Metastatic Malignant Disease Research Articles

Metastatic Malignant Pseudomyogenic Hemangioendothelioma: An Exceedingly Rare Entity That Challenges Conventional Paradigms.

Pseudomyogenic hemangioendothelioma (PMHE), a rare soft tissue tumor predominantly affecting young adults, often presents as multiple nodules in various tissue planes of a limb. Malignant transformation and metastatic disease are unusual and pose diagnostic and therapeutic challenges. A 17-year-old patient from Western India, with a history of recurrent excisions for a toe swelling presented to our center for evaluation and management. A below-knee amputation was performed, and histopathology revealed PMHE. Adjuvant therapy was deemed unnecessary given the borderline nature of the tumor. Shortly thereafter, he developed features of local recurrence and underwent above-knee amputation. An expert histopathological review confirmed the diagnosis and noted features of malignant transformation-progression to a higher grade with greater cytological atypia, confluent growth, and increased mitotic activity over time. Upon further distant progression in the lung, he was started on a palliative regimen of weekly paclitaxel, vinblastine, and propranolol but eventually succumbed to his illness. In contrast to conventional descriptions of low mitotic activity, minimal nuclear atypia, and absence of necrosis, our patient exhibited increased mitotic rates, nuclear atypia, and evolving necrosis in serial histopathological evaluations. The fulminant clinical progression within a short interval was also atypical. Our patient's clinical course underscores the need for meticulous histopathological and molecular characterization and vigilant clinical surveillance after resection in patients with PMHE. Providing the standard of care for malignant disease in the adjuvant setting is challenging owing to the rarity and the lack of treatment guidelines.

Endoscopic stenting for malignant gastric outlet obstruction: focusing on comparison of endoscopic stenting and surgical gastrojejunostomy.

Malignant gastric outlet obstruction (GOO) is a condition characterized by blockage or narrowing where the stomach empties its contents into the small intestine due to primary malignant tumors or metastatic diseases. This condition leads to various symptoms such as nausea, vomiting, abdominal pain, and weight loss. To manage malignant GOO, different treatment options have been employed, including surgical gastrojejunostomy (SGJ), gastroduodenal stenting (GDS) using self-expandable metallic stent (SEMS), and endoscopic ultrasound-guided gastrojejunostomy (EUS-GJ). This review focuses on comparing the clinical outcomes of endoscopic stenting (GDS and EUS-GJ) with SGJ for malignant GOO. Studies have shown that GDS with SEMS provides comparable clinical outcomes and safety for the palliation of obstructive symptoms. The choice between covered and uncovered SEMS remains controversial, as different studies have reported varying results. EUS-GJ, performed via endoscopic ultrasound guidance, has shown promising efficacy and safety in managing malignant GOO, but further studies are needed to establish it as the primary treatment option. Comparative analyses suggest that GDS has higher recurrence and reintervention rates compared to EUS-GJ and SGJ, with similar overall procedural complications. However, bleeding rates were lower with GDS than with SGJ. Randomized controlled trials are required to determine the optimal treatment approach for malignant GOO.

Cancer of unknown primary—state of the art

SummaryThe Cancer of Unknown Primary (CUP) syndrome does not represent a single clinical entity but comprises a diverse group of malignant tumors. CUP is defined as a histologically confirmed metastatic malignant disease for which the primary tumor cannot be identified after completing initial diagnostics. Although its incidence has decreased, managing CUP patients remains a significant clinical challenge, particularly for those in the poor prognosis group, where the overall survival is merely 3 months. In this context, accurate diagnostics and prompt treatment initiation are crucial. While platinum-based chemotherapy still plays a central role in CUP therapy, the future holds promise with the advent of next-generation targeted therapies and immunotherapies guided by the results of advanced sequencing tools. These advancements offer hope for improving the bleak outcomes faced by these patients.

The role of tapentadol in cancer pain pharmacotherapy in patients with metastatic malignant disease.

