Hair Follicle Transit-Amplifying Cells Phagocytose Dead Cells after Radiotherapeutic and Chemotherapeutic Injuries for Timely Regeneration.

Efficient clearance of dead cells is critical for tissue regeneration after injuries. How dead cells are removed from the skin after radiotherapy and chemotherapy is unclear. In this study, we found that radiotherapeutic and chemotherapeutic damage induced extensive apoptosis of highly proliferative transit-amplifying cells in hair follicles. These apoptotic cells disappeared rapidly in the early stage of regenerative attempts, and the lost structures were regenerated with transient and low-level inflammation. Without the recruitment of macrophages as scavengers, the dying cells were engulfed directly by adjacent surviving transit-amplifying cells, which produced mature phagosomes through fusion with lysosomes in a manner similar to professional phagocytosis and remained active in proliferation. Autophagy did not contribute significantly to the clearance of engulfed cell debris. Perturbing phagocytosis in the transit-amplifying cells hindered apoptotic cell removal, delayed structural recovery, and aggravated hair loss. Therefore, transit-amplifying cells are capacitated with both proliferative and efferocytic functions that facilitate tissue regeneration after tissue injury.

Vertebral artery sparing volumetric modulated arc therapy in nasopharyngeal carcinoma.

Vascular stenosis is a late radiation complication that develops in long-term survivors of nasopharyngeal carcinoma. Vertebral arteries (VAs) are major vessels responsible for posterior circulation. In this study, we evaluated the feasibility of VA-sparing volumetric modulated arc therapy (VMAT) techniques. A total of 20 patients with nasopharyngeal carcinoma treated by a TrueBeam linear accelerator were enrolled in this study. The original VMAT plan was designed without the contouring of VAs as organs at risk (OARs). The same image set of the original VMAT plan was used to contour the VAs for each patient. A new VA-sparing VMAT plan was developed by avoiding VAs as OARs. Finally, a paired t-test was used to compare the dosimetric differences. The VA-sparing VMAT plan had similar target coverage and dose to those of other OARs. The VA-sparing plan yielded a significantly low VA dose from 53 to 40 Gy, with V35Gy changing from 97% to 56%, V50Gy changing from 67% to 35%, and V63Gy changing from 15% to approximately 7%-10% (p < 0.001 for all comparisons). VAs should be correctly identified as OARs. Photon VMAT with VA sparing can help substantially decrease the VA dose.

Prostaglandin E2 prevents radiotherapy-induced alopecia by attenuating transit amplifying cell apoptosis through promoting G1 arrest.

BACKGROUND: Growing hair follicles (HFs) harbor actively dividing transit amplifying cells (TACs), rendering them highly sensitive to radiotherapy (RT). Clinically, there is still a lack of treatment options for radiotherapy-induced alopecia (RIA). OBJECTIVE: Our present study aimed to investigated the effect and mechanism of local prostaglandin E2 (PGE2) treatment in RIA prevention. METHODS: We compared the response of growing HFs to radiation with and without local PGE2 pretreatment in a mouse model in vivo. The effect of PGE2 on the cell cycle was determined in cultured HF cells from fluorescent ubiquitination-based cell cycle indicator mice. We also compared the protective effects of PGE2 and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor against RIA. RESULTS: The local cutaneous PGE2 injection reduced RIA by enhancing HF self-repair. Mechanistically, PGE2 did not activate HF stem cells, but it preserved more TACs for regenerative attempts. Pretreatment of PGE2 lessened radiosensitivity of TACs by transiently arresting them in the G1 phase, thereby reducing TAC apoptosis and mitigating HF dystrophy. The preservation of more TACs accelerated HF self-repair and bypassed RT-induced premature termination of anagen. Promoting G1 arrest by systemic administration of palbociclib isethionate (PD0332991), a CDK4/6 inhibitor, offered a similar protective effect against RT. CONCLUSIONS: Locally administered PGE2 protects HF TACs from RT by transiently inducing G1 arrest, and the regeneration of HF structures lost from RT is accelerated to resume anagen growth, thus bypassing the long downtime of hair loss. PGE2 has the potential to be repurposed as a local preventive treatment for RIA.

Radiation-induced sarcoma of head and neck: Clinical characteristics and molecular signatures.

