Granulocyte-Macrophage Colony-Stimulating Factor in Combination With Chemoradiation for Recurrent or Metastatic Cervical Cancer.

Recurrent or metastatic cervical cancer carries a bleak prognosis and presents a formidable challenge in terms of treatment. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases the body's immune response by enhancing antigen presentation, which has been rarely reported in recurrent or metastatic cervical cancer. A 44-year-old woman presented to the hospital with vaginal bleeding four years after radical hysterectomy for stage IB2 squamous cell carcinoma (SCC) of the cervix (grade II-III). Gynecological examination and imaging revealed a vaginal mass, and the biopsy confirmed the recurrence of grade III SCC. The patient was treated with chemoradiation (CRT) combined with immunoadjuvant GM-CSF and achieved complete remission and a progression-free survival of two years.

Efficacy of lymph node dissection on stage IIICr of cervical cancer before CCRT: study protocol for a phase III, randomized controlled clinical trial (CQGOG0103).

BACKGROUND: Cervical cancer is still present a major public health problem, especially in developing countries. In International Federation of Gynaecology and Obstetrics 2018, allowing assessment of retroperitoneal lymph nodes by imaging and/or pathological findings and, if deemed metastatic, the case is designated as stage IIIC (with r and p notations). Patients with lymph node metastases have lower overall survival (OS), progression free survival (PFS), and survival after recurrence, especially those who have unresectable macroscopical positive lymph nodes. Retrospective analysis suggests that there may be a benefit to debulking macroscopic nodes that would be otherwise difficult to sterilize with standard doses of radiation therapy. However, there are no prospective study reporting that resecting macroscopic nodes before concurrent chemoradiation therapy (CCRT) would improve PFS or OS of cervical cancer and no guidelines for surgical resection of bulky lymph nodes. The CQGOG0103 study is a prospective, multicenter and randomized controlled trial (RCT) evaluating lymph node dissection on stage IIICr of cervical cancer. METHODS: Eligible patients are histologically confirmed cervical squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma. Stage IIICr (confirmed by computed tomography [CT]/magnetic resonance imaging/positron emission tomography/CT) and the short diameter of image-positive lymph node ≥15 mm. 452 patients will be equally randomized to receive either CCRT (pelvic external-beam radiotherapy [EBRT]/extended-field EBRT + cisplatin [40 mg/m²] or carboplatin [the area under curve=2] every week for 5 cycles + brachytherapy) or open/minimally invasive pelvic and para-aortic lymph node dissection followed by CCRT. Randomization is stratified by status of para-aortic lymph node. The primary endpoint is PFS. Secondary endpoints are OS and surgical complications. A total of 452 patients will be enrolled from multiple hospitals in China within 4 years and followed up for 5 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04555226.

HPV and radiosensitivity of cervical cancer: a narrative review.

Background and Objective: Cervical cancer (CC), the most common gynecological malignancy, is divided into two categories: human papillomavirus-related [HPV positive (HPV+)] and non-HPV-related [HPV negative (HPV-)]. Compared with HPV- CC, HPV+ CC has better radiosensitivity and prognosis. We conducted a literature search and summarized relevant studies to explore the detailed mechanisms by which HPV+ improves the prognosis of CC compared to HPV-. Methods: PubMed was used to search the literature on human papillomavirus, cervical cancer, and radiotherapy up to June 2022. Key Content and Findings: Compared with HPV- CC, HPV+ CC has better radiotherapy outcomes and better prognosis. HPV improves the radiotherapy sensitivity of CC by inhibiting damaged DNA repair, increasing cell cycle arrest, reducing hypoxia, increasing cellular immune response, and other mechanisms. However, the effect of HPV on radiotherapy sensitivity of CC is not consistent and is affected by HPV type, viral load, and many other factors. Partial HPV+ CCs, due to hypoxia and other factors, are resistant to radiotherapy and have a poor prognosis. HPV- CC has poor radiotherapy sensitivity and poor prognosis. With the spread of the vaccine, HPV- CC will gradually increase, which is a cause for concern. Conclusions: The radiosensitivity was significantly increased in patients with HPV+ CC, compared to HPV- patients. HPV improves the radiotherapy sensitivity of cervical cancer through a number of pathways. Meanwhile, the relationship between HPV and radiotherapy sensitivity is influenced by a number of factors. Some HPV+ CCs showed radiotherapy resistance, and HPV- CCs deserve further attention.

A clinical study of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in preventing neutropenia during concurrent chemoradiotherapy of cervical cancer.

