Palliative Care for Patients with Gynecologic Cancer in Japan: A Japan Society of Gynecologic Palliative Medicine (JSGPM) Survey

Futagami, Masayuki,Yokoyama, Yoshihito,Sato, Tetsumi,Hirota, Kazuyoshi,Shimada, Muneaki,Miyagi, Etsuko,Suzuki, Nao,Fujimura, Masaki Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.10

Purpose: To evaluate palliative care for patients with gynecologic cancer in Japan. Materials and Method: A questionnaire asking facility characteristics, systems to coordinate palliative care, current status of end-of-life care, provision of symptom relief, palliative radiation therapy and chemotherapy, and cases of death from gynecological cancer, was mailed to facilities treating gynecologic cancer. Results: A total of 115 facilities (29.3% of the total) responded to the questionnaire. Of these, 33.0 (29.0%) had a palliative care ward. End-of-life care was managed by obstetricians and gynecologists in 72.0% of the facilities. The site where end-of-life care was provided was most often a ward in the department where the respondent worked. The waiting period for transfer to a hospice was 2 weeks or more in 52% of facilities. Before the start of primary treatment, pain control was managed by obstetrians and gynecologists in 98.0% of facilities. Palliative radiation therapy or chemotherapy was administered at 93.9% and 92.0% of facilities, respectively. Of the 115 facilities, 34.0 (29.6%) reported cases of death from gynecological cancer. There were 1,134 cases of death. The median time between the last cycle of chemotherapy and death was 85 days for all gynecological cancers. The proportion of patients receiving chemotherapy in the last 30 and 14 days of life were 17.4% and 7.1%, respectively. Conclusions: This large-scale survey showed characteristics of palliative care given to patients with gynecologic cancer in Japan. Assessment of death cases showed that the median time between the last cycle of chemotherapy and death was relatively short.

Inhibiting Vascular Endothelial Growth Factor in Injured Intervertebral Discs Attenuates Pain-Related Neuropeptide Expression in Dorsal Root Ganglia in Rats

Jun Sato,Kazuhide Inage,Masayuki Miyagi,Yoshihiro Sakuma,Kazuyo Yamauchi,Masao Koda,Takeo Furuya,Junichi Nakamura,Miyako Suzuki,Go Kubota,Yasuhiro Oikawa,Takeshi Sainoh,Kazuki Fujimoto,Yasuhiro Shiga 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.4

Study Design: An experimental animal study. Purpose: To evaluate effects of anti-vascular endothelial growth factor (VEGF) on the content and distribution of the calcitonin generelated peptide (CGRP) in the dorsal ganglia in a rat model. Overview of Literature: Increased expression of VEGF in degenerative disc disease increases the levels of inflammatory cytokines and nerve ingrowth into the damaged discs. In animal models, increased levels of VEGF can persist for up to 2 weeks after an injury. Methods: Through abdominal surgery, the dorsal root ganglia (DRG) innervating L5/L6 intervertebral disc were labeled (FluoroGold neurotracer) in 24, 8-week old Sprague Dawley rats. The rats were randomly allocated to three groups of eight rats each. The anti- VEGF group underwent L5/6 intervertebral disc puncture using a 26-gauge needle, intradiscal injection of 33.3 μg of the pegaptanib sodium, a VEGF165 aptamer. The control-puncture group underwent disc puncture and intradiscal injection of 10 μL saline solution, and the sham-surgery group underwent labeling but no disc puncture. Two rats in each group were sacrificed on postoperative days 1, 7, 14, and 28 after surgery. L1–L6 DRGs were harvested, sectioned, and immunostained to detect the content and distribution of CGRP. Results: Compared with the control, the percentage of CGRP-positive cells was lower in the anti-VEGF group (p <0.05; 40.6% and 58.1% on postoperative day 1, 44.3% and 55.4% on day 7, and 42.4% and 59.3% on day 14). The percentage was higher in the control group compared with that of the sham group (p <0.05; sham group, 34.1%, 40.7%, and 33.7% on postoperative days 1, 7, and 14, respectively). Conclusions: Decreasing CGRP-positive cells using anti-VEGF therapy provides fundamental evidence for a possible therapeutic role of anti-VEGF in patients with discogenic lower back pain.