BACKGROUND: Radiation-induced sarcoma of the head and neck (RISHN) is a rare yet devastating potential complication of radiotherapy treatment. We aimed to evaluate the clinicopathological characteristics and molecular signatures of RISHN in patients who underwent radiotherapy for head and neck cancer (HNC) to identify high-risk patients and enable earlier cancer detection. METHODS: This study retrospectively evaluated 24 sarcoma patients who received radiotherapy for HNC between 1994 and 2019. Patients were divided into two groups based on RISHN latency period. Patient demographics, initial tumor staging, risk factors, and survival between groups were analyzed, and whole-exome sequencing (WES) of selected samples was performed. RESULTS: The median age at diagnosis of RISHN was 54 years, and the male-to-female ratio was 2:1. The latency period ranged from 0.8 to 64.4 years (median 6.5 years), with a median survival of 21.5 months. Primary cancer in the oral cavity, treatment with alkylating agents, alcohol consumption, betel nut chewing, and smoking were identified as risk factors for short (<5 years) latency periods. The majority of RISHN cases occurred in the oral cavity (58.3%). WES analysis showed that tumor necrosis factor and cell cycle checkpoint pathways were differentially involved in both patient groups. CONCLUSIONS: Although case numbers were small, our cohort represents the largest case series of RISHN from a single institution to date. Clinicians must be aware of factors affecting RISHN development and latency, and risk factor identification may lead to earlier detection and prevention in the future.

Post-irradiation sarcoma after definitive radiation therapy for nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: Postirradiation sarcoma (PIS) is a rare radiation-induced malignancy after nasopharyngeal carcinoma (NPC) treatment. MATERIALS AND METHODS: We retrospectively screened 9,185 NPC patients between 2000 and 2020 and identified 41 patients with PIS according to the modified Cahan's criteria: (1) the PIS must have arisen within a previous radiation field; (2) a latent period must have existed; (3) histologically proved sarcoma; (4) the tissue in which the PIS arose must have been healthy prior to the radiation. The initial radiation therapy techniques used were 2D (25; 61.0%), 3D (7; 17.1%), and IMRT (9; 22%). RESULTS: The time (year) from radiotherapy (RT) to PIS was longer when using 2D or 3D irradiation techniques (median, 14.2; range, 3.4-28.1; Q1-Q3, 8.6-19.7) than when using IMRT (median, 6.6; range, 3.8-15.7; Q1-Q3, 4.5-11.7; P =.026). The time (year) from RT to PIS diagnosis was significantly longer when using lower radiation energy from cobalt-60 (median, 15.8; range, 10.4-28.4; Q1-Q3, 12.5-23.8) than when using a higher radiation energy of 6 or 10 MV (median, 10.2; range, 3.4-23.3; Q1-Q3, 6.5-16.1; P =.006). The 2-year overall survival rates for patients who underwent surgery, radical radiotherapy, systemic therapy alone and no treatment were 60.7 %, 42.9 %, 0 % and 0 %, respectively (P =.000). Of the 3 retrievable initial RT dosimetry plans for NPC, the D95 values (dose that covers 95 % of the PIS volume) for PIS were 6267, 6344 and 5820 cGy, respectively. CONCLUSION: High radiation energy and modern techniques may shorten NPC PIS latency. Surgery may be associated with improved survival if feasible.

Spindle Cell Carcinoma of the Head and Neck: Clinical Characteristics and Molecular Signatures.

OBJECTIVE/HYPOTHESIS: Spindle cell carcinoma of the head and neck (HNSpCC) is a rare variant of head and neck squamous cell carcinoma (HNSCC). This study evaluated the clinical characteristics and molecular signatures of such tumors. STUDY DESIGN: Retrospective analysis. METHODS: Medical records of patients diagnosed with HNSpCC from 1996 to 2018 were reviewed. The clinicopathologic features, treatment modalities, and survival status were carefully recorded. Whole exome sequencing (WES) was performed to evaluate the genetic signatures of HNSpCC. RESULTS: We found that among all 71 patients included in this study, the majority of them were male, with tumors developing predominantly in the oral cavity. The 1-, 3-, and 5-year disease-specific survival (DSS) rates were 64.6%, 49.5%, and 43.9%, respectively. A high local recurrence (LR) and distant metastasis (DM) rate (47.9%-25.3%, respectively) were observed. A significant proportion (28.2%) of patients with the worst prognosis had history of previous head and neck cancer (HNC) and had been treated with radiotherapy (RT). WES revealed that those post-RT SpCC shared common mutations with their previous HNC (pre-RT SCC), but gained additional genetic traits, such as hypoxia and cell-ECM interaction that were favorable for survival in an irradiated microenvironment. Distinct genetic landscapes in primary and post-RT SpCC were also found. CONCLUSIONS: This study demonstrates that HNSpCC is a unique entity with more aggressive behavior than conventional HNSCC. HNSpCC arising from a previously irradiated field is a predictor of dismal survival. Both genetic and microenvironmental factors contribute to this highly invasive tumor. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2183-2191, 2023.

