Palliative Treatment of Leptomeningeal Carcinomatosis From Renal Cell Carcinoma With Local CyberKnife Radiotherapy and Systemic Pazopanib Therapy: A Case Report.

Leptomeningeal carcinomatosis (LMC) from renal cell carcinoma (RCC) is rare. There is no established treatment strategy for LMC, and the prognosis is extremely poor. We describe a case of LMC from RCC treated with local CyberKnife radiotherapy (CKR) and systemic therapy with pazopanib. The patient was a 63-year-old man with brain metastases from right RCC. Surgery and CKR were performed for the brain metastases, and the lesions were subsequently controlled. The patient developed isolated lesions in the pituitary stalk, right internal auditory canal, left ventricular choroid plexus (CP), left facial nerve, and medulla oblongata after the surgery and CKR for brain metastases. We diagnosed LMC and treated the patient with systemic therapy with pazopanib. We performed local therapy with CKR for lesions of the pituitary stalk, right internal auditory canal, left facial nerve, and medulla oblongata. The CP lesion was not treated with CKR because the lesion tended to shrink after systemic therapy with pazopanib. There were no symptoms due to LMC until the end of life and no adverse events due to CKR. Ten years and five months after the nephrectomy for RCC, one year and four months after the initial CKR for brain metastases, and nine months after the diagnosis of LMC, the patient died due to pleural effusion from lung metastases. Our case suggests that CKR combined with pazopanib may be effective as a palliative treatment for LMC from RCC.

Successful Treatment of Facial Merkel Cell Carcinoma Using CyberKnife Radiotherapy Alone: A Case Report.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin tumor. Herein, we present a case of MCC which was successfully treated with radiotherapy alone using CyberKnife® (CK) (Accuray Incorporated, Sunnyvale, California, United States). An 86-year-old female patient presented with multiple painless pink rash skin tumors on the left cheek. The patient was diagnosed with MCC based on a lesion biopsy (T2cN2M0, stage IIIB). The patient was referred for CK radiotherapy (CKR) at our institution because of her advanced age and inoperative lesions. The patient underwent CKR alone, with a planning target volume (PTV) of 14.9 ml, a prescribed dose of 30 Gy, a maximum dose of 46.2 Gy, and an isodose line (the minimum dose of 95% of the PTV) of 65% in 10 fractions for 13 days. The lesions had completely regressed on the last day of CKR. Left cervical lymph node metastasis (CLNM) appeared 10 months after CKR. The patient underwent a second CKR for CLNM, the PTV was 4.6 ml, and the prescribed dose was 27 Gy in three fractions for three days. The CLNM had completely regressed one month later after the second CKR. Primary lesions did not recur for 33 months after the initial CKR, and CLNM did not reappear for 23 months after the second CKR with good cosmetic results. No CKR-related adverse event occurred in our follow-up period. Our present case indicates that CKR is an effective treatment option for patients with MCC, particularly elderly patients who may not be suitable candidates for extensive surgical resection.

Highly Radiosensitive Diffuse Large B-cell Lymphoma of the Skull Treated With Low-Dose CyberKnife Radiotherapy: A Case Report.

Diffuse large B-cell lymphoma (DLBCL) of the skull is rare, and there are no reports of treatment using CyberKnife (CK). Here, we report the case of a patient with skull DLBCL treated with low-dose CK radiotherapy (CKR), resulting in effective local control. The patient was a 75-year-old man who was initially diagnosed with multiple skull metastases (frontal, occipital, right orbital bones) from renal pelvic cancer. We initially created a CKR treatment plan for the frontal bone lesion with a marginal dose of 35 Gy and a maximum of 64.8 Gy in five fractions every other day. Because the frontal bone lesion shrank rapidly from the start of the treatment, we completed CKR with a marginal dose of 21 Gy and a maximum of 38.9 Gy in three fractions over five days. At six weeks after CKR, the MRI showed complete resolution of not only the frontal bone lesion but also the occipital and orbital bone lesions that we did not directly target for irradiation. The maximum doses irradiated to the occipital and orbital bone lesions were 0.31 Gy and 0.34 Gy. Because of the marked shrinkage of the skull lesions, we suspected that the patient had a radiosensitive neoplastic disease. FDG-PET/CT revealed multiple lymph nodes and bone metastases. The patient underwent a scrotal biopsy, and the histologic diagnosis was DLBCL. The patient subsequently received chemotherapy for DLBCL. Ten months after CKR and six months after the start of chemotherapy for DLBCL, the patient died due to gastrointestinal bleeding. The skull lesions were well-controlled locally without adverse events due to CKR until the end of the life. Our present case suggests the importance of diagnosis and the effectiveness of low-dose CKR in the skull DLBCL.