Improvements in Intractable Lumbar and LowerExtremity Symptoms after Systemic Administration of Tocilizumab, an Anti-interleukin-6 Receptor Antibody

Sainoh Takeshi,Orita Sumihisa,Miyagi Masayuki,Suzuki-Narita Miyako,Sakuma Yoshihiro,Oikawa Yasuhiro,Kubota Go,Sato Jun,Shiga Yasuhiro,Fujimoto Kazuki,Eguchi Yawara,Koda Masao,Aoki Yasuchika,Akazawa Ts 대한척추외과학회 2022 Asian Spine Journal Vol.16 No.1

Study Design: Prospective cohort study (open-label, single-arm, and non-blinded).Purpose: This study aims to determine the effects of systemic administration of tocilizumab, an anti-interleukin-6 (IL-6) receptor antibody on refractory low back pain and leg symptoms.Overview of Literature: IL-6 overexpression is associated with neuropathic pain pathogenesis, which is potentially followed by chronic low back pain, including leg pain and numbness. This finding suggest that inhibition of IL-6 at the site of pain or in the transmission pathway could provide novel therapeutic targets for chronic low back pain.Methods: This prospective, single-arm study included 11 patients (eight men; mean age, 62.7 years) with ≥3-months’ chronic pain history due to lumbar disease. Subcutaneous TCZ injections were administered twice, at a 2-week interval. We evaluated low back pain, leg pain, and leg numbness using numeric rating scales and the Oswestry Disability Index (ODI; baseline and 6 months postinjection); serum IL-6 and tumor necrosis factor-α levels (baseline and 1 month postinjection); and clinical adverse events.Results: Intractable symptoms reduced after TCZ administration. Low back pain improved for 6 months. Improvements in leg pain and numbness peaked at 4 and 1 month, respectively. Improvements in ODI were significant at 1 month and peaked at 4 months. Serum IL-6 was increased at 1 month. IL-6 responders (i.e., patients with IL-6 increases >10 pg/mL) showed particularly significant improvements in leg pain at 2 weeks, 1 month, and 2 months compared with nonresponders. We observed no apparent adverse events.Conclusions: Systemic TCZ administration improved symptoms effectively for 6 months, with peak improvements at 1–4 months and no adverse events. Changing serum IL-6 levels correlated with leg pain improvements; further studies are warranted to elucidate the mechanistic connections between lumbar disorders and inflammatory cytokines.

Evaluation of Lumbar Intervertebral Disc Degeneration Using T1ρ and T2 Magnetic Resonance Imaging in a Rabbit Disc Injury Model

Tetsuhiro Ishikawa,Atsuya Watanabe,Hiroto Kamoda,Masayuki Miyagi,Gen Inoue,Kazuhisa Takahashi,Seiji Ohtori 대한척추외과학회 2018 Asian Spine Journal Vol.12 No.2

Study Design: An in vivo histologic and magnetic resonance imaging (MRI) study of lumbar intervertebral disc (IVD) degeneration was conducted. Purpose: To clarify the sensitivity and efficacy of T1ρ/T2 mapping for IVD degeneration, the correlation between T1ρ/T2 mapping and degenerative grades and histological findings in the lumbar IVD were investigated. Overview of Literature: The early signs of IVD degeneration are proteoglycan loss, dehydration, and collagen degradation. Recently, several quantitative MRI techniques have been developed; T2 mapping can be used to evaluate hydration and collagen fiber integrity within cartilaginous tissue, and T1ρ mapping can be used to evaluate hydration and proteoglycan content. Methods: Using New Zealand White rabbits, annular punctures of the IVD were made 10 times at L2/3, 5 times at L3/4, and one time at L4/5 using an 18-gauge needle (n=6) or a 21-gauge needle (n=6). At 4 and 8 weeks post-surgery, MRI was performed including T1ρ and T2 mapping. The degree of IVD degeneration was macroscopically assessed using the Thompson grading system. All specimens were cut for hematoxylin and eosin, safranin-O, and toluidine blue staining. Results: Disc degeneration became more severe as the number of punctures increased and when the larger needle was used. T1ρ and T2 values were significantly different between grade 1 and grade 3 IVDs, grade 1 and grade 4 IVDs, grade 2 and grade 3 IVDs, and grade 2 and grade 4 IVDs (p <0.05). There was a significant difference between grade 1 and grade 2 IVDs only in terms of T1ρ values (p <0.05). Conclusions: T1ρ and T2 quantitative MRI could detect these small differences. Our results suggest that T1ρ and T2 mapping are sensitive to degenerative changes of lumbar IVDs and that T1ρ mapping can be used as a clinical tool to identify early IVD degeneration.