PURPOSE: To evaluate the effectiveness and safety of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in preventing neutropenia during chemoradiotherapy in patients with cervical cancer. METHODS: From August 2018 to April 2020, 60 patients who were pathologically confirmed as cervical cancer were randomly divided into two groups at a ratio of 2:1: PEG-modified-rhG-CSF experimental group and control group. The primary endpoints were the incidence of grade 3-4 neutropenia. Secondary endpoints included the duration of grade 3-4 neutropenia, the incidence of grade 4 neutropenia, the incidence of febrile neutropenia (FN), delay rate of chemotherapy, prolonged time of chemotherapy, time to complete radiotherapy and safety. RESULTS: The incidence of grade 3-4 neutropenia in the experimental group was significantly lower than the control group (10% vs. 77.78%, P < 0.001). However, there was no statistical significance between the two groups in the duration of grade 3-4 neutropenia (3.75 days vs. 5.07 days, P = 0.871). The experimental group was better than the control group in the incidence of grade 4 neutropenia, the incidence of FN and delay rate of chemotherapy, and the difference was statistically significant (P < 0.05). Besides, the prolonged time of chemotherapy and the time to complete radiotherapy in the experimental group were less than those in the control group, but the difference was not statistically significant (P > 0.05). The incidence of adverse events in the experimental group and control group were 55.00 and 94.44%, respectively, and the difference was statistically significant (P = 0.003). CONCLUSION: PEG-rhG-CSF preventive treatment used in the course of chemoradiotherapy for patients with cervical cancer can reduce the incidence of neutropenia and improve the incidence of delayed chemotherapy cycles. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04542356 . Registered 9 September 2020 - Retrospectively registered.

Volumetric Modulated Arc Therapy versus Fixed-Field Intensity-Modulated Radiotherapy in Radical Irradiation for Cervical Cancer without Lymphadenectasis: Dosimetric and Clinical Results.

BACKGROUND: The aim of this study was to compare the dosimetric parameters, clinical complications, and efficacy of volumetric modulated arc therapy (VMAT) and fixed-field intensity-modulated radiotherapy (f-IMRT) in radical radiotherapy for cervical cancer without lymphadenectasis. METHODS: 84 cervical cancer patients undergoing treatment with VMAT and f-IMRT were selected. Dose-volume histograms were used to evaluate the dose distribution in the planning target volume (PTV) and organs at risk. The clinical complications and efficacy were observed. RESULTS: The homogeneity index (HI) and the conformity index (CI) of VMAT plans were both superior to the HI and CI of f-IMRT plans (p = 0.043, 0.025). VMAT plans resulted in a reduction in the V30 of the rectum and V40 of the bladder (p = 0.002). Furthermore, the monitor units (MUs) for VMAT were less than a quarter of those for f-IMRT. The treatment time for VMAT was less than a half of that for f-IMRT. Both clinical complications and efficacy showed no significant differences. CONCLUSION: VMAT plans showed superior dose coverage of the PTV, better protection of the rectum and bladder in dosimetry, and significantly reduced MUs and treatment time compared with f-IMRT. Clinical results were similar for both plans.

The preference choices of Conopomorpha sinensis Bradley (Lepidoptera: Gracilariidae) for litchi based on its host surface characteristics and volatiles.

Conopomorpha sinensis Bradley is a host-specific pest of Litchi chinensis and Euphoria longan. Here, we demonstrated that C. sinensis has evolved special physical and chemical mechanisms for host plant location that enable it to survive and reproduce. Females favored laying their eggs on the convex surface of litchi fruit that had particular volatile characteristics. Experiments using a H-type olfactometer showed that female C. sinensis were attracted to litchi flowers, tender shoots, immature fruits, and mature fruits, with the highest attraction rate to mature fruits (74.67 ± 2.31%). There were no significant differences in the attraction of male C. sinensis to different litchi tissues. Further oviposition preference tests using the pericarp, pulp, and seeds of mature litchi fruits revealed that female C. sinensis prefer to lay their eggs on the pericarp. Litchi volatiles were found to be important in attracting C. sinensis to fruits for oviposition. Analysis of volatiles from different litchi tissues by HS-SPME-GC-MS revealed 31 similar volatiles, some of which may be important in the oviposition preference choices of C. sinensis on litchi fruit.

Elevational pattern of bird species richness and its causes along a central Himalaya gradient, China.

This study examines the relative importance of six variables: area, the mid-domain effect, temperature, precipitation, productivity, and habitat heterogeneity on elevational patterns of species richness for breeding birds along a central Himalaya gradient in the Gyirong Valley, the longest of five canyons in the Mount Qomolangma National Nature Reserve. We conducted field surveys in each of twelve elevational bands of 300 m between 1,800 and 5,400 m asl four times throughout the entire wet season. A total of 169 breeding bird species were recorded and most of the species (74%) were small-ranged. The species richness patterns of overall, large-ranged and small-ranged birds were all hump-shaped, but with peaks at different elevations. Large-ranged species and small-ranged species contributed equally to the overall richness pattern. Based on the bivariate and multiple regression analyses, area and precipitation were not crucial factors in determining the species richness along this gradient. The mid-domain effect played an important role in shaping the richness pattern of large-ranged species. Temperature was negatively correlated with overall and large-ranged species but positively correlated with small-ranged species. Productivity was a strong explanatory factor among all the bird groups, and habitat heterogeneity played an important role in shaping the elevational richness patterns of overall and small-ranged species. Our results highlight the need to conserve primary forest and intact habitat in this area. Furthermore, we need to increase conservation efforts in this montane biodiversity hotspot in light of increasing anthropogenic activities and land use pressure.

