Hypofractionated re-irradiation with bevacizumab for relapsed chemorefractory glioblastoma after prior high dose radiotherapy: a feasible option for patients with large-volume relapse.

PURPOSE: There remains no standard of care for patients with recurrent and chemorefractory glioblastoma. Re-irradiation (reRT) provides an additional management option. However, published series predominantly focus on small reRT volumes utilizing stereotactic hypofractionated regimens. Concerns regarding toxicity have limited utilisation of reRT for larger recurrences, however this may be mitigated with use of bevacizumab (BEV). METHODS AND MATERIALS: A prospective database of patients managed with the EORTC-NCIC (Stupp) protocol 60 Gy chemoradiotherapy protocol for glioblastoma between 2007 and 2021 was reviewed for those patients receiving reRT for chemorefractory relapse. Serial MRI and PET were used to establish true progression and exclude patients with pseudoprogression or radionecrosis from reRT. The primary endpoint was overall survival (OS) from date of reRT. Prognostic factors were also assessed. RESULTS: 447 patients managed for glioblastoma under the Stupp protocol were identified, of which 372 had relapsed and were thus eligible for reRT. 71 patients underwent reRT. Median relapse-free survival from diagnosis for the reRT and overall cohorts were similar at 11.6 months (95%CI:9.4-14.2) and 11.8 months (95%CI:9.4-14.2) respectively. 60/71 (85%) reRT patients had received BEV prior to reRT and continued concurrent BEV during reRT. Of the 11 patients not managed with BEV during reRT, 10 required subsequent salvage BEV. ReRT patients were younger (median 53 vs. 59 years, p < 0.001), had better performance status (86% vs. 69% ECOG 0-1, p = 0.002) and more commonly had MGMT promoter-methylated tumours (54% vs. 40%, p = 0.083) compared to non-reRT patients. Median reRT PTV volume was 135cm3 (IQR: 69-207cm3). Median OS from reRT to death was 7.1 months (95%CI:6.3-7.9). Patients aged < 50, 50-70 and > 70 years had post-reRT median OS of 7.7, 6.4 and 6.0 months respectively (p = 0.021). Median post-reRT survival was longer for patients with ECOG performance status 0-1 compared to 2-3 (8.1 vs. 6.3 months, p = 0.039). PTV volume, site of relapse, MGMT promoter-methylation status and extent of initial surgical resection were not associated with post-reRT survival. ReRT was well-tolerated. Out of the 6 patients (8%) admitted to hospital after reRT, only one was for reRT toxicity. This was a CTCAE grade 3 radiation necrosis event in a patient managed without prior BEV. CONCLUSION: Patients with recurrent glioblastoma who have been previously treated with 60 Gy radiotherapy have a meaningful survival benefit from large volume re-irradiation which is well tolerated. ReRT should not be ignored as a salvage treatment option in patients with chemorefractory progressive disease.

CDKN2A/B Homozygous Deletions in Astrocytomas: A Literature Review.

Genomic alterations of CDKN2A and CDKN2B in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of CDKN2A and/or CDKN2B (CDKN2A/B) homozygous deletions (HD) on the prognosis of isocitrate dehydrogenase (IDH)-mutant astrocytomas. This is highlighted by the adoption of CDKN2A/B HD as an essential criterion for astrocytoma and IDH-mutant central nervous system (CNS) WHO grade 4 in the fifth edition of the World Health Organisation (WHO) Classification of Central Nervous System Tumours (2021). The CDKN2A and CDKN2B genes are located on the short arm of chromosome 9. CDKN2A encodes for two proteins, p14 and p16, and CDKN2B encodes for p15. These proteins regulate cell growth and angiogenesis. Interpreting the impact of CDKN2A/B alterations on astrocytoma prognosis is complicated by recent changes in tumour classification and a lack of uniform standards for testing CDKN2A/B. While the prognostic impact of CDKN2A/B HD is established, the role of different CDKN2A/B alterations-heterozygous deletions (HeD), point mutations, and promoter methylation-is less clear. Consequently, how these alternations should be incorporated into patient management remains controversial. To this end, we reviewed the literature on different CDKN2A/B alterations in IDH-mutant astrocytomas and their impact on diagnosis and management. We also provided a historical review of the changing impact of CDKN2A/B alterations as glioma classification has evolved over time. Through this historical context, we demonstrate that CDKN2A/B HD is an important negative prognostic marker in IDH-mutant astrocytomas; however, the historical data is challenging to interpret given changes in tumour classification over time, variation in the quality of evidence, and variations in the techniques used to identify CDKN2A/B deletions. Therefore, future prospective studies using uniform classification and detection techniques are required to improve the clinical interpretation of this molecular marker.