Do Physical Symptoms Predict the Outcome of Surgical Fusion in Patients with Discogenic Low Back Pain?

Seiji Ohtori,Sumihisa Orita,Kazuyo Yamauchi,Yawara Eguchi,Yasuchika Aoki,Junichi Nakamura,Masayuki Miyagi,Miyako Suzuki,Gou Kubota,Kazuhide Inage,Takeshi Sainoh,Jun Sato,Yasuhiro Shiga,Koki Abe,Kazuki 대한척추외과학회 2016 Asian Spine Journal Vol.10 No.3

Study Design: Retrospective case series. Purpose: To determine whether symptoms predict surgical outcomes for patients with discogenic low back pain (DLBP). Overview of Literature: Specific diagnosis of DLBP remains difficult. Worsening of pain on flexion is a reported symptom of DLBP. This study sought to determine whether symptoms predict surgical outcomes for patients with DLBP. Methods: We investigated 127 patients with low back pain (LBP) and no dominant radicular pain. Magnetic resonance imaging was used to select patients with disc degeneration at only one level. If pain was provoked during discography, we performed fusion surgery (87 patients). Visual analogue scale score and responses to a questionnaire regarding symptoms including worsening of pain on flexion or extension were assessed. Symptom sites before surgery were categorized into LBP alone, or LBP plus referred inguinal or leg pain. We followed 77 patients (average 3.0 years) and compared symptoms before surgery with surgical outcome. Results: Sixty-three patients with a good outcome showed postsurgical pain relief (≥60% pain relief) and 14 patients with a poor outcome did not (<60% pain relief). In patients with good outcomes, worsening of LBP was evident in 65% of cases on flexion and in 35% on extension. However, these findings were not significantly different from those in patients with poor outcomes. The percentage of patients with LBP alone was significantly lower and the percentage of patients with LBP plus referred inguinal or leg pain was significantly higher in the group with good surgical outcome compared with patients in the group with poor surgical outcome (p <0.05). Conclusions: Worsening of pain on extension may be a symptom of DLBP. Surgical outcomes were superior in patients with both LBP and either referred inguinal or leg pain compared with those having LBP alone.

Perioperative Evaluation of Respiratory Muscle Strength after Scoliosis Correction in Patients with Duchenne Muscular Dystrophy

Wataru Saito1,Kosuke Mizuno,Gen Inoue,Takayuki Imura1,Toshiyuki Nakazawa,Masayuki Miyagi,Eiki Shirasawa,Kentaro Uchida,Masashi Takaso 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.5

Study Design: Retrospective cohort study. Purpose: To investigate the effect of spinal correction on respiratory muscle strength in patients with Duchenne muscular dystrophy (DMD). Overview of Literature: Several studies have reported that scoliosis correction in patients with DMD does not improve pulmonary function. In these studies, pulmonary function was evaluated using the traditional spirometric values of percent vital capacity (%VC) and percent forced vital capacity (%FVC). However, traditional spirometry may not be suitable for patients with DMD because the results can be influenced by patient fatigue or level of understanding. Therefore, we evaluated respiratory function focusing on respiratory muscle strength using maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and sniff nasal inspiratory pressure (SNIP), in addition to %VC and %FVC. Methods: We retrospectively reviewed 16 patients with DMD who underwent spinal correction surgery between 2006 and 2011 at Kitasato University Hospital. All patients were males, and the mean age was 13.5 years. Respiratory muscle strength was evaluated using MIP, MEP, and SNIP. Measurements were obtained preoperatively and at 1 and 6 months postoperatively, and %VC and %FVC were obtained preoperatively and within 6 months postoperatively. Results: The mean preoperative and postoperative %VC values were 54.0% and 51.7%, whereas the mean %FVC values were 53.9% and 53.2%, respectively. The mean MIP, MEP, and SNIP values obtained preoperatively and at 1 and 6 months postoperatively were as follows: MIP, 40.5, 42.7 and 47.2 cm H2O; MEP, 26.0, 28.0, and 29.0 cm H2O; and SNIP, 33.4, 33.0, and 33.0 cm H2O; respectively. The mean MIP and MEP values significantly improved postoperatively. There were no significant differences in SNIP, %VC, or %FVC preand postoperatively. Conclusions: By focusing on respiratory muscle strength, our results suggest that scoliosis correction in patients with DMD might have a favorable effect on respiratory function.