Treating Low-Grade Myxofibrosarcoma With Stereotactic Body Radiation Therapy Using CyberKnife®.

Myxofibrosarcoma (MFS) is one of the most common soft tissue sarcomas. Low-grade MFS has a high local recurrence rate, similar to that of high-grade MFS. Hence, appropriate adjuvant therapy is required to control low-grade MFS. In this report, we present a case in which recurrent low-grade MFS was successfully treated with stereotactic body radiation therapy (SBRT) using CyberKnife® (CK) (Accuray Incorporated, Sunnyvale, CA). A 76-year-old man underwent SBRT using CK for recurrent low-grade MFS in the right posterior chest wall after undergoing resection and skin grafting four and three times, respectively. We planned CK treatment separately for each in two parts. For the lesion on the scapula side, the target volume was 109 cm3 and the total prescribed dose was 34.6 Gy, while the lesion on the spinal side had a target volume of 72 cm3 and a total prescribed dose of 36 Gy, both in five fractions. Each SBRT was performed on alternate days in a span of 14 days. The tumors gradually reduced in size with tolerable levels of toxicity. SBRT using CK could be a safe and effective adjuvant therapy for low-grade MFS.

Stereotactic Radiotherapy for Localized External Auditory Canal Carcinomas: Report of Four Cases.

External auditory canal carcinoma (EACC) is sometimes diagnosed at an early stage because it arises superficially in the ear canal and may cause ear obstruction symptoms early. In addition, in the early stage of EACCs, involvement of lymph nodes or distant metastases are reported less frequently. And so, stereotactic radiotherapy (SRT) concentrating high-dose radiation on the primary tumor may be an effective option. The aim of this study is to evaluate the preliminary results of upfront SRT for early-stage localized EACCs. Four cases (four females, 84 to 98 years old) with EACC of N0M0 (=no lymph node involvement and no distant metastasis) were treated. All four tumors (0.30 - 11.1 ml in volume) were diagnosed as squamous cell carcinoma histologically. A total dose of 24 - 33 Gy in 3 - 5 fractions (D95 [dose delivered to 95% of the target volume]=100% dose) was delivered by SRT using CyberKnife. All four cases were alive at the end of the follow-up period of 19 to 106 months. In three cases (tumor volume, 0.3 - 3.5 ml) the treated tumors had regressed or disappeared by the end of the follow-up period of 106, 28, and 19 months respectively. In the remaining one case, the treated tumor (11.1 ml) regrew and cervical lymph node metastasis occurred, and both were treated with SRT again 6 months and 20 months after the initial SRT respectively. The tumors were still stable at 39 months after the initial SRT. In conclusion, in three cases the small tumors had regressed or disappeared without lymph node involvement or distant metastasis. In the remaining case, additional SRT was performed for recurrent tumors, after which the patient's condition remained stable. SRT may be an effective option for early-stage EACCs.

Neuroendocrine Carcinoma of Uterine Cervix: Stereotactic Radiotherapy for Brain Metastasis and Stereotactic Body Radiotherapy for Renal and Pancreatic Metastases.

A case of cervical neuroendocrine carcinoma (NEC) of the uterine cervix (NECUC) was presented. After total hysterectomy with bilateral salpingo-oophorectomy and adjuvant chemotherapy, a left renal tumor and a pancreatic lesion developed and were both diagnosed on pathological examination as metastases from NEC. In addition, a brainstem metastasis causing neurologic signs developed. The brain lesion was treated by stereotactic radiotherapy (SRT) and the renal and pancreatic lesions by stereotactic body radiotherapy (SBRT). Despite control of the renal and pancreatic lesions, multiple small lung metastases developed later. Recurrence and newly developed brain metastases were treated by repeat stereotactic radiosurgery (SRS)/SRT successfully. Chemotherapy was continued and controlled the lung metastases until three and a half years after the initial operation of the uterus.