Leptomeningeal neuraxis relapse in glioblastoma is an uncommon but not rare event associated with poor outcome.

BACKGROUND: Spinal neuraxis leptomeningeal metastasis (LM) relapse in glioblastoma is an uncommon event that is challenging to manage. This study aims to determine the incidence, associated factors, and outcome of LM relapse in patients with glioblastoma managed with radical intent. METHODS: Patients managed for glioblastoma using the EORTC-NCIC (Stupp) Protocol from 2007 to 2019 were entered into a prospective ethics-approved database. Follow-up included routine cranial MRI surveillance with further imaging as clinically indicated. LM relapse was determined by MRI findings and/or cerebrospinal fluid analysis. The chi-square test of independence was used to evaluate clinico-pathologic factors associated with increased risk of subsequent LM relapse. Median survival post-LM relapse was calculated using Kaplan-Meier technique. RESULTS: Four-hundred-and-seven patients were eligible, with median follow-up of 60 months for surviving patients. Eleven (2.7%) had LM at first relapse and in total 21 (5.1%) experienced LM in the entire follow-up period. Sites of LM relapse were 8 (38%) focal spinal, 2 (10%) focal brainstem medulla and 11 (52%) diffuse spinal. Median overall survival from initial diagnosis for the entire cohort was 17.6 months (95% CI 16.7-19.0). Median survival from LM relapse to death was 39 days (95% CI: 19-107). Factors associated with LM relapse were age less than 50 years (p < 0.01), initial disease located in the temporal lobe (p < 0.01) and tumours lacking MGMT promoter methylation (p < 0.01). CONCLUSIONS: LM relapse is an uncommon but not rare event in patients managed radically for glioblastoma. It is associated with poor outcome with the majority of patients deceased within two months of recognition.

Efficacy and volume stability of a customized allogeneic bone block for the reconstruction of advanced alveolar ridge deficiencies at the anterior maxillary region: a retrospective radiographic evaluation.

OBJECTIVES: The aim of this retrospective case series was to evaluate the efficacy and volume stability of a customized allogeneic bone block (CABB) for the hard tissue reconstruction of severely atrophied anterior maxillary ridges. MATERIALS AND METHODS: Hard tissue alterations between baseline (T1), 2-month follow-up (T2), and 6-month follow-up (T3) cone-beam computed tomography scans were evaluated with semi-automatic segmentation. Following automatic spatial alignment of the datasets, 3D subtraction analysis was performed. The volume stability of the inserted allogeneic bone block was determined on the basis of the ratio of the T3 and T2 hard tissue volumes. RESULTS: The newly formed hard tissue volume at T2 averaged at of 0.75 cm3 ± 0.57 cm3, whereas at T3, an average of 0.52 cm3 ± 0.42 cm3 volumetric hard tissue gain could be detected. The T3/T2 ratio was found to be 67.83% ± 18.72% on average. The dice similarity coefficient between the T2 and T3 hard tissue models averaged at 0.73 ± 0.15. CONCLUSIONS: Cancellous CABBs are a reliable option for the reconstruction of severely atrophied alveolar ridges. The resorption rates of these grafts are similar to those found in the literature; however, with precise manufacturing and proper intraoperative flap management, the resorption rates may be reduced. CLINICAL RELEVANCE: With precise knowledge of the resorption patterns, the shape of blocks can be altered in the future to compensate for the volumetric loss.

Implications of Concurrent IDH1 and IDH2 Mutations on Survival in Glioma-A Case Report and Systematic Review.