The aim of this study was to establish the effects of prolonged formulation of tapentadol in combination with palliative radiotherapy on bone metastatic changes in oncology patients with primary breast cancer and proven bone metastases. The research was conducted as a prospective study at the Clinic for Oncology, University Clinical Center Nis, Nis, Serbia, during a three-month interval of monitoring the patients. The first group comprised 30 patients with mentioned malignancy for which tapentadol was prescribed, and they underwent palliative radiotherapy for bone metastatic changes. The second group comprised 30 patients with the same disease treated only with pain relief radiotherapy to metastatic changes. All the patients were interviewed using the Pain Detect questionnaire. Significantly more patients from the first group had severe pain in comparison to patients from the control group (χ2=16.596; p<0.001) at the second measurement and also at the third measurement (χ2=15.357; p<0.001). At the third measurement, pain with a neuropathic component was significantly more present in patients from the control group (χ2=8.541; p=0.014). There was a significant pain reduction in both groups - Tapentadol group (χ2=59.513; p<0.001) and control group (χ2=60.000; p<0.001) - and also a significant reduction of neuropathic pain component: Tapentadol group (χ2=56.267; p<0.001) and control group (χ2=60,000; p<0.001). There was a statistically significant positive correlation between tapentadol dose and pain intensity according to the numerical pain scale at all three measurements. Tapentadol prolonged-release formulation is an effective pharmacotherapy solution, along with palliative radiotherapy, for pain relief in patients with skeletal metastatic breast cancer. Palliative radiotherapy in these patients does not provide adequate neuropathic pain component relief.

Diffuse Sarcoidosis Presenting as Metastatic Malignant Disease-Like Picture: A Case Report.

Sarcoidosis is a chronic inflammatory condition characterized by the formation of granulomas, which can impact various organs and tissues throughout the body. It frequently affects the lungs and mediastinal lymph nodes. The presence of multiple lytic lesions in the spine can be concerning, as it may indicate an undiagnosed or advanced metastatic malignancy. We present an unusual and interesting case of sarcoidosis in which the patient had multiple lytic lesions in the vertebrae, which resembled the presentation of metastatic malignant disease. A 46-year-old woman with no known medical history presented to our cancer center complaining of neck pain and bilateral shoulder pain. After conducting extensive investigations, an atypical manifestation of sarcoidosis was identified. The patient was administered corticosteroids, which effectively managed the disease and resulted in a substantial improvement in her symptoms. Before considering surgical intervention or radiotherapy for cases involving multiple lytic lesions in the spine with an unknown primary cause, it is essential to conduct a comprehensive diagnostic evaluation. This thorough work-up is necessary to establish a clear diagnosis. If the patient's neurological condition permits, a complete assessment can help prevent substantial morbidity. In certain cases, a patient's condition may involve an atypical manifestation of pathologies that are not related to metastatic diseases, suggesting that simpler treatment approaches might be adequate.

Cytoreductive radical prostatectomy versus no local treatment in patients with metastatic prostate cancer.

Prostate cancer is one of the most frequent cancers in Chile, with 8157 new cases in 2020. Worldwide, 5 to 10% of men have metastatic disease at diagnosis, and androgen deprivation therapy with or without chemotherapy is the standard of care for these patients. The use of local treatment in this setting has no formal recommendation due to the lack of high-quality evidence. Some retrospective studies have sought to elucidate the benefit of surgery on the primary tumor in the setting of metastatic disease since it has been proven to be an effective local treatment for other metastatic malignant diseases. Despite these efforts, the benefit of cytoreductive radical prostatectomy as local treatment in these patients remains unclear. We searched Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, and Cochrane, among others. We extracted data from systematic reviews, reanalyzed data from primary studies, conducted a meta-analysis, and generated a summary results table using the GRADE approach. We identified 12 systematic reviews, including seven studies in total, none of which was a trial. Only six of those seven primary studies were used in the results summary. Despite the lack of high-quality evidence, the results summary shows the benefits of performing surgery on the primary tumor in terms of all-cause mortality, cancer-specific mortality, and disease progression. There was also a potential benefit in local complications related to the progression of the primary tumor, supporting the implementation of this intervention in patients with metastatic disease. The absence of formal recommendations highlights the need to evaluate the benefits of surgery on a case-by-case basis, presenting the available evidence to patients for a shared decision-making process and considering future local complications that could be difficult to manage.