Change of Lumbar Ligamentum Flavum after Indirect Decompression Using Anterior Lumbar Interbody Fusion

Seiji Ohtori,Sumihisa Orita,Kazuyo Yamauchi,Yawara Eguchi,Yasuchika Aoki,Junichi Nakamura,Masayuki Miyagi,Miyako Suzuki,Gou Kubota,Kazuhide Inage,Takeshi Sainoh,Jun Sato,Kazuki Fujimoto,Yasuhiro Shiga 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.1

Study Design: Retrospective case series. Purpose: The purpose of this study was to examine changes in the ligamentum flavum thickness and remodeling of the spinal canal after anterior fusion during a 10-year follow-up. Overview of Literature: Extreme lateral interbody fusion provides minimally invasive treatment of the lumbar spine; this anterior fusion without direct posterior decompression, so-called indirect decompression, can achieve pain relief. Anterior fusion may restore disc height, stretch the flexure of the ligamentum flavum, and increase the spinal canal diameter. However, changes in the ligamentum flavum thickness and remodeling of the spinal canal after anterior fusion during a long follow-up have not yet been reported. Methods: We evaluated 10 patients with L4 spondylolisthesis who underwent stand-alone anterior interbody fusion using the iliac crest bone. Magnetic resonance imaging was performed 10 years after surgery. The cross-sectional area (CSA) of the dural sac and the ligamentum flavum at L1–2 to L5–S1 was calculated using a Picture Archiving and Communication System. Results: Spinal fusion with correction loss (average, 4.75 mm anterior slip) was achieved in all patients 10 years postsurgery. The average CSAs of the dural sac and the ligamentum flavum at L1–2 to L5–S1 were 150 mm2 and 78 mm2, respectively. The average CSA of the ligamentum flavum at L4–5 (30 mm2) (fusion level) was significantly less than that at L1–2 to L3–4 or L5–S1. Although patients had an average anterior slip of 4.75 mm, the average CSA of the dural sac at L4–5 was significantly larger than at the other levels. Conclusions: Spinal stability induced a lumbar ligamentum flavum change and a sustained remodeling of the spinal canal, which may explain the long-term pain relief after indirect decompression fusion surgery.

Neural Mechanisms of Discogenic Back Pain: How Does Nerve Growth Factor Play a Key Role?

Yasuchika Aoki,Seiji Ohtori,Koichi Nakagawa,Arata Nakajima,Gen Inoue,Masayuki Miyagi,Kazuhisa Takahashi 대한척추신경외과학회 2011 Neurospine Vol.8 No.2

It was reported that nerve fibers were present in the inner part of lumbar intervertebral discs from patients with discogenic pain. Because there are no nerve fibers in the inner part of annulus fibrosus in normal condition, this finding suggests nerve ingrowth into the disc may be a cause of discogenic pain. Disc degeneration is often asymptomatic, thus, to understand the differences between symptomatic and asymptomatic disc, it is necessary to understand the pathogenesis of discogenic pain. We recently revealed that over 90% of the nociceptive dorsal root ganglion (DRG) neurons innervating the disc are sensitive to nerve growth factor (NGF), which is related to inflammatory pain. This indicates that discogenic pain is closely related to inflammation and NGF may play a key role. The increase of inflammatory mediators in symptomatic discs has been reported; we therefore studied the effects of disc inflammation and found that it induces sensitization of disc-innervating neurons and nerve ingrowth into the disc. More recently, it was shown that annular rupture induces nerve ingrowth, an increase of inflammatory mediators in the disc, and upregulation of calcitonin gene-related peptide, a pain-related molecule in DRGs. These findings led us to believe that annular rupture triggers inflammation and nerve ingrowth, inflammatory mediators then further promote nerve ingrowth into the disc and sensitization of disc-innervating neurons, and discogenic pain finally becomes chronic. NGF, found in symptomatic discs, may act as a key factor in generating chronic discogenic pain by sensitizing disc-innervating neurons and stimulating nerve ingrowth into the disc.