Both IDH1 (isocitrate dehydrogenase 1) and IDH2 (isocitrate dehydrogenase 2) mutations play a vital role in the development of gliomas through disruption of normal cellular metabolic processes. Here we describe a case of a patient with an IDH-mutant astrocytoma, in which both IDH1 and IDH2 mutations were detected within the same tumour. The patient remains disease-free, nine and a half years after her initial diagnosis. Interrogation of cancer genomic databases and a systematic review was undertaken, demonstrating the rarity of the co-occurrence of IDH1 and IDH2 mutations in a variety of cancer types, and in glioma specifically. Due to the favourable outcome observed in this patient, the potential effect of concurrent IDH1 and IDH2 mutations on survival was also investigated.

Large tumour volume reduction of IDH-mutated anaplastic glioma involving the insular region following radiotherapy.

BACKGROUND: The impact of near-total resection of IDH-mutated anaplastic glioma (IDHmutAG) is well-established but there remains uncertainty of benefit in tumours of the insular cortex where the extent of safe resection may be limited. This study aimed to assess tumour volume reduction in patients following IMRT and impact of residual post-surgical volume. METHODS AND MATERIALS: Patients with IDHmutAG involving insular cortex managed with IMRT from 2008 to 2019 had baseline patient, tumour and treatment factors recorded. Volumetric assessment of residual disease on MRI was performed at baseline, month+ 3 and month+ 12 post-IMRT. Potential prognostic factors were analysed for tumour reduction and relapse-free survival, and assessed by log-rank and Cox regression analyses. RESULTS: Thirty two patients with IDHmutAG of the insular cortex were managed with median follow-up post-IMRT of 67.2 months. Pathology was anaplastic astrocytoma (AAmut) in 20, and anaplastic oligodendroglioma (AOD) in 12 patients. Median pre-IMRT volume on T1 and T2Flair was 24.3cm3 and 52.2cm3. Twenty-seven patients were alive with 5-year relapse-free survival of 80%. There was a median 67 and 64% reduction from baseline occurring at 3 months post-IMRT for T1 and T2Flair respectively; and subsequent median 78 and 73% at 12 months. At 12 months AOD patients had median 83% T1 volume reduction compared to 63% in AAmut (p < 0.01). There was no difference on T2Flair volume (p = 0.64). No other pathological factors influenced volume reduction at 12 months. No factors were associated with relapse-free survival including baseline T1 (p = 0.52) and T2Flair (p = 0.93) volume. CONCLUSION: IMRT provides large tumour volume reduction in IDHmutAG of the insular cortex. While maximal safe debulking remains standard of care when feasible, this patient cohort reported no significant negative impact of residual disease volume on relapse-free survival.

Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma.

BACKGROUND: Glioblastoma is associated with a poor prognosis in the elderly. Survival has been shown to increase among patients 70 years of age or younger when temozolomide chemotherapy is added to standard radiotherapy (60 Gy over a period of 6 weeks). In elderly patients, more convenient shorter courses of radiotherapy are commonly used, but the benefit of adding temozolomide to a shorter course of radiotherapy is unknown. METHODS: We conducted a trial involving patients 65 years of age or older with newly diagnosed glioblastoma. Patients were randomly assigned to receive either radiotherapy alone (40 Gy in 15 fractions) or radiotherapy with concomitant and adjuvant temozolomide. RESULTS: A total of 562 patients underwent randomization, 281 to each group. The median age was 73 years (range, 65 to 90). The median overall survival was longer with radiotherapy plus temozolomide than with radiotherapy alone (9.3 months vs. 7.6 months; hazard ratio for death, 0.67; 95% confidence interval [CI], 0.56 to 0.80; P<0.001), as was the median progression-free survival (5.3 months vs. 3.9 months; hazard ratio for disease progression or death, 0.50; 95% CI, 0.41 to 0.60; P<0.001). Among 165 patients with methylated O6-methylguanine-DNA methyltransferase (MGMT) status, the median overall survival was 13.5 months with radiotherapy plus temozolomide and 7.7 months with radiotherapy alone (hazard ratio for death, 0.53; 95% CI, 0.38 to 0.73; P<0.001). Among 189 patients with unmethylated MGMT status, the median overall survival was 10.0 months with radiotherapy plus temozolomide and 7.9 months with radiotherapy alone (hazard ratio for death, 0.75; 95% CI, 0.56 to 1.01; P=0.055; P=0.08 for interaction). Quality of life was similar in the two trial groups. CONCLUSIONS: In elderly patients with glioblastoma, the addition of temozolomide to short-course radiotherapy resulted in longer survival than short-course radiotherapy alone. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00482677 .).