Investigating early progression of Hodgkin lymphoma in a two-center analysis.

BACKGROUND/PURPOSE: The early progression of disease (POD) of Hodgkin lymphoma (HL) leads to a poor prognosis. To identify risk factors for early POD, this retrospective two-center cohort analysis was conducted. METHODS: Medical records of HL patients between 1998 and 2020 from two referral centers were reviewed. RESULTS: Two-hundred and sixty-nine patients were analyzed. The distribution of early vs. advanced stages was 51.1 vs. 48.9%, respectively. The 5-year progression free survival (PFS) was 63%, and the overall survival (OS) was 87% with a median follow-up of 52.0 months. The complete remission (CR) rate was 85.7%. Disease progression or relapsed disease occurred in 33.9% (n = 85) of patients while 17.0% of this cohort had early POD within 12 months of induction therapy. Patients with early POD had a worse median OS than those without (p < 0.001). Failure to achieve post-induction CR and high international prognostic score (IPS, 3-7) were independent risk factors for early POD. Compared with chemotherapy alone, consolidative radiotherapy after induction chemotherapy was associated with a lower risk of early POD (21.3% vs. 6.2%, p = 0.006). CONCLUSION: High IPS was an independent risk factor for early POD, which was less observed in those with consolidative radiotherapy.

An innovative targeted therapy for fluoroscopy-induced chronic radiation dermatitis.

Fluoroscopy-induced chronic radiation dermatitis (FICRD) is a complication of fluoroscopy-guided intervention. Unlike acute radiation dermatitis, FICRD is different as delayed onset and usually appears without preexisting acute dermatitis. Unfortunately, the chronic and progressive pathology of FICRD makes it difficult to treat, and some patients need to receive wide excision and reconstruction surgery. Due to lack of standard treatment, investigating underlying mechanism is needed in order to develop an effective therapy. Herein, the Hippo pathway is specifically identified using an RNA-seq analysis in mild damaged skin specimens of patients with FICRD. Furthermore, specific increase of the Yes-associated protein (YAP1), an effector of the Hippo pathway, in skin region with mild damage plays a protective role for keratinocytes via positively regulating the numerous downstream genes involved in different biological processes. Interestingly, irradiated-keratinocytes inhibit activation of fibroblasts under TGF-ß1 treatment via remote control by an exosome containing YAP1. More importantly, targeting one of YAP1 downstream genes, nuclear receptor subfamily 3 group C member 1 (NR3C1), which encodes glucocorticoid receptor, has revealed its therapeutic potential to treat FICRD by inhibiting fibroblasts activation in vitro and preventing formation of radiation ulcers in a mouse model and in patients with FICRD. Taken together, this translational research demonstrates the critical role of YAP1 in FICRD and identification of a feasible, effective therapy for patients with FICRD. KEY MESSAGES: • YAP1 overexpression in skin specimens of radiation dermatitis from FICRD patient. • Radiation-induced YAP1 expression plays protective roles by promoting DNA damage repair and inhibiting fibrosis via remote control of exosomal YAP1. • YAP1 positively regulates NR3C1 which encodes glucocorticoid receptor expression. • Targeting glucocorticoid receptor by prednisolone has therapeutic potential for FICRD patient.

Adjuvant therapy may be omitted for oral cavity cancer with only one positive lymph node.

