septoria tritici and Phytophthora infestans), antibacterial (against Bacillus subtilis and Aliivibrio fischeri), and antiproliferative (against PC-3 and HT-29 human cancer cell lines) activities. The known peperobtusin A (5) was the most active compound against the PC-3 cancer cell line with IC50 values of 25.6 µM and 36.0 µM in MTT and CV assays, respectively. This compound also induced 90% inhibition of bacterial growth of the Gram-positive B. subtilis at a concentration of 100 µM. In addition, compound 3 showed anti-oomycotic activity against P. infestans with an inhibition value of 56% by using a concentration of 125 µM. However, no anthelmintic activity was observed.

Albatrellus confluens (Alb. & Schwein.) Kotl. & Pouz.: Natural Fungal Compounds and Synthetic Derivatives with In Vitro Anthelmintic Activities and Antiproliferative Effects against Two Human Cancer Cell Lines.

Neglected tropical diseases affect the world's poorest populations with soil-transmitted helminthiasis and schistosomiasis being among the most prevalent ones. Mass drug administration is currently the most important control measure, but the use of the few available drugs is giving rise to increased resistance of the parasites to the drugs. Different approaches are needed to come up with new therapeutic agents against these helminths. Fungi are a source of secondary metabolites, but most fungi remain largely uninvestigated as anthelmintics. In this report, the anthelmintic activity of Albatrellus confluens against Caenorhabditis elegans was investigated using bio-assay guided isolation. Grifolin (1) and neogrifolin (2) were identified as responsible for the anthelmintic activity. Derivatives 4-6 were synthesized to investigate the effect of varying the prenyl chain length on anthelmintic activity. The isolated compounds 1 and 2 and synthetic derivatives 4-6, as well as their educts 7-10, were tested against Schistosoma mansoni (adult and newly transformed schistosomula), Strongyloides ratti, Heligmosomoides polygyrus, Necator americanus, and Ancylostoma ceylanicum. Prenyl-2-orcinol (4) and geranylgeranyl-2-orcinol (6) showed promising activity against newly transformed schistosomula. The compounds 1, 2, 4, 5, and 6 were also screened for antiproliferative or cytotoxic activity against two human cancer lines, viz. prostate adenocarcinoma cells (PC-3) and colorectal adenocarcinoma cells (HT-29). Compound 6 was determined to be the most effective against both cell lines with IC50 values of 16.1 µM in PC-3 prostate cells and 33.7 µM in HT-29 colorectal cells.

Wounds Inhibit Tumor Growth In Vivo.

OBJECTIVE: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo. SUMMARY OF BACKGROUND DATA: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo. METHODS: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells. RESULTS: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds. CONCLUSION: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.