Long-Term Efficacy of Variable-Thread Tapered Implants-A Retrospective, Clinical and Radiological Evaluation.

Background and Objective: There is multifaceted evidence that variable-thread tapered implants (VTTIs) offer high primary stability but few regarding the long-term success. This retrospective clinical and radiological cohort study assessed the long-term outcome of VTTIs. Material and Methods: All patients treated in an OMFS practice with NobelActive Internal® VTTI between October 2007 and September 2011 were invited for clinical examination. The outcome variables were (i) survival rate, (ii) implant success according to the "Health Scale for Dental Implants" and (iii) prevalence of peri-implantitis. Furthermore, the effect of local and systemic risk factors was investigated. Results: In 81 subjects (46 females and 35 males, mean age 65.6 years) 270 implants (157 VTTIs and 113 others as a control group) were analyzed. In 7 out of 81 patients (8.6%), 8 out of 157 VTTIs (5.1%) and 5 out of 113 other implants (4.4%) were lost. Peri-implantitis, defined as (i) presence of bleeding on gentle probing (0.25 N) or exudation and (ii) radiographic bone loss exceeding 0.5 mm since implant insertion to last follow-up, was the most common reason for implant loss (11 out of 13, 84.6%). Sixty-six out of 87 VTTIs (75.9%) were successful. Seventeen out of 42 patients (40.5%) developed peri-implantitis on 29 out of 79 VTTI sites (36.7%). Plaque and missing keratinized peri-implant mucosa were identified as potential risk factors for the development of peri-implantitis. Conclusion: Variable-thread tapered implants showed good long-term results, even in low bone quality. Peri-implantitis was the most common reason for implant failure and may be connected to certain risk factors.

Reflecting on survivorship outcomes to aid initial decision making in patients treated for IDH-mutated anaplastic glioma.

BACKGROUND: Patients with anaplastic glioma (AG) harboring an isocitrate dehydrogenase mutation have potential durable survival after intensity-modulated radiotherapy (IMRT) and chemotherapy. Understanding long-term functioning, and the factors that have an impact on later effects, is important for decision making. METHODS: Consecutive patients with AG who received IMRT were reviewed with regard to 6 survivorship domains, including Eastern Cooperative Oncology Group (ECOG) performance status, Medical Research Council (MRC) neurological status, late toxicity, comorbidity, functional status (employment/driving), and psychosocial events. Assessments were performed at baseline before RT; at month +6; and at years +1, +3, and +5 after RT. The primary endpoints were ECOG at year +3 and employment at year +3. RESULTS: A total of 146 patients were included, with a median follow-up of 5.1 years. The 6-year overall survival rate was 78.7% (95% CI, 71.1%-87.0%). Baseline ECOG performance status was 0 to 1 in 82.2% of patients but improved at year +1 (95.7%) and year +3 (97.2%). Employment rates at year +3 and year +5 were 70.1% and 76.5%, respectively, compared with 61.6% at baseline. Worse ECOG performance status at year +3 was related to the anaplastic astrocytoma subtype (P = .001), delayed RT (P = .081), multiple craniotomies performed before RT (P = .002), worse ECOG performance status before RT (P < .001), worse MRC neurological status before RT (P < .001), seizures (P = .038), neurocognitive disturbance (P < .001), and the presence of recurrent disease (P = .004). Absent or impaired employment at year +3 was found to be related to older age (P = .007), delayed timing of RT (P = .023), multiple craniotomies prior to RT (P = .005), worse ECOG performance status before RT (P < .001), worse MRC neurological status before RT (P < .001), and neurocognitive disturbance (P < .001). CONCLUSIONS: Patients with AG with an isocitrate dehydrogenase mutation have the potential for prolonged survival. Functional status appears to be good in patients who are free of disease progression at 3 to 5 years after IMRT, with >95% of patients having high ECOG performance status and >75% being employed.