Up-Regulation of Pain Behavior and Glial Activity in the Spinal Cord after Compression and Application of Nucleus Pulposus onto the Sciatic Nerve in Rats

Masaki Norimoto,Yoshihiro Sakuma,Miyako Suzuki,Sumihisa Orita,Kazuyo Yamauchi,Gen Inoue,Yasuchika Aoki,Tetsuhiro Ishikawa,Masayuki Miyagi,Hiroto Kamoda,Gou Kubota,Yasuhiro Oikawa,Kazuhide Inage,Takesh 대한척추외과학회 2014 Asian Spine Journal Vol.8 No.5

Study Design: Experimental animal study. Purpose: To evaluate pain-related behavior and changes in glial activity in the spinal dorsal horn after combined sciatic nerve compression and nucleus pulposus (NP) application in rats. Overview of Literature: Mechanical compression and inflammation caused by prostaglandins and cytokines at disc herniation sites induce pain. Structural changes and pain-associated cytokines in the dorsal root ganglia and spinal dorsal horn contribute to prolonged pain. Glial cells in the spinal dorsal horn may also function in pain transmission. Methods: The sciatic nerve was compressed with NP for 2 seconds using forceps in the NP+nerve compression group; the shamoperated group received neither compression nor NP; and the control group received no operation. Mechanical hyperalgesia was measured for 3 weeks using von Frey filaments. Glial activity in the spinal dorsal horn was examined 7 days and 14 days postsurgery using anti-glial fibrillary acidic protein and anti-Ionized calcium binding adaptor molecule-1 antibodies to detect astrocytes and microglia, respectively. Results: Mechanical hyperalgesia was detected throughout the 14-day observation in the NP+nerve compression group, but not in control or sham-operated groups (p <0.05). Both astrocytes and microglia were significantly increased in the spinal dorsal horn of the NP+nerve compression group compared to control and sham groups on days 7 and 14 (p <0.05). Conclusions: Nerve compression with NP application produces pain-related behavior, and up-regulates astrocytes and microglia in the spinal dorsal horn, suggesting that these glia may be related to pain transmission.

Transient Receptor Potential Vanilloid 1-Immunoreactive Innervation Increases in Fractured Rat Femur

Yuya Kawarai,Seiji Ohtori,Miyako Suzuki,Kensuke Yoshino,Gen Inoue,Sumihisa Orita,Kazuyo Yamauchi,Yasuchika Aoki,Tetsuhiro Ishikawa,Masayuki Miyagi,Hiroto Kamoda,Go Kubota,Yoshihiro Sakuma,Yasuhiro Oik 연세대학교의과대학 2014 Yonsei medical journal Vol.55 No.1

Purpose: Pain from vertebral or femoral neck fractures is a particularly important problem in clinical orthopaedics. Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, and there are recent reports on an association between bone pain and TRPV1. However, an increase in TRPV1 activity has not been reported following femoral fracture. Materials and Methods: We applied a neurotracer [Fluoro-gold (FG)] onto femur to detect dorsal root ganglia (DRGs) innervating the cortex of the femur in 30 Sprague Dawley rats. Seven days after application, a closed mid-diaphyseal fracture of the femur was performed. FG labeled TRPV1-immunoreactive (ir) DRGs innervating the femur were examined in nonfractured controls, and 3 days, 1 week, 2 weeks, and 4 weeks after fracture. We evaluated bone healing of the femur and compared the ratio of TRPV1-ir DRG neurons innervating the femur at the time points. Results: Four weeks after fracture,complete bone union was observed. There was no significant difference in the ratio of FG labeled DRG neurons to total DRG neurons at each time point. The percentages of TRPV1-ir neurons in DRGs innervating the femur at 3 days and 1 week after fracture were significantly higher than those in control, 2 weeks, and 4 weeks after fracture (p<0.05). Conclusion: Fracture induced an increase of TRPV1-ir neurons in DRGs innervating the fractured femur within 3 days, and decreased during bone healing over 4 weeks. These findings show that TRPV1 may play a role in sensory sensation of bone fracture pain.