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The skeletal system is the third most common site for cancer metastases, surpassed only by the lungs and liver. Many tumors, especially those of the breast, prostate, lungs, and kidneys, have a strong predilection to metastasize to bone, which causes pain, hypercalcemia, pathological skeletal fractures, compression of the spinal cord or other nervous structures, decreased mobility, and increased mortality. Metastatic cancer-induced bone pain (CIBP) is a type of chronic pain with unique and complex pathophysiology characterized by nociceptive and neuropathic components. Its treatment should be multimodal (pharmacological and non-pharmacological), including causal anticancer and symptomatic analgesic treatment to improve quality of life (QoL). The aim of this paper is to discuss the mechanisms involved in the occurrence and persistence of cancer-associated bone pain and to review the treatment methods recommended by experts in clinical practice. The final part of the paper reviews experimental therapeutic methods that are currently being studied and that may improve the efficacy of bone pain treatment in cancer patients in the future.

Background Metachronous cancer in patients with head and neck cancer (HNC) is common and is associated with a poor prognosis. We aimed to evaluate the incidence of metachronous cancer at different sites according to age at diagnosis of index HNC. Methods We collected data on 2011 patients with oral cancer, oropharynx cancer, hypopharyngeal cancer, and laryngeal cancer as index cancers using the Osaka International Cancer Institute Cancer Registry database between 2005 and 2016. Among these, we analyzed 1953 patients after excluding 5 patients who were not followed-up and 53 patients with simultaneous multiple index cancers. We evaluated the cumulative incidence of metachronous cancer in the esophagus, lung, and other sites according to age at diagnosis of the index HNC using the Kaplan–Meier method. Multivariate logistic regression analysis was performed to identify factors that influenced the incidence of metachronous cancers following HNC. Results The cumulative incidence of metachronous esophageal cancer in young patients (< 65 years) was significantly higher than that in old patients (≥ 65 years) (12.1% vs 8.5% at 5 years, and 16.5% vs 11.2% at 10 years; p  = 0.015). On the other hand, the cumulative incidence of the other cancers in young patients was significantly lower than that in old patients (7.8% vs 12.2% at 5 years, and 13.9% vs 15.3% at 10 years; p  = 0.017). The cumulative incidence of lung cancer was not significance according to age at diagnosis of the index HNC. In the multivariate analysis, histological type (squamous cell carcinoma) and lesion location (hypopharynx and larynx) were independently associated with metachronous cancers. Moreover, age at diagnosis of the index HNC (< 65 years), histological type (squamous cell carcinoma) and lesion location (hypopharynx) were significant predictors of metachronous esophageal cancer incidence and lesion location (hypopharynx) was a significant predictor of metachronous lung cancer incidence. Conclusion Risk stratification of metachronous cancers with age and other predictors may help to properly manage patients with HNC. Trial registration The present study is a non-intervention trial.

Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters—diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel–Lindau (VHL) disease—and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of “neuroendocrine tumor” (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published.

Metastatic dissemination occurs very early in the malignant progression of a cancer but the clinical manifestation of metastases often takes years. In recent decades, 5-year survival of patients with many solid cancers has increased due to earlier detection, local disease control and adjuvant therapies. As a consequence, we are confronted with an increase in late relapses as more antiproliferative cancer therapies prolong disease courses, raising questions about how cancer cells survive, evolve or stop growing and finally expand during periods of clinical latency. I argue here that the understanding of early metastasis formation, particularly of the currently invisible phase of metastatic colonization, will be essential for the next stage in adjuvant therapy development that reliably prevents metachronous metastasis.Metastatic dissemination can occur early during cancer progression, yet clinically overt metastases are often not detected for many years after surgical removal of the primary tumour. In this Perspective, Klein argues that understanding the ‘invisible’ phase of metastatic colonization is necessary to explain this phenomenon and develop better therapies to prevent metastasis.