Role of delayed salvage bevacizumab at symptomatic progression of chemorefractory glioblastoma.

BACKGROUND: Assess benefit of salvage bevacizumab (BEV) at time of symptomatic progression in patients with refractory glioblastoma (GBM). METHODS: Patients managed with adjuvant long course chemo-radiation therapy for GBM were entered into a prospective database. At chemorefractory symptomatic progression, patients were offered BEV or best supportive care. Re-irradiation (ReRT) was used with BEV in selected patients. BEV continued indefinitely until deterioration limited hospital based infusion. The primary endpoint was median survival calculated from date of decision for BEV to proceed (BEVstart), or decision to decline BEV (BEVreject). RESULTS: Fifty-five patients were managed of which 48 patients have relapsed disease. The median survival post relapse was 6 months (95%CI: 4.6-7.4). At relapse, 28 patients received BEV with only 14% delivered at first relapse. The median number of BEV cycles was 8 (range 1-25). ReRT was subsequently used in 16 (33%) relapsed patients. BEV treated patients were associated with improved median survival post relapse with 9 months vs 3 months (p < 0.01). The median survival from BEV related decision-making at symptomatic refractory progression to death was 4 months (95%CI: 2.0-6.0). BEVstart was associated with improved survival from this date with median survival of 6 months vs 1 month with BEVreject (p < 0.01). Median survival with ReRT from this date was 8 months vs 3 months without ReRT (p = 0.01). In the BEV patients at eventual progression, death occurred at a median of 30 days post BEV cessation. CONCLUSION: In this clinic managing selected patients with chemorefractory progressive glioblastoma, delayed salvage bevacizumab, often in combination with re-irradiation, may provide an increase in survival duration compared with best supportive care.

Reconstruction of a Unilateral Alveolar Cleft Using a Customized Allogenic Bone Block and Subsequent Dental Implant Placement in an Adult Patient.

Cleft lip and palate is the most common congenital deformity with severe effects on the quality of life of affected patients. The deformity often includes an alveolar cleft (AC). In most cases, osteoplasty will be performed using autogenous bone transplants harvested from the iliac crest. Thus, this treatment represents a highly invasive procedure. With freeze-dried bone allografts (FDBAs) becoming an increasingly accepted alternative to autogenous bone grafting for several indications, their application might also be suitable for AC reconstruction. We present the use of a customized allogenic bone block in a guided bone regeneration procedure for reconstruction of a unilateral AC and the successful insertion of dental implants after a healing period of 6 months. The use of FDBA seems to represent a successful treatment option for AC reconstruction. The allogenic bone block demonstrated high volume stability with ideal integration and revascularization, resulting in functional bone tissue suitable for implantation and esthetic rehabilitation. Nevertheless, further investigations, especially concerning the long-term stability of the augmented bone and dental implants, are needed to draw definite conclusion regarding the performance of allogenic bone blocks in orofacial cleft osteoplasty.

Bilateral maxillary augmentation using CAD/CAM manufactured allogenic bone blocks for restoration of congenitally missing teeth: A case report.

OBJECTIVE: Various biomaterials have been successfully applied in alveolar bone regeneration, however, the reconstruction of extensive osseous defects remains challenging and is often unfeasible with granular grafting materials. Several studies have outlined allogenic bone blocks as valid alternative to autologous block grafting. CLINICAL CONSIDERATIONS: In this report, we demonstrate the regeneration of two large osseous defects in the maxilla with allogenic bone blocks made from human donor bone. The bone blocks were customized using the CAD/CAM technology in order to enable the insertion of four dental implants. CONCLUSIONS: Both blocks perfectly matched the defect geometry, showed limited resorption, led to the formation of sufficient amounts of mineralized bone in both horizontal and vertical dimensions and enabled the installation of implants according to the treatment plan. The implementation of innovative technologies for individualization of allogenic bone blocks simplifies the restoration of complex and extensive osseous defects and poses great benefits for both practitioners and patients. CLINICAL SIGNIFICANCE: The here presented procedure demonstrates the successful regeneration of two extensive osseous defects in a patient suffering from hypodontia using two CAD/CAM manufactured allogenic bone blocks, rendering the procedure far less invasive as compared to guided bone regeneration carried out with autologous transplants. Furthermore, to the best of our knowledge, this is the first case report that radiographically demonstrates the new formation of a cortical bone layer following block grafting with solely cancellous bone blocks.