Mucinous Cystic Neoplasms of the Liver: Epidemiology, Diagnosis, and Management.

Mucinous cystic neoplasms (MCNs) are rare tumors of the liver, occasionally seen in the biliary tree. Epidemiologic data are limited by their indolence and recent changes to diagnostic criteria. They are considered premalignant lesions capable of invasive behavior. While their etiology remains unknown, their female predominance, age of onset, and hormonally responsive ovarian-type stroma suggest ectopic organogenesis during embryologic development. MCNs can typically be recognized on imaging; yet, invasiveness is often indeterminate, and percutaneous tissue biopsy has shown limited value. Therefore, complete excision is recommended for all lesions as focal malignant transformation and metastatic disease has been reported.

Zopiclone versus placebo for short-term treatment of insomnia in patients with advanced cancer—a double-blind, randomized placebo-controlled clinical multicenter phase IV trial

PurposeInsomnia is frequent in patients with advanced cancer, and a variety of pharmacological agents is used to treat this condition. Still, few clinical trials have investigated the effectiveness of pharmacological sleep therapies in this patient group. We aimed to study the short-term effectiveness of zopiclone on sleep quality in patients with advanced cancer who report insomnia.MethodsA randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase IV clinical trial in adult patients with metastatic malignant disease and insomnia. Patients were treated with zopiclone or placebo for six subsequent nights. Primary end point was patient-reported sleep quality during the final study night (NRS 0–10). Secondary end points were patient-reported sleep onset latency (SOL) and total sleep time (TST).ResultsForty-one patients were randomized, with 18 being analyzed in the zopiclone group and 21 in the placebo group. Median age was 66, median Karnofsky performance score was 80, and 56% were male. Mean sleep quality at end of study was 2.9 (CI 2.3 to 3.8) in the zopiclone group and 4.5 (CI 3.6 to 5.4) in the placebo group (p = 0.021). At end of study, SOL was significantly different between the treatment groups: zopiclone 29 min (CI 13 to 51) and placebo 62 min (CI 40 to 87) (p = 0.045). TST was not significantly different across groups: zopiclone 449 min (403 to 496) and placebo 411 min (CI 380 to 440) (p = 0.167).ConclusionZopiclone improved short-term patient-reported sleep quality in this cohort of patients with advanced cancer.Trial registrationClinicalTrials.gov Identifier: NCT02807922.

An efficient five-lncRNA signature for lung adenocarcinoma prognosis, with AL606489.1 showing sexual dimorphism.

Background: Lung adenocarcinoma (LUAD) is a sex-biased and easily metastatic malignant disease. A signature based on 5 long non-coding RNAs (lncRNAs) has been established to promote the overall survival (OS) prediction effect on LUAD. Methods: The RNA expression profiles of LUAD patients were obtained from The Cancer Genome Atlas. OS-associated lncRNAs were identified based on the differential expression analysis between LUAD and normal samples followed by survival analysis, univariate and multivariate Cox proportional hazards regression analyses. OS-associated lncRNA with sex dimorphism was determined based on the analysis of expression between males and females. Functional enrichment analysis of the Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was performed to explore the possible mechanisms of 5-lncRNA signatures. Results: A 5-lncRNA signature (composed of AC068228.1, SATB2-AS1, LINC01843, AC026355.1, and AL606489.1) was found to be effective in predicting high-risk LUAD patients as well as applicable to female and male subgroups and <65-year and ≥65-year age subgroups. The forecasted effect of the 5-lncRNA signature was more efficient and stable than the TNM stage and other clinical risk factors (such as sex and age). Functional enrichment analysis revealed that the mRNA co-expressed with these five OS-related lncRNAs was associated with RNA regulation within the nucleus. AL606489.1 demonstrated a sexual dimorphism that may be associated with microtubule activity. Conclusion: Our 5-lncRNA signature could efficaciously predict the OS of LUAD patients. AL606489.1 demonstrated gender dimorphism, which provides a new direction for mechanistic studies on sexual dimorphism.