Tumor-associated trypsin inhibitor (TATI) was originally isolated from the urine of a patient with ovarian cancer. It was later shown to be produced by many other tumors and several normal tissues. It had earlier been isolated from the pancreas and was hence called pancreatic secretory trypsin inhibitor (PSTI). It belongs to a family of protease inhibitors presently called serine peptidase inhibitor Kazal type (SPINK). In the SPINK family TATI/PSTI is SPINK1, which is the name used in this review. In addition to being a protease inhibitor, SPINK1 also acts as an acute-phase reactant and a growth factor. Furthermore, it has been shown to modulate apoptosis. Overexpression of SPINK1 predicts an unfavorable outcome in several cancers and determination of SPINK1 in serum can be used to identify patients at increased risk of aggressive disease. Thus serum SPINK1 can be used as a prognostic tumor marker. Because SPINK1 acts as a growth factor and an inhibitor of apoptosis in some cancers, it has also been suggested that it can be a therapeutic target in cancer. However, because SPINK1 is the major physiological inhibitor of trypsin, inhibition of SPINK1 may increase the risk of pancreatitis. Taking into account the many functions of SPINK1, assessing the role of SPINK1 in cancer has several potentially important clinical applications ranging from a biomarker to a potential new target for cancer therapy.

The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1–7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20–50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS. Mild autonomous cortisol secretion from benign adrenocortical adenomas (usually diagnosed incidentally) is associated with cardiometabolic risk and other comorbidities, but without the signs of overt Cushing syndrome. This Review outlines the mechanisms, complications and comorbidities, diagnosis and management of mild autonomous cortisol secretion. Key points Mild autonomous cortisol secretion (MACS) is diagnosed based on the 1 mg overnight dexamethasone test and is found in 20–50% of patients with adrenal adenomas lacking signs and symptoms of Cushing syndrome. Patients with adrenal adenomas show distinct changes in the steroid and global metabolome, which correlate with the degree of cortisol excess across MACS and Cushing syndrome. MACS is associated with an increased likelihood of having cardiovascular risk factors and an increased risk of mortality. Management of MACS must be individualized based on patient characteristics; the options range from adrenalectomy to long-term follow-up and conservative management of comorbidities. Post-operative adrenal insufficiency is seen in around 50% of patients with MACS who undergo unilateral adrenalectomy.

Bone is the most frequent site for metastasis for many cancers, notably for tumours originating in the breast and the prostate. Tumour cells can escape from the primary tumour site and colonize the bone microenvironment. Within the bone, these disseminated tumour cells, as well as those arising in the context of multiple myeloma, may assume a state of dormancy, remaining quiescent for years before resuming proliferation and causing overt metastasis, which causes bone destruction via activation of osteoclast-mediated osteolysis. This structural damage can lead to considerable morbidity, including pain, fractures and impaired quality of life. Although treatment of bone metastases and myeloma bone disease is rarely curative, disease control is often possible for many years through the use of systemic anticancer treatments on a background of multidisciplinary supportive care. This care should include bone-targeted agents to inhibit tumour-associated osteolysis and prevent skeletal morbidity as well as use of appropriate local treatments such as radiation therapy, orthopaedic surgery and specialist palliative care to minimize the impact of metastatic bone disease on physical functioning. In this Primer, we provide an overview of the clinical features, the pathophysiology and the specific treatment approaches to prevent and treat bone metastases from solid tumours as well as myeloma bone disease. The majority of individuals with cancer, notably those with breast or prostate cancer, will develop bone metastases. In this Primer, Coleman and colleagues discuss the epidemiology, pathophysiology and diagnosis of metastatic bone disease and highlight the specific treatment strategies to prevent disease progression and to manage skeletal morbidities.

Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy.