Stereotactic Radiosurgery and Stereotactic Radiotherapy for Malignant Skull Base Tumors.

The role of stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) for malignant skull base tumors was summarized and discussed. The treatment of skull base tumors remains challenging. Their total resection is often difficult. SRS/SRT is one useful treatment option for residual or recurrent tumors after surgical resection in cases of primary skull base tumors. If skull base metastasis and skull base invasion are relatively localized, they can be candidates for SRS/SRT. Low rates of cervical lymph node involvement in early-stage (N0M0, no lymph node involvement or distant metastasis) nasal and paranasal carcinomas (NpNCa) and external auditory canal carcinomas (EACCa) have been reported in the literature. Such cases might be good candidates for SRS/SRT as the initial therapy. We previously reported the results of SRS/SRT for various malignant extra-axial skull base tumors. In addition, treatment results of early-stage head and neck carcinomas were summarized. Those of our data and those of other reported series were reviewed here to clarify the usefulness of SRS/SRT for malignant extra-axial skull base tumors.

Role of high-dose salvage radiotherapy for oligometastases of the localised abdominal/pelvic lymph nodes: a retrospective study.

BACKGROUND: Abdominal/pelvic lymph node (LN) oligometastasis, a pattern of treatment failure, is observed occasionally, and radiotherapy may work as salvage therapy. The optimal prescription dose, however, is yet to be determined. This study assessed the efficacy of high-dose radiotherapy. METHODS: The medical records of 113 patients at 4 institutes were retrospectively analysed who had 1 to 5 abdominal/pelvic LN oligometastases and were treated with definitive radiotherapy between 2008 and 2018. The exclusion criteria included non-epithelial tumours, uncontrolled primary lesions, palliative intent, and re-irradiation. The prescription dose was evaluated by using the equivalent dose in 2 Gy fractions (EQD2). Patients receiving EQD2 ≥ 60 Gy were placed into the high-dose group, and the remaining others the low-dose group. Kaplan-Meier analyses were performed to evaluate overall survival (OS), local control (LC), and progression-free survival (PFS). Univariate log-rank and multivariate Cox proportional hazards model analyses were performed to explore predictive factors. Adverse events were compared between the high-dose and low-dose groups. RESULTS: The primary tumour sites included the colorectum (n = 28), uterine cervix (n = 27), endometrium (n = 15), and ovaries (n = 10). The rate of 2-year OS was 63.1%, that of LC 59.7%, and that of PFS 19.4%. On multivariate analyses, OS were significantly associated with solitary oligometastasis (hazard ratio [HR]: 0.48, p = 0.02), LC with high-dose radiotherapy (HR: 0.93, p < 0.001), and PFS with long disease-free interval (HR: 0.59, p = 0.01). Whereas high-dose radiotherapy did not significantly improve 2-year OS in the entire cohort (74.8% in the high-dose vs. 52.7% in the low-dose; p = 0.08), it did in the subgroup of solitary oligometastasis (88.8% in the high-dose vs. 56.3% in the low-dose; p = 0.009). As for Late grade ≥ 3 adverse event, ileus was observed in 7 patients (6%) and gastrointestinal bleeding in 4 (4%). No significant association between the irradiation dose and adverse event incidence was found. CONCLUSIONS: As salvage therapy, high-dose radiotherapy was recommendable for oligometastasis in the abdominal/pelvic LNs. For solitary oligometastasis, LC and OS were significantly better in the high-dose group.

[A Case of Intractable Pain Caused by Retroperitoneal Primary Unknown Cancer Recurrence That Was Improved by Palliative Cyberknife Therapy].

A 79-year-old man was diagnosed with retroperitoneal primary unknown cancer recurrence who underwent open fenestration and drainage(because radical cure resection is difficult). Two years after the fenestration, the patient developed severe hip pain and numbness of the right lower limb. Abdominal CT revealed a cystic tumor recurrence extending from the lower abdomen to the right perineum. We selected a palliative cyberknife therapy for pain control. Fractionated radiation using a cyberknife was administered for 5 days(25 Gy in 5 fractions). The hip pain was relieved, and a CT scan showed a reduction in size of the perineal tumor after the cyberknife treatment. The cyberknife therapy may be an effective and promising palliative treatment for patients with pelvic recurrence.