Differentiating malignant pleural mesothelioma and metastatic pleural disease based on a machine learning model with primary CT signs: A multicentre study

Rationale and ObjectivesIt is still a challenge to make confirming diagnosis of malignant pleural mesothelioma (MPM), especially differentiating from metastatic pleural disease (MPD). The aim of this study was to develop a model to distinguish MPM with MPD based on primary CT signs. Materials and methodsWe retrospectively recruited 150 MPM patients and 147 MPD patients from two centers and assigned them to training (115 MPM patients and 113 MPD patients) and testing (35 MPM patients and 34 MPD patients) cohorts. The images were analyzed for pleural thickening, hydrothorax, lymphadenopathy, thoracic volume and calcified pleural plaque (CPP). The selected clinical characteristics and primary CT signs comprised the model by multivariate logistic regression in the training cohort. Then the model was tested on the external testing cohort. ROC curve and F1 score were used to validate the capability of the model in both two cohorts. ResultsThere were significant differences between two groups: (1) carcinoembryonic antigen (CEA); (2) nodular and mass pleural thickening; (3) the enhancement of pleura; (4) focal, diffuse and circumferential pleural thickening; (5) the thickest pleura; (6) thickening of diaphragmatic pleura; (7) multiple nodules and effusion of interlobar pleura; (8) hilar LN and ring enhancement of LN; (9) punctate and stipe CPP. The AUC and F1 score of the model were 0.970 and 0.857 in the training cohort, 0.955 and 0.818 in the testing cohort. ConclusionThe model holds promise for use as a diagnostic tool to distinguish MPM from MPD.

The associations of age, sex, and comorbidities with survival of hospitalized patients with coronavirus disease 2019: data from 4014 patients from a tertiary-center registry

AimTo investigate how age, sex, and comorbidities affect the survival of hospitalized coronavirus disease 2019 (COVID-19) patients.MethodsWe retrospectively analyzed the records of 4014 consecutive adults hospitalized for COVID-19 in a tertiary-level institution from March 2020 to March 2021.ResultsThe median age was 74 years. A total of 2256 (56.2%) patients were men. The median Charlson-comorbidity-index (CCI) was 4 points; 3359 (82.7%) patients had severe or critical COVID-19. A significant interaction between age, sex, and survival (P < 0.05) persisted after adjustment for CCI. In patients <57 years, male sex was related to a favorable (odds ration [OR] 0.50, 95% confidence interval [CI] 0.29-0.86), whereas in patients ≥57 years it was related to an unfavorable prognosis (OR 1.19, 95% CI 1.04-1.37). Comorbidities associated with inferior survival independently of age, sex, and severe/critical COVID-19 on admission were chronic heart failure, atrial fibrillation, acute myocardial infarction, acute cerebrovascular insult, history of venous thromboembolism, chronic kidney disease, major bleeding, liver cirrhosis, mental retardation, dementia, active malignant disease, metastatic malignant disease, autoimmune/rheumatic disease, bilateral pneumonia, and other infections on admission.ConclusionAmong younger patients, female sex might lead to an adverse prognosis due to undisclosed reasons (differences in fat tissue distribution, hormonal status, and other mechanisms). Patient subgroups with specific comorbidities require additional considerations during hospital stay for COVID-19. Future studies focusing on sex differences and potential interactions are warranted.

Bazedoxifene, a GP130 Inhibitor, Modulates EMT Signaling and Exhibits Antitumor Effects in HPV-Positive Cervical Cancer.