OBJECTIVE: Whether to administer adjuvant treatment is a matter of great debate for oral cavity cancer harboring a single positive node without extranodal extension and positive margin (defined as low/intermediate risk pN1new in this study). METHODS: A total of 243 low/intermediate risk pN1new patients with oral cavity cancer who received curative surgery were included. Overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS) were compared between patients receiving adjuvant treatment and observation alone. RESULTS: For patients receiving adjuvant therapy vs observation, the differences in outcomes were not statistically significant in terms of 5-year OS, LRFS, RRFS, and DMFS. For subgroup analysis, in low/intermediate pN1new patients with one or more minor risk factors, adjuvant therapy was not significantly associated with OS, LRFS, RRFS, or DMFS in pN1new patients. CONCLUSION: For low/intermediate risk pN1new patients with oral cavity cancer, adjuvant therapy might be omitted. LEVEL OF EVIDENCE: 4.

Lower proximal cup and outer root sheath cells regenerate hair bulbs during anagen hair follicle repair after chemotherapeutic injury.

The cell dynamics and cell origin for anagen hair follicle (HF) repair following chemotherapeutic injury are unclear. We first mapped the HF response to cyclophosphamide (CYP) at natural anagen VI in mice. We found that 30-60 mg/kg of CYP leads to dose-dependent HF dystrophy that was spontaneously repaired with anagen resumption, while 120 mg/kg of CYP prematurely induced catagen/telogen entry. To explore how anagen HF repair is achieved in the dystrophic anagen pathway, we analysed the cell dynamics at 30 mg/kg of CYP. Hair bulbs first shrunk due to matrix cell apoptosis associated with DNA double-strand breaks. DNA damage was repaired, and ordered hair bulb structures were restored within 96 hours. Bulge stem cells did not undergo apoptosis nor proliferation. K5+ basal lower proximal cup cells and outer root sheath cells quickly replenished the cells in the germinative zone and regenerated the concentric layered structures of the lower HF segment. Therefore, anagen HFs are able to summon extra-bulge progenitor cells in close proximity to the damaged matrix for quick repair after CYP injury.

Outcome of bimodality definitive chemoradiation does not differ from that of trimodality upfront neck dissection followed by adjuvant treatment for >6 cm lymph node (N3) head and neck cancer.

Currently, data regarding optimal treatment modality, response, and outcome specifically for N3 head and neck cancer are limited. This study aimed to compare the treatment outcomes between definitive chemoradiotherapy (CCRT) to the neck and upfront neck dissection followed by adjuvant CCRT. Ninety-three N3 squamous cell carcinoma head and neck cancer patients were included. Primary tumor treatment was divided to definitive CCRT (CCRT group) or curative surgery followed by adjuvant CCRT (surgery group). Neck treatment was also classified into two treatment modalities: definitive CCRT to the neck (CCRT group) or curative neck dissection followed by adjuvant CCRT (neck dissection group). Overall, the 2-year overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS) were 51.8%, 47.3%, 45.6%, and 43.6%, respectively. In both oropharyngeal cancer and nonoropharyngeal cancer patients, in terms of OS, LRFS, RRFS or DMFS no difference was noted regarding primary tumor treatment (CCRT vs. surgery) or neck treatment (CCRT vs. neck dissection). In summary, N3 neck patients treated with definitive CCRT may achieve similar outcomes to those treated with upfront neck dissection followed by adjuvant CCRT. Caution should be made to avoid overtreatment for this group of patients.

The breast graded prognostic assessment is associated with the survival outcomes in breast cancer patients receiving whole brain re-irradiation.

INTRODUCTION: Whole brain (WB) re-irradiation for breast cancer patients with progressive brain metastasis after first-course WB radiotherapy (WBRT) is controversial. In this study, we sought to investigate the association between the molecular sub-classifications and breast-specific Graded Prognostic Assessment (GPA, which includes the Karnofsky performance status, molecular subtypes, and age as its indices) and the outcomes of breast cancer patients who received WB re-irradiation. METHODS: Twenty-three breast cancer patients who received WB re-irradiation for relapsed and progressive intracranial lesions after first-course WBRT between 2004 and 2016 were retrospectively reviewed. Patients were divided according to the 4 molecular subtypes of luminal A/B (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), luminal HER2 (HR+/HER2+), HER2 (HR-/HER2+), and triple negative (HR-/HER2-). The clinical and radiological responses and survival rates after WB re-irradiation were analyzed. RESULTS: At 1 month after WB re-irradiation, 13 of 23 patients (56.5%) exhibited disappearance or alleviation of neurological symptoms. The median survival time after WB re-irradiation was 2.93 months (95% confidence interval [CI], 1.79-4.08). After WB re-irradiation, patients with HER2-negative tumors had poorer median survival times than those with HER2-positive tumors (2.23 vs. 3.0 months, respectively; p = 0.022). Furthermore, patients with high breast GPA scores (2.5-4.0, n = 11) had longer median survivals than those with low-scores (0-2.0, n = 12) after WB re-irradiation (4.37 vs. 1.57 months, respectively; p < 0.005). CONCLUSIONS: WB re-irradiation may be a feasible treatment option for certain breast cancer patients who develop brain metastatic lesions after first-course WBRT when these lesions are ineligible for radiosurgery or surgery.