Interfractional variation in bladder volume and its impact on cervical cancer radiotherapy: Clinical significance of portable bladder scanner.

PURPOSE: A constant bladder volume (BV) is essential to direct the radiotherapy (RT) of pelvic tumors with precision. The purpose of this study was to investigate changes in BV and their impact on cervical cancer RT and to assess the clinical significance of a portable bladder scanner (BS) in achieving a constant BV. METHODS: A standard bladder phantom (133 ml) and measurements of actual urine volume were both used as benchmarks to evaluate the accuracy of the BS. Comparisons of BS with computed tomography (CT), cone-beam CT (CBCT), and an ultrasound diagnostic device (iU22) were made. Twenty-two consecutive patients with cervical cancer treated with external beam radical RT were divided into an experimental group (13 patients) and a control group (9 patients). In the experimental group, the BV was measured multiple times by BS pre-RT until it was consistent with that found by planning CT. Then a CBCT was performed. The BV was measured again immediately post-RT, after which the patient's urine was collected and recorded. In the control group, CBCT only was performed pre-RT. Interfractional changes in BV and their impact on cervical cancer RT were investigated in both groups. The time of bladder filling was also recorded and analyzed. RESULTS: In measuring the volume of the standard bladder phantom, the BS deviated by 1.4% in accuracy. The difference between the measurements of the BS and the iU22 had no statistical significance (linear correlation coefficient 0.96, P < 0.05). The BV measured by the BS was strongly correlated with the actual urine volume (R = 0.95, P < 0.05), planning CT (R = 0.95, P < 0.05), or CBCT (R = 0.91, P < 0.05). Compared with the BV at the time of CT, its value changed by -36.1% [1 SD (standard deviation) 42.3%; range, -79.1%-29.4%] in the control group, and 5.2% (1 SD 21.5%; range, -13.3%-22.1%) in the experimental group during treatment. The change in BV affected the target position in the superior-inferior (SI) direction but had little or no effect in the anterior-posterior and right-left directions. Based on the collected data, the target displacement in the SI direction was reduced from 2.0 to 0.4 mm, while the CTV-to-PTV (CTV: clinical target volume; PTV: planning target volume) margin in the SI direction was reduced from 11.1 to 6.4 mm. The BV increased by 3.7 ± 1.0 ml/min (range, 1.7-4.7 ml/min), which depended on the amount of water ingested by the patient (R = 0.96, P < 0.05). No correlation was found between the rate of urinary inflow and the patient's body mass. The authors were able to reduce the workload of measuring by using individual patient information including the patient's age, the water-drinking amount, time at which water-drinking began, and patient's diet. CONCLUSIONS: Changes in the BV have an influence on the RT of cervical cancer. A consistent and reproducible BV is acquired by using a portable BS, whereby the target displacement and CTV-to-PTV margin can be both reduced in the SI direction.

Rho kinase inhibitor fasudil regulates microglia polarization and function.

Macrophages/microglia exhibit phenotypic and functional heterogeneity under physiological and pathological conditions. Owing to this heterogeneity, the polarization of macrophages/microglia is capable of effecting both detrimental and beneficial outcomes in various disease processes. In this study, murine microglial cell line BV-2 and primary microglia were used as cell models to elucidate the polarization of microglia. Using flow cytometry, Western blot, chemical/enzymatic determination, and immunohistochemistry, treatment with LPS primed microglia into the M1 phenotype in both BV-2 cells and primary microglia, while fasudil skewed LPS-stimulated M1 toward M2 microglia, which showed lower NF-κB activity and inflammatory cytokines IL-1ß, IL-6, and TNF-α, and increased anti-inflammatory cytokine IL-10. To examine whether the regulatory role of LPS and fasudil on microglia can occur in vivo, mice were administered LPS (25 µg/10 µl) via nasal instillation every other day for 1 month. The results demonstrated that LPS also triggered iNOS(+)/CD11b(+) M1 microglia in the brain, while fasudil increased Arg-1(+)/CD11b(+) M2 microglia, although the difference did not reach statistical significance. Fasudil-conditioned microglia medium promoted a neuroprotective effect against PC12 neurons, suggesting that fasudil-induced M2 microglia contribute to the survival of neurons. These results indicate a new treatment option whereby fasudil inhibits the inflammatory response by controlling a helpful polarization in microglia/macrophages.

