Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma

Tumor Treating Fields (TTFields), an approved therapy for glioblastoma (GBM) and malignant mesothelioma, employ noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to disrupt the mitotic spindle, leading to chromosome missegregation and apoptosis. Emerging evidence suggests that TTFields may also induce inflammation. However, the mechanism underlying this property and whether it can be harnessed therapeutically are unclear. Here, we report that TTFields induced focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that intensely recruited and activated 2 major DNA sensors — cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) — and their cognate cGAS/stimulator of interferon genes (STING) and AIM2/caspase 1 inflammasomes to produce proinflammatory cytokines, type 1 interferons (T1IFNs), and T1IFN-responsive genes. In syngeneic murine GBM models, TTFields-treated GBM cells induced antitumor memory immunity and a cure rate of 42% to 66% in a STING- and AIM2-dependent manner. Using single-cell and bulk RNA sequencing of peripheral blood mononuclear cells, we detected robust post-TTFields activation of adaptive immunity in patients with GBM via a T1IFN-based trajectory and identified a gene panel signature of TTFields effects on T cell activation and clonal expansion. Collectively, these studies defined a therapeutic strategy using TTFields as cancer immunotherapy in GBM and potentially other solid tumors.     

Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.     

Impact of treatment modality on quality of life of head and neck cancer patients: Findings from an academic medical institution

Purpose

The objective of this pilot study was to determine how different treatment modalities (surgery, radiation, and chemotherapy) impact quality of life (QOL) in a population of head and neck cancer (HNC) survivors.

Long term results from a prospective database on high dose rate (HDR) interstitial brachytherapy for primary cervical carcinoma

Objective

Present long-term outcomes in primary cervical cancer treated with external beam and high dose rate interstitial brachytherapy.

A PLEA FOR INCIDENTAL APPENDECTOMY IN PEDIATRIC PATIENTS WITH MALIGNANCY

The evaluation of right lower quadrant (RLQ) abdominal pain in pediatric patients with malignancy can be difficult. However, since the mortality rate from peritoneal infections in these patients is very high, the differential diagnosis of RLQ peritoneal irritation, mainly of acute appendicitis (AA) versus neutropenic enterocolitis (NE), is crucial. Three cases of pediatric patients with malignancy demonstrating these difficulties are represented to enlighten this problem. The first patient died of multiorgan failure after operation for perforated appendicitis without generalized peritonitis. The second had a severe life-threatening postoperative complication because of delayed diagnosis of acute appendicitis. The third patient with malignant pelvic spread, underwent an unnecessary abdominal exploration for suspected AA. In all these cases and probably in many others, the clinical outcome could have been different if a previous incidental appendectomy had been performed during the primary abdominal operation. Incidental appendectomy in oncologic patients is recommended to facilitate the differential diagnosis of RLQ pain and to exclude the diagnosis of AA.     

Complementary and alternative therapies and health literacy in cancer patients

The aim was to determine health literacy and the use of complementary and alternative therapies (CATs) in patients with cancer and to investigate the relationship between CAT usage and health literacy. The study cohort consisted of 250 oncology patients. The Patient Interview Form and the Adult Literacy in Medicine Scale were used for collecting data. The use of at least one CAT was reported by 24% of the patients surveyed. Herbal therapies (32.6%) constituted the most popular method, and the most popular herbal therapy was Nigella sativa (54.6%). A total of 29.8% of the patients using CATs reported using herbal therapies for an enhanced immune system. Illiterate patients and those who live in rural areas/towns displayed low levels of health literacy. Healthcare professionals should investigate patients' use of complementary and alternative approaches, and health literacy should be improved so that patients can be informed regarding the possible benefits and disadvantages of CATs.     

Implementing patient question-prompt lists into routine cancer care

Objective

To examine the feasibility and acceptability of routine provision of patient question prompt lists (QPLs) to promote patient participation and patient-clinician communication in medical consultations.

Methods

Four cancer centres across NSW, Australia (two rural, two urban) were invited to participate, involving distribution of QPLs to patients seeing a medical or radiation oncologist, or palliative care clinician. Patients rated their satisfaction after their next consultation. Cancer specialists provided their views at the end of the study.

Results

Sixty-four percent (389/606) of patients attending consultations received a QPL. Of patients offered a QPL (426), 91% accepted. Of 139 patients surveyed post-consultation, 89% reported reading the QPL and, of these, 44% referred to the QPL during the consultation at least once. All of 10 cancer specialists providing their views post-implementation reported that QPL implementation in routine practice was feasible and did not strain resources.

Conclusions

Cancer patients and cancer specialists showed support for routine dissemination of the QPL.

Practice implications

For successful implementation of evidence-based tools we recommend promotion by local clinical champions, negotiation with clinic staff about dissemination methods, raised patient awareness through on-site project facilitators, media, consumer and support groups, and availability of resources in hard copy and via online sources.     

Women's experiences of Group Cognitive Behaviour Therapy for hot flushes and night sweats following breast cancer treatment: an interpretative phenomenological analysis

Objectives

Many women with breast cancer experience problematic treatment-related menopausal symptoms (HF/NS). This study explores how these women experienced a Group Cognitive Behaviour Therapy (CBT) intervention to help them manage their treatment-related HF/NS. The study was conducted as part of a randomised control trial/RCT (MENOS 1) evaluating the intervention among this target group.

Methods

In-depth semi-structured interviews were conducted with twenty trial participants to explore how they experienced the intervention and its effects. The interviews were analysed using interpretative phenomenological analysis.

Results

The analysis revealed four superordinate themes: Making sense of symptom change; new ways of coping and regaining control; tailoring the treatment to meet individual needs and resources; and valuing the group context, social support and social comparisons. All the women found Group CBT improved their ability to cope with their HF/NS, while also developing an appreciation of the role of psychological factors in their symptom experience. Through the knowledge and understanding acquired women developed a more accepting stance to their symptoms, as well as gaining a ‘sense of control’.

Conclusions

The results are consistent with the main RCT outcomes which showed that Group CBT led to a clinically significant reduction in ‘HF/NS problem rating’ relative to ‘treatment as usual’, as well as improvements in mood and physical and social functioning. The results complement the trial outcomes by illuminating women's experience of different components of the intervention and highlighting possible mechanisms of change.