The extent of edema and tumor synchronous invasion into the subventricular zone and corpus callosum classify outcomes and radiotherapy strategies of glioblastomas.

BACKGROUND AND PURPOSE: Irradiating glioblastoma preoperative edema (PE) remains controversial. We investigated the associations between tumors' PE extent with invasion into synchronous subventricular zone and corpus callosum (sSVZCC) and treatment outcomes to provide the clinical evidence for radiotherapy decision-making. MATERIAL AND METHODS: Extensive PE (EPE) was defined as PE extending ≥2 cm from the tumor edge and extensive progressive disease (EPD) as tumors spreading ≥2 cm from the preoperative tumor edge along PE. The survival and progression patterns were analyzed according to EPE and sSVZCC invasion. RESULTS: In total, 136 patients were followed for a median of 74.9 (range, 47.6-102.1) months. The median overall survival and progression-free survival were 19.7 versus 28.6 months (p = 0.005) and 11.0 versus 17.4 months (p = 0.011) in patients with EPE+ versus EPE-, and were 18.7 versus 25.4 months (p = 0.021) and 10.7 versus 14.6 months (p = 0.020) in those with sSVZCC+ versus sSVZCC-. The EPD rates for tumors with EPE-/sSVZCC-, EPE-/sSVZCC+, EPE+/sSVZCC-, and EPE+/sSVZCC+ were 2.8%, 7.1%, 37.0%, and 71.9%, respectively. In EPE+/sSVZCC+, tumor migration was associated with the PE extending along the corpus callosum (77.8%) and subventricular zone (50.0%). CONCLUSIONS: Our results support the need for developing individualized irradiation strategies for glioblastomas according to EPE and sSVZCC.

Activation of mTORC1 Signaling is Required for Timely Hair Follicle Regeneration from Radiation Injury.

Transit amplifying cells (TACs) are highly proliferative in nature and tend to be sensitive to ionizing radiation. Due to the abundance of TACs that support the elongation of hair shafts, growing hair follicles are highly sensitive to radiation injury. How hair follicles repair themselves after radiation injury is unclear. In this study, we observed that in 4 Gy irradiated mice, hair follicle dystrophy was induced with apoptosis-driven loss of hair matrix cells, which are the TACs that fuel hair growth. The dystrophy was repaired within 96 h without significant hair loss, indicating that a regenerative attempt successfully restored the TAC population to resume anagen growth. Soon after irradiation, mTORC1 signaling was activated in the TAC compartment and its activation was maintained until the regeneration process was completed. Inhibition of mTORC1 by rapamycin treatment increased radiation-induced cell apoptosis, reduced cell proliferation and delayed restoration of Wnt signaling in the hair matrix after radiation injury, leading to prolonged dystrophy and hair loss. These results demonstrate that mTORC1 signaling is activated after irradiation and is required for timely regeneration of the TAC pool of hair follicles, so that hair growth can resume after radiation injury.

Mobilizing Transit-Amplifying Cell-Derived Ectopic Progenitors Prevents Hair Loss from Chemotherapy or Radiation Therapy.