[A Case of Local Recurrence and Lung Metastasis from a Rectal Cancer Treated with Systemic Chemotherapy and Cyberknife].

A 73-year-old man underwent abdominoperineal resection for a rectal cancer. He developed a hip pain 3 years and 6 months after the surgery. A CT scan revealed a local recurrence in the perineum and multiple lung metastases in the bilateral lung. He received systemic chemotherapy consisting of XELOX with bevacizumab. Thereafter, the hip pain was slightly relieved. The hip pain worsened 1 year and 6 months after the recurrence. The border between the perineal tumor and skin was very narrow, and conventional radiation therapy could cause a perineal skin necrosis and subsequent poor wound healing. Therefore, we selected a Cyberknife treatment. The hip pain was relieved and a CT scan showed a reduction of the perineal tumor's size after the Cyberknife treatment. A Cyberknife treatment may be effective and promising as palliation for patients with local recurrence of rectal cancer.

[Gamma knife radiosurgery for temporal bone chondroblastoma: case report].

A case with chondroblastoma arising from the right temporal bone was reported. A 52-year-old woman demonstrated residual tumor growth after surgical excision. The patient presented continuous right temporalgia and right facial twitch while opening her mouth. The tumor was an expansile mass (tumor volume: 12.8 cm3) and showed homogeneous hypo-intensity on T1 and T2-weighted images, but little contrast enhancement. The patient underwent gamma knife radiosurgery (GKR: marginal dose: 12 Gy, maximum dose: 24 Gy). One month later, her symptoms improved completely. The size of the tumor was reduced to 6.4 cm3 twenty months after GKR. The patient has been free of recurrence and side effects for four years since GKR. GKR may be useful to control residual chondroblastoma of the skull after surgery.

[A case of brain metastasis from gastric cancer involving bilateral middle cerebellar peduncles].

A case with brain metastasis involving bilateral middle cerebellar peduncles (bMCP) was reported. A 71-year-old male with gastric cancer was treated for multiple brain metastasis by gamma knife radiosurgery (GKR) in September, 2004. Two months after the initial GKR, MRI showed asymmetrical enhanced lesions involving bMCP. A few months later, MRI revealed an expansional infiltration of bMCP lesions. The patient had presented with headache loss of appetite, cerebellar ataxia, diplopia and slight dysmetria. PET showed 2-deoxy-2- [18F] fluoro-D-glucose (FDG) uptake of the bMCP lesions. The lesions were diagnosed as brain metastasis of gastric cancer. The patient underwent his second GKR (marginal dose : 19Gy, maximum dose 38Gy) MRI revealed the disappearance of the tumors 3 months after the second GKR. One year later, the patient showed no evidence of recurrence. For the last time, our case was diagnosed as brain metastasis from gastric cancer without meningeal carcinomatosis. It was suggested that FDG-PET can provide additional information about the lesion of bMCP. GKR may be useful to treat the tumor in bMCP.

Alterations in hippocampal neurogenesis following traumatic brain injury in mice.

Clinical and experimental data show that traumatic brain injury (TBI)-induced cognitive changes are often manifest as deficits in hippocampal-dependent functions of spatial information processing. The underlying mechanisms for these effects have remained elusive, although recent studies have suggested that the changes in neuronal precursor cells in the dentate subgranular zone (SGZ) of the hippocampus might be involved. Here, we assessed the effects of unilateral controlled cortical impact on neurogenic cell populations in the SGZ in 2-month-old male C57BL6 mice by quantifying numbers of dying cells (TUNEL), proliferating cells (Ki-67) and immature neurons (Doublecortin, Dcx) up to 14 days after TBI. Dying cells were seen 6 h after injury, peaked at 24 h and returned to control levels at 14 days. Proliferating cells were decreased on the ipsilateral and contralateral sides at all the time points studied except 48 h after injury when a transient increase was seen. Simultaneously, immature neurons were reduced up to 84% relative to controls on the ipsilateral side. In the first week post-TBI, reduced numbers of Dcx-positive cells were also seen in the contralateral side; a return to control levels occurred at 14 days. To determine if these changes translated into longer-term effects, BrdU was administered 1 week post-injury and 3 weeks later the phenotypes of the newly born cells were assessed. TBI induced decreases in the numbers of BrdU-positive cells and new neurons (BrdU/NeuN) on the ipsilateral side without apparent changes on the contralateral side, whereas astrocytes (BrdU/GFAP) were increased on the ipsilateral side and activated microglia (BrdU/CD68) were increased on both ipsi- and contralateral sides. No differences were noted in oligodendrocytes (BrdU/NG2). Taken together, these data demonstrate that TBI alters both neurogenesis and gliogenesis. Such alterations may play a contributory role in TBI-induced cognitive impairment.