Radiation, inflammation and the immune response in cancer.

Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response-(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.

Convergent priorities and tensions: a qualitative study of the integration of complementary and alternative therapies with conventional cancer treatment.

PURPOSE: Demand for complementary and alternative medicine (CAM) is high among cancer patients. This, alongside growing evidence for the efficacy of some CAM therapies, is driving change within cancer centres, where evidence-based CAM therapies are increasingly provided alongside standard cancer treatments. In Australia, commitment to equitable access to healthcare is strong, and some cancer centres are now providing integrative services at no cost to the patient. This represents a significant shift in healthcare provision. This study aimed to examine health professional and patient dynamics in an integrated cancer service where CAM is provided at no cost to patients alongside standard cancer treatments. It specifically sought to understand what might drive or hinder further integration of CAM with standard treatment in the cancer context. METHODS: Qualitative interviews were undertaken with twenty key stakeholders-cancer patients, cancer nurses, and oncologists-who were delivering or receiving care in an Australian public hospital where acupuncture services are provided at no cost to patients alongside standard chemotherapy and radiation treatments. RESULTS: Findings point to key areas where the concerns and priorities of cancer patients, cancer nurses, and oncologists converge and diverge in ways that reflect core personal and professional interests regarding patient care needs, the evidence base for CAM efficacy and safety, and rising healthcare costs. CONCLUSIONS: Understanding points of convergence and divergence could assist clinicians and service providers in negotiating ways forward for integrative cancer services.

Treatment of a bilaterally severely resorbed posterior mandible due to early tooth loss by Guided Bone Regeneration using customized allogeneic bone blocks: A case report with 24 months follow-up data.

OBJECTIVE: The use of allogeneic bone grafts for alveolar ridge reconstruction has become an often-discussed alternative to augmentation procedures using autografts. Nevertheless, there still is a lack of literature concerning long-time experiences of allografts for alveolar ridge reconstruction. Especially the results of the use of allogeneic bone blocks for mandible reconstructions need to be further investigated. CLINICAL CONSIDERATIONS: In this case report, we present the use of customized allogenic bone blocks in Guided Bone Regeneration (GBR) procedures for severely deficient mandibulary bones, the implantation after a healing period of 5 month and the 24-month follow-up data. CONCLUSIONS: Customized allogeneic bone blocks seem to be a successful alternative to augmentations with autologous bone blocks reconstructing highly resorbed mandibulary alveolar ridges, showing highest volume stability and no signs of bone resorption after implant loading. CLINICAL SIGNIFICANCE: The application of customized allogeneic bone blocks has shown to be a successful augmentation technique even compared with with autologous bone blocks reconstructing highly resorbed mandibulary alveolar ridges demonstrating no compromises regarding clinical outcome, functionality and esthetics.

Health and well-being benefits of spending time in forests: systematic review.