Genotoxicity-induced hair loss from chemotherapy and radiotherapy is often encountered in cancer treatment, and there is a lack of effective treatment. In growing hair follicles (HF), quiescent stem cells (SC) are maintained in the bulge region, and hair bulbs at the base contain rapidly dividing, yet genotoxicity-sensitive transit-amplifying cells (TAC) that maintain hair growth. How genotoxicity-induced HF injury is repaired remains unclear. We report here that HFs mobilize ectopic progenitors from distinct TAC compartments for regeneration in adaptation to the severity of dystrophy induced by ionizing radiation (IR). Specifically, after low-dose IR, keratin 5+ basal hair bulb progenitors, rather than bulge SCs, were quickly activated to replenish matrix cells and regenerated all concentric layers of HFs, demonstrating their plasticity. After high-dose IR, when both matrix and hair bulb cells were depleted, the surviving outer root sheath cells rapidly acquired an SC-like state and fueled HF regeneration. Their progeny then homed back to SC niche and supported new cycles of HF growth. We also revealed that IR induced HF dystrophy and hair loss and suppressed WNT signaling in a p53- and dose-dependent manner. Augmenting WNT signaling attenuated the suppressive effect of p53 and enhanced ectopic progenitor proliferation after genotoxic injury, thereby preventing both IR- and cyclophosphamide-induced alopecia. Hence, targeted activation of TAC-derived progenitor cells, rather than quiescent bulge SCs, for anagen HF repair can be a potential approach to prevent hair loss from chemotherapy and radiotherapy. Cancer Res; 77(22); 6083-96. ©2017 AACR.

Locoregional Recurrence Risk for Postmastectomy Breast Cancer Patients With T1-2 and One to Three Positive Lymph Nodes Receiving Modern Systemic Treatment Without Radiotherapy.

BACKGROUND: Administering postmastectomy radiotherapy (PMRT) to patients with T1-2 breast cancer and one to three positive axillary lymph nodes (ALNs) is controversial. The current study assessed the association of clinicopathologic features and molecular subclassification with locoregional recurrence (LRR) in patients who did not receive PMRT. METHODS: Between January 2004 and December 2008, 293 patients with T1-2 breast cancer and one to three positive ALNs not receiving PMRT were analyzed. Most of the patients received an anthracycline- or taxane-based regimen or both. The patients were divided according to the four molecular subtypes as follows: luminal A/B, luminal human epidermal growth factor receptor 2 (HER2), HER2, and triple-negative breast cancer. Overall survival (OS) and LRR were calculated using the Kaplan-Meier method, and the clinicopathologic prognostic factors were compared using log-rank tests and the Cox regression model. RESULTS: After a median follow-up period of 82.8 months, the 10-year LRR and OS were respectively 10 %, and 88.9 %. The patients with triple-negative breast cancer had a higher 5-year LRR rate (10.6 %) than those without this disease (4.2 %) (p = 0.05). Multivariate analysis showed that young age (≤40 years), tumor larger than 3 cm, and the presence of extensive intraductal components were significant risk factors for LRR. The 5-year LRR was 3.1 % for the patients without the aforementioned risk factors, 7.9 % for those with one risk factor, and 25 % for those with two or more risk factors (p < 0.001). CONCLUSIONS: Administering modern systemic therapy to early breast cancer patients not receiving PMRT reduced the LRR rate. Younger patients, those with a tumor larger than 3 cm, and those with extensive intraductal components might benefit from PMRT.

Adverse prognosis and distinct progression patterns after concurrent chemoradiotherapy for glioblastoma with synchronous subventricular zone and corpus callosum invasion.

BACKGROUND AND PURPOSE: The subventricular zone (SVZ) and the corpus callosum (CC) invasion status are separately associated with adverse prognosis for glioblastoma. We investigated the prognosis and progression patterns of glioblastoma with and without synchronous SVZ and CC (sSVZCC) invasion. MATERIAL AND METHODS: Glioblastoma patients completing concurrent chemoradiotherapy with temozolomide were retrospectively categorized by the preoperative sSVZCC invasion status. The associations between sSVZCC invasion and the survival and progression patterns were analyzed. RESULTS: In total, 108 patients, including 36 with sSVZCC invasion, were followed for a median period of 60.2 (range 34.2-86.3) months. The median overall survival (OS) of patients with and without sSVZCC were 18.6 and 26.4 months, respectively (p=0.005). Using multivariate analyses with the factors of age, performance, surgery extent, and tumor size, sSVZCC invasion remained significant for a poor OS (hazard ratio, 1.96; 95% confidence interval, 1.19-3.21). The rates of progression at tumor bed, preoperative edematous areas, bilateral hemispheres, and ventricles for tumors with and without sSVZCC invasion were 75% and 63.9% (p=0.282), 41.7% and 9.7% (p<0.001), 47.2% and 13.9% (p<0.001), and 38.9% and 13.9% (p=0.006), respectively. CONCLUSIONS: The sSVZCC invasion status determined the distinct prognosis and progression areas of glioblastoma, which suggests individualized radiotherapy and drug administration strategies.