Targeting the shift from M1 to M2 macrophages in experimental autoimmune encephalomyelitis mice treated with fasudil.

We observed the therapeutic effect of Fasudil and explored its mechanisms in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Fasudil, a selective Rho kinase (ROCK) inhibitor, was injected intraperitoneally at 40 mg/kg/d in early and late stages of EAE induction. Fasudil ameliorated the clinical severity of EAE at different stages, and decreased the expression of ROCK-II in spleen, accompanied by an improvement in demyelination and inhibition of inflammatory cells. Fasudil mainly inhibited CD4(+)IL-17(+) T cells in early treatment, but also elevated CD4(+)IL-10(+) regulatory T cells and IL-10 production in late treatment. The treatment of Fasudil shifted inflammatory M1 to anti-inflammatory M2 macrophages in both early and late treatment, being shown by inhibiting CD16/32, iNOS, IL-12, TLR4 and CD40 and increasing CD206, Arg-1, IL-10 and CD14 in spleen. By using Western blot and immunohistochemistry, iNOS and Arg-1, as two most specific markers for M1 and M2, was inhibited or induced in splenic macrophages and spinal cords of EAE mice treated with Fasudil. In vitro experiments also indicate that Fasudil shifts M1 to M2 phenotype, which does not require the participation or auxiliary of other cells. The polarization of M2 macrophages was associated with the decrease of inflammatory cytokine IL-1ß, TNF-α and MCP-1. These results demonstrate that Fasudil has therapeutic potential in EAE possibly through inducing the polarization of M2 macrophages and inhibiting inflammatory responses.

Fasudil ameliorates disease progression in experimental autoimmune encephalomyelitis, acting possibly through antiinflammatory effect.

AIM: The purpose of this investigation was to further explore the mechanism(s) underlying the amelioration in EAE caused by Fasudil, particularly focusing on anti-inflammatory effect. METHODS: We induced a chronic-progressive experimental autoimmune encephalomyelitis (EAE) in B6 mice immunized with myelin oligodendrocyte glycoprotein(35-55) and performed Fasudil intervention in early and late stages of the disease. RESULTS: The administration of Fasudil (40 mg/kg, i.p) had a therapeutic effect in delaying the onset and ameliorating the severity of EAE, accompanied by the improvement in myelination and the decrease in inflammatory cells in spinal cords. Fasudil inhibited TLR-4, p-NF-kB/p65, and inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and enhanced IL-10 production in spinal cords. The ratio of arginase/iNOS was enhanced mainly in the spinal cords of EAE mice treated with Fasudil, reflecting a shift toward the M2 (antiinflammation) macrophage/microglia phenotype. The administration of Fasudil also induced the upregulation of CB2 receptor in spinal cords, but did not significantly trigger CB1 receptor. Levels of neurotrophic factors NGF, BDNF, and GDNF in the CNS were not altered by Fasudil. CONCLUSION: Fasudil ameliorates disease progression in EAE, acting possibly through antiinflammatory pathway.

In vivo99mTc-HYNIC-annexin V imaging of early tumor apoptosis in mice after single dose irradiation.

BACKGROUND: Apoptosis is a major mode of hematological tumor death after radiation. Early detection of apoptosis may be beneficial for cancer adaptive treatment. 99mTc-HYNIC-annexinV has been reported as a promising agent for in vivo apoptosis imaging. The purpose of this study is to evaluate the feasibility of in vivo99mTc-HYNIC-annexinV imaging of radiation- induced apoptosis, and to investigate its correlation with radiosensitivity. METHODS: Ten days after inoculation of tumor cells in the right upper limbs, the mice were randomly divided into two groups. The imaging group (4 mice each level, 4 dose levels) was injected with 4-8 MBq 99mTc-HYNIC-annexinV 24 hours after irradiation and imaged 1 hr post-injection, and the mice were sacrificed immediately after imaging for biodistribution analysis of annexin V. The observation group (4 mice each level, 2 dose levels) was only observed for tumor regression post-radiation. The number of apoptotic cells in a tumor was estimated with TUNEL assay. RESULTS: The 99mTc-HYNIC-annexin V uptake in E14 lymphoma significantly increased as the radiation dose escalated from 0 to 8 Gy, and significantly correlated with the number of TUNEL-positive cells (r = 0.892, P < 0.001). The Annexin-V uptake and the number of TUNEL-positive cells in El4 lymphoma were significantly greater than those in S180 sarcoma. With 8 Gy, S180 sarcoma tumor showed scanty apoptosis and less shrinkage while El4 lymphoma showed remarkable apoptosis and complete remission. CONCLUSION: 99mTc-HYNIC-annexinV in vivo imaging is a feasible method to detect early radiation-induced apoptosis in different tumors, and might be predictive for radiation sensitivity.