BACKGROUND: Numerous studies have reported that spending time in nature is associated with the improvement of various health outcomes and well-being. This review evaluated the physical and psychological benefits of a specific type of exposure to nature, forest therapy. METHOD: A literature search was carried out using MEDLINE, PubMed, ScienceDirect, EMBASE, and ProQuest databases and manual searches from inception up to December 2016. Key words: "Forest" or "Shinrin -Yoku" or "Forest bath" AND "Health" or "Wellbeing". The methodological quality of each randomized controlled trials (RCTs) was assessed according to the Cochrane risk of bias (ROB) tool. RESULTS: Six RCTs met the inclusion criteria. Participants' ages ranged from 20 to 79 years. Sample size ranged from 18 to 99. Populations studied varied from young healthy university students to elderly people with chronic disease. Studies reported the positive impact of forest therapy on hypertension (n = 2), cardiac and pulmonary function (n = 1), immune function (n = 2), inflammation (n = 3), oxidative stress (n = 1), stress (n = 1), stress hormone (n = 1), anxiety (n = 1), depression (n = 2), and emotional response (n = 3). The quality of all studies included in this review had a high ROB. CONCLUSION: Forest therapy may play an important role in health promotion and disease prevention. However, the lack of high-quality studies limits the strength of results, rendering the evidence insufficient to establish clinical practice guidelines for its use. More robust RCTs are warranted.

Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.

BACKGROUND: Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy. METHODS: We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0-1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m2 daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer's [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819. FINDINGS: Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months' follow-up (mean between group difference [averaged over all timepoints] 0·06, 95% CI -4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up. INTERPRETATION: The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma. FUNDING: Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Systemic inflammation is an independent predictive marker of clinical outcomes in mucosal squamous cell carcinoma of the head and neck in oropharyngeal and non-oropharyngeal patients.

BACKGROUND: Currently there are very few biomarkers to identify head and neck squamous cell carcinoma (HNSCC) cancer patients at a greater risk of recurrence and shortened survival. This study aimed to investigate whether a marker of systemic inflammation, the neutrophil-to-lymphocyte ratio (NLR), was predictive of clinical outcomes in a heterogeneous cohort of HNSCC cancer patients. METHODS: We performed a retrospective analysis to identify associations between NLR and clinicopathological features to recurrence free survival (RFS) and overall survival (OS). Univariate analysis was used to identify associations and selected variables were included in multivariable Cox regression analysis to determine predictive value. RESULTS: A total of 145 patients with stage I-IV HNSCC that had undergone radiotherapy were analysed. Seventy-six of these patients had oropharyngeal cancer and 69 had non-oropharyngeal HNSCC and these populations were analysed separately. NLR was not associated to any clinicopathological variable. On univariate analysis, NLR showed associations with RFS and OS in both sub-populations. Multivariable analysis showed patients with NLR > 5 had shortened OS in both sub-populations but NLR > 5 only predicted RFS in oropharyngeal patients. Poor performance status predicted OS in both sub-populations and current smokers had shortened OS and RFS in non-oropharyngeal patients. CONCLUSIONS: The results show patients with NLR > 5 predict for shorter overall survival. Further prospective validation studies in larger cohorts are required to determine the clinical applicability of NLR for prognostication in HNSCC patients.

Small increases in enhancement on MRI may predict survival post radiotherapy in patients with glioblastoma.

To assess impact of volumetric changes in tumour volume post chemoradiotherapy in glioblastoma. Patients managed with chemoradiotherapy between 2008 and 2011 were included. Patients with incomplete MRI sets were excluded. Analyses were performed on post-operative MRI, and MRIs at 1 month (M+1), 3 months (M+3), 5 months (M+5), 7 months (M+7), and 12 months (M+12) post completion of RT. RANO definitions of response were used for all techniques. Modified RANO criteria and two volumetric analysis techniques were used. The two volumetric analysis techniques involved utility of the Eclipse treatment planning software to calculate the volume of delineated tissue: surgical cavity plus all surrounding enhancement (Volumetric) versus surrounding enhancement only (Rim). Retrospective analysis of 49 patients with median survival of 18.4 months. Using Volumetric analysis the difference in MS for patients who had a <5 % increase versus ≥5 % at M+3 was 23.1 versus 15.1 months (p = 0.006), and M+5 was 26.3 versus 15.1 months (p = 0.006). For patients who were classified as progressive disease using modified RANO criteria at M+1 and M+3 there was a difference in MS compared with those who were not (M+1: 13.1 vs. 19.4 months, p = 0.017, M+3: 13.2 vs. 20.1 months, p = 0.096). An increase in the volume of cavity and enhancement of ≥5 % at M+3 and M+5 post RT was associated with reduced survival, suggesting that increases in radiological abnormality of <25 % may predict survival.