Background Patients with cancer of the lung or oesophagus, undergoing curative treatment, usually require a thoracotomy and a complex oncological resection. These surgeries carry a risk of major morbidity and mortality, and risk assessment, preoperative optimisation, and enhanced recovery after surgery (ERAS) pathways are modern approaches to optimise outcomes. Pre-operative fitness is an established predictor of postoperative outcome, accordingly, targeting pre-operative fitness through exercise prehabilitation has logical appeal. Exercise prehabilitation is challenging to implement however due to the short opportunity for intervention between diagnosis and surgery. Therefore, individually prescribed, intensive exercise training protocols which convey clinically meaningful improvements in cardiopulmonary fitness over a short period need to be investigated. This project will examine the influence of exercise prehabilitation on physiological outcomes and postoperative recovery and, through evaluation of health economics, the impact of the programme on hospital costs . Methods The PRE-HIIT Randomised Controlled Trial (RCT) will compare a 2-week high intensity interval training (HIIT) programme to standard preoperative care in a cohort of thoracic and oesophageal patients who are > 2-weeks pre-surgery. A total of 78 participants will be recruited (39 per study arm). The primary outcome is cardiorespiratory fitness. Secondary outcomes include, measures of pulmonary and physical and quality of life. Outcomes will be measured at baseline (T0), and post-intervention (T1). Post-operative morbidity will also be captured. The impact of PRE-HIIT on well-being will be examined qualitatively with focus groups/interviews post-intervention (T1). Participant’s experience of preparation for surgery on the PRE-HIIT trial will also be explored. The healthcare costs associated with the PRE-HITT programme, in particular acute hospital costs, will also be examined. Discussion The overall aim of this RCT is to examine the effect of tailored, individually prescribed high intensity interval training aerobic exercise on pre-operative fitness and postoperative recovery for patients undergoing complex surgical resections, and the impact on use of health services. Trial registration The study is registered with Clinical Trials.Gov ( NCT03978325 ). Registered on 7th June 2019.

Abstract Patients with advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have impaired nutritional and physical performance due to the cancer pathophysiology and its treatment. The NUTRIGETNE study sought to characterize the nutritional status of patients with advanced GEP-NENs in Spain. This is a cross-sectional study that included patients with advanced GEP-NENs receiving active oncological treatment. Patients had a complete physical examination, anthropometry, bioelectrical impedance, dynamometry, laboratory analysis, and a comprehensive nutritional risk assessment. Malnutrition was defined according to Global Leadership Initiative on Malnutrition (GLIM) criteria. The study included 399 patients out of the 400 planned (Pearson’s χ2; α 0.05). Median age was 62 years (22-83). Tumors most commonly originated in the small intestine (43.9%) and the pancreas (41.6%), 94.7% were metastatic, and 36.7%, 49.4%, and 12.5% were G1, G2, and G3, respectively. Malnutrition prevalence was 61.9% (25.8% moderate; 36.1% severe), mainly due to low muscle mass (50.9%), which was the most prevalent GLIM phenotypic criteria. Moreover, malnutrition showed a correlation with decreased hand grip strength (mean 23 vs 31.9 kg; P <.001) and phase angle (median 5o vs 5.6o; P <.001). The prevalence of sarcopenia was 15%. Malnutrition was more frequent in patients with diabetes (74.4% vs 56.7%; P <.001), NECs (82.1% vs 60.3%; P =.062), and in those treated with chemotherapy (71.2% vs 59.7%; P =.058), whereas it did not correlate with tumor origin (P =.507), histological grade (P =.781), or functionality (P =.465). Malnutrition was correlated to body mass index (BMI) (P =.015), although it was also diagnosed in a high proportion of patients with no weight loss (63%, 54.1%, and 65.1% of patients with normal BMI, overweight, and obesity, respectively). Cachexia was present in 109 (27.3%) patients. Malnutrition is very prevalent and commonly underdiagnosed in patients with GEP-NENs. It is associated with sarcopenia and a worse QoL, requiring a multifactorial nutritional assessment. Certain factors such as the presence of diabetes may require closer monitoring due to a higher risk of malnutrition.