Surgical treatment of a lenticulostriate artery aneurysm. Case report.

A previously healthy 61-year-old man presented with basal ganglia hemorrhage caused by rupture of a small aneurysm arising from the distal lenticulostriate artery associated with moyamoya-like disease and manifesting as left hemiparesis and dysarthria. The patient underwent frontotemporal craniotomy. Neck clipping of the aneurysm was performed through the hematoma cavity. He was transferred for rehabilitation with left hemiparesis. Three-dimensional computed tomography angiography was very useful for preoperative planning and evaluation of the anatomical correlation between the aneurysm and the hemorrhage.

Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis.

During treatment of brain tumors, some head and neck tumors, and other diseases, like arteriovenous malformations, the normal brain is exposed to ionizing radiation. While high radiation doses can cause severe tissue destruction, lower doses can induce cognitive impairments without signs of overt tissue damage. The underlying pathogenesis of these impairments is not well understood but may involve the neural precursor cells in the dentate gyrus of the hippocampus. To assess the effects of radiation on cognitive function, 2-month-old mice received either sham treatment (controls) or localized X irradiation (10 Gy) to the hippocampus/cortex and were tested behaviorally 3 months later. Compared to controls, X-irradiated mice showed hippocampal-dependent spatial learning and memory impairments in the Barnes maze but not the Morris water maze. No nonspatial learning and memory impairments were detected. The cognitive impairments were associated with reductions in proliferating Ki-67-positive cells and Doublecortin-positive immature neurons in the subgranular zone (SGZ) of the dentate gyrus. This study shows significant cognitive impairments after a modest dose of radiation and demonstrates that the Barnes maze is particularly sensitive for the detection of radiation-induced cognitive deficits in young adult mice. The significant loss of proliferating SGZ cells and their progeny suggests a contributory role of reduced neurogenesis in the pathogenesis of radiation-induced cognitive impairments.

Extreme sensitivity of adult neurogenesis to low doses of X-irradiation.

Therapeutic irradiation of the brain is associated with a number of adverse effects, including cognitive impairment. Although the pathogenesis of radiation-induced cognitive injury is unknown, it may involve loss of neural precursor cells from the subgranular zone (SGZ) of the hippocampal dentate gyrus and alterations in new cell production (neurogenesis). Young adult male C57BL mice received whole brain irradiation, and 6-48 h later, hippocampal tissue was assessed using immunohistochemistry for detection of apoptosis and numbers of proliferating cells and immature neurons. Apoptosis peaked 12 h after irradiation, and its extent was dose dependent. Forty-eight h after irradiation, proliferating SGZ cells were reduced by 93-96%; immature neurons were decreased from 40 to 60% in a dose-dependent fashion. To determine whether acute cell sensitivity translated into long-term changes, we quantified neurogenesis 2 months after irradiation with 0, 2, 5, or 10 Gy. Multiple injections of BrdUrd were given to label proliferating cells, and 3 weeks later, confocal microscopy was used to determine the percentage of BrdUrd-labeled cells that showed mature cell phenotypes. The production of new neurons was significantly reduced by X-rays; that change was dose dependent. In contrast, there were no apparent effects on the production of new astrocytes or oligodendrocytes. Measures of activated microglia indicated that changes in neurogenesis were associated with a significant inflammatory response. Given the known effects of radiation on cognitive function and the relationship between hippocampal neurogenesis and associated memory formation, our data suggest that precursor cell radiation response and altered neurogenesis may play a contributory if not causative role in radiation-induced cognitive impairment.

Irradiation induces neural precursor-cell dysfunction.

In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.