Persistent HPV (Human Papillomavirus) infection is the primary cause of cervical cancer. Despite the development of the HPV vaccine to prevent infections, cervical cancer is still a fatal malignant tumor and metastatic disease, and it is often difficult to treat, so a new treatment strategy is needed. The FDA-approved drug Bazedoxifene is a novel inhibitor of protein–protein interactions between IL-6 and GP130. Multiple ligand simultaneous docking and drug repositioning approaches have demonstrated that an IL-6/GP130 inhibitor can act as a selective estrogen modulator. However, the molecular basis for GP130 activation in cervical cancer remains unclear. In this study, we investigated the anticancer properties of Bazedoxifene in HPV-positive cervical cancer cells. In vitro and in vivo experiments showed that Bazedoxifene inhibited cell invasion, migration, colony formation, and tumor growth in cervical cancer cells. We also confirmed that Bazedoxifene inhibits the GP130/STAT3 pathway and suppresses the EMT (Epithelial-mesenchymal transition) sub-signal. Thus, these data not only suggest a molecular mechanism by which the GP130/STAT3 pathway may promote cancer, but also may provide a basis for cervical cancer replacement therapy.

Molecular Imaging with 18F-FDG PET/CT and 99mTc-MIBI SPECT/CT in Osteitis Fibrosa Cystica Generalisata.

Benign so-called “brown tumors” secondary to hyperparathyroidism are a rare diagnostic pitfall due to their impressively malignant-like character in various imaging modalities. We present the case of a 65-year-old male patient with multiple unclear osteolytic lesions on prior imaging suspicious for metastatic malignant disease. Eventually, findings of 18F-FDG PET/CT staging and 99mTc-MIBI scintigraphy resulted in revision of the initially suspected malignant diagnosis. This case illustrates how molecular imaging findings non-invasively corroborate the correct diagnosis of osteitis fibrosa cystica generalisata with the formation of multiple benign brown tumors.

Pulmonary metastasectomy in germ cell tumors and prostate cancer.

Pulmonary oligo-metastases and oligo-recurrences are terms used to define a set of clinical conditions consisting of limited metastatic malignant disease characterized by an intermediate aggressive behavior compared to diffuse metastatic conditions. If the primary tumor has been controlled and extra-thoracic lesions are excluded, there is a suggestion in the medical literature that removal of such lesions could potentially prolong survival. The lungs are a common metastatic spreading site, especially from epithelial malignancies and sarcomas; pulmonary surgical or interventional metastasectomy have been proposed with curative intent in case of limited tumor load (usually less than 5 lesions). There are many series reporting data about colorectal, renal or breast lung metastasectomy, but the absence of multi centric prospective trials determines a lack of definitive evidence, especially for less common tumors such as metastatic germ cell and prostate cancer. They rarely present in the oligo-metastatic form and their management is often based on personal experience. The aim of our article is to review the latest evidence in the treatment of pulmonary metastatic germ cell and prostate tumors. We cover the full range of treatments: from surgery to ablative radiotherapy and combination of local and systemic therapy. Despite the absence of evidence based guidelines, it emerges that pulmonary metastasectomy should always be considered when general criteria for resection have been met. In germ cell tumors surgery should be mainly reserved for residual disease after chemotherapy, whereas in prostate cancer, pulmonary metastasectomy should be preferred to avoid or delay hormonal deprivation therapy and its side effects.

A145 ENDOSCOPICALLY NON-VISIBLE INTERVAL COLONIC ADENOCARCINOMA DESPITE HIGH-QUALITY SURVEILLANCE.

Abstract Background Colonoscopy remains the gold-standard for screening and surveillance of colorectal cancer (CRC). Regular colonoscopy with polypectomy has been associated with reduced CRC incidence and mortality. However, interval CRC, defined as cancer diagnosed between initial screening and subsequent surveillance colonoscopies, occurs at rates of 2–14%. Identified risk factors for interval cancers include patient-related factors (older age, diverticular disease, proximal CRC), endoscopy-related factors (colonoscopy by non-gastroenterologists or in an outpatient setting; endoscopists with low rates of completion, adenoma detection or polypectomy) and biologic factors (microsatellite instability (MSI), CpG island methylation). We report a patient with interval metastatic ileo-cecal adenocarcinoma despite multiple, high-quality surveillance colonoscopies, not endoscopically visible as no visible intra-luminal mucosal component was present. Aims To describe a case of an interval CRC without an endoscopically visible intra-luminal component. Methods Case description and literature review. Results A 69-year-old male, with a history of multiple advanced colonic polyps requiring multiple surveillance colonoscopies and polypectomies, presented with symptoms of bowel obstruction. An abdominal CT scan revealed findings of terminal ileitis and upstream small bowel obstruction. Colonoscopy was performed, revealing obstruction of the ileo-cecal valve with a firm cecal submucosal lesion without abnormal overlying mucosal abnormalities. Exploratory laparoscopy revealed a mass at the ileo-cecal valve with associated peritoneal deposits. A right hemicolectomy was performed, and pathological examination demonstrated metastatic invasive adenocarcinoma involving the cecum, the terminal ileum and ileo-cecal valve without extension into the lumen or formation of an overt polypoid mass. The tumour extended into the wall of the distal ileum in a circumferential fashion, involving the immediate deep serosa, but with only minimal, focal mucosal ileal involvement and no overt polypoid mass. An independent review of the case and resection specimen by a second pathologist confirmed absence of significant ileal or colonic mucosal involvement and no obstructing intraluminal component. Conclusions This case illustrates a rare presentation of an interval CRC that was not identified despite several high-quality surveillance colonoscopies, as only minimal mucosal involvement was present. As endoscopy remains the gold-standard for early detection and removal of pre-malignant lesions and early malignancy, the patient’s presentation with interval malignant bowel obstruction and metastatic disease, despite adequate quality surveillance, demonstrates an inherent limitation of colonoscopy. To our knowledge, this is only the third documented case of endoscopically non-visible interval CRC. Funding Agencies NoneNone

Laparoscopic segment V and VI resection with pedicular lymph nodes dissection for intrahepatic cholangiocarcinoma

Background: Two international consensus conferences (Louisville and Morioka) followed by one European Southampton consensus guidelines definitely emphasized the benefits of laparoscopic liver resection (LLR) for both benign and malignant tumors, including primary and metastatic diseases. In this video, we present a case of total laparoscopic segment V and VI resection with pedicular lymph node dissection for intrahepatic cholangiocarcinoma. Methods: This video present the case of a 73 yo male patient who was found an incidental liver mass during COPD work-up. Preoperative liver work-up with MRI and PET-CT showed a 26mm liver mass located in segments V-VI with 2 hypermetabolic hepatic pedicle lymph nodes. Biopsy of the liver mass had all the characteristics of an intrahepatic cholangiocarcinoma with no underlying liver disease. Liver function was normal. After discussion of the case in MDT, laparoscopic segment V and VI resection with pedicular lymph nodes dissection was decided. Results: Surgery was uneventful. Operative time was 120 minutes and blood loss 300ml. Liver transection was performed under 2 intermittent clamping of 15 minutes. Patient was discharged at POD 3. Analysis of the specimen revealed a 26mm cholangiocarcinoma classified pT2N0R0. Patients was free of disease 6 months after surgery. Conclusion: This case demonstrates that laparoscopic liver surgery for intrahepatic cholangiocarcinoma is safe and feasible with acceptable oncologic outcome.

HSP70 as a Diagnostic and Prognostic Marker in Egyptian Women With Breast Cancer

BackgroundHeat shock protein 70 (HSP70) is a significant cellular stress response protein that has intrinsic and extrinsic pathways to protect cells against apoptosis. It is one of the most induced proteins in cancer cells. The aim of the present study is to investigate the significant role of the HSP70 expression in Egyptian patients with breast cancer (BC) and its potential to be as a diagnostic and prognostic marker. Materials and MethodsHSP70 was examined in 155 cases in this prospective study; patients were subdivided into 3 groups: 60 patients with malignant metastatic disease, 60 patients with malignant non-metastatic disease, and 35 patients with benign lesions as control. HSP70 expression was detected using enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). ResultsMost cases of breast cancer expressed HSP70 in both serum (98.3%) and tumor tissue (90%). A strong positive correlation was found between HSP70 IHC and ELISA (r = 0.811). The mean HSP70 levels, as detected in both patients’ serum by ELISA and tumor tissue by IHC, was significantly higher in patients with BC than in benign cases (P = .001). HSP70 was significantly higher in patients with metastatic BC than in those with non-metastatic BC (P = .001). HSP70 showed positive correlation with tumor size (pT stage) and number of lymph node metastases (P ≤ .001). ConclusionHSP70 is over-expressed in patients with metastatic and non-metastatic BC than in benign cases. A high level of HSP70 either in patient’s serum or in tumor tissue correlated significantly with advanced disease in patients with BC. This present study suggests that HSP70 can serve as a BC biomarker for early screening, diagnosis, and follow-up.

Selected pathobiological features and principles of pharmacological pain management.

Pain induced by inflammation and nerve injury arises from abnormal neural activity of primary afferent nociceptors in response to tissue damage, which causes long-term elevation of the sensitivity and responsiveness of spinal cord neurons. Inflammatory pain typically resolves following resolution of inflammation; however, nerve injury—either peripheral or central—may cause persistent neuropathic pain, which frequently manifests as hyperalgesia or allodynia. Neuralgias, malignant metastatic bone disease, and diabetic neuropathy are some of the conditions associated with severe, often unremitting chronic pain that is both physically and psychologically debilitating or disabling. Therefore, optimal pain management for patients with chronic neuropathic pain requires a multimodal approach that comprises pharmacological and psychological interventions. Non-opioid analgesics (e.g., paracetamol, aspirin, or other non-steroidal anti-inflammatory drugs) are first-line agents used in the treatment of mild-to-moderate acute pain, while opioids of increasing potency are indicated for the treatment of persistent, moderate-to-severe inflammatory pain. N-methyl D-aspartate receptor antagonists, antidepressants, anticonvulsants, or a combination of these should be considered for the treatment of chronic neuropathic pain. This review discusses the various neural signals that mediate acute and chronic pain, as well as the general principles of pain management.

Prospective Cohort of Referrals to a Cancer of Unknown Primary Clinic, including Direct Access from Primary Care

AimsThe UK National Health Service has well-developed site-specific referral pathways for patients with suspected cancer, but historically there has been inequality of access for patients with suspected Metastatic malignant disease of Unknown primary Origin (MUO). The Brighton cancer of unknown primary (CUP) clinic covers a population of about 650 000. As well as ‘in-house’ referrals, direct general practitioner referrals are also accepted (since 2015), aiming to shorten the diagnostic pathway and improve patient support. We present data from the first 3 years of activity. Materials and methodsReferrals were screened by an oncologist, ensuring adherence to the strict referral criterion of imaging evidence of a suspected diagnosis of MUO. A standardised data collection form was completed at each clinic appointment by the CUP team. Outcomes were cross-checked against clinic lists, letters and multidisciplinary meeting (MDM) records. A data analysis was carried out of all referrals to the CUP clinic (2015–2018), including general practitioner referrals. ResultsIn total, 258 patients were seen in the CUP clinic in the first 3 years. The median age was 71 years (range 23–95 years). Source of referral: general practitioner (30%); physician (27%); acute oncology (24%); other MDM (16%); surgeon (3%). A final diagnosis of cancer was made in 83% of referrals, with a primary site identified in 83% of those cancer cases: 19% haematological, 11% lung, 9% urological, 8% upper gastrointestinal, 6% breast, 5% skin, 4% gynaecological, 4% lower gastrointestinal, 0.3% thyroid and 0.3% sarcoma. 10% of referrals remained with a MUO diagnosis (not fit for further investigation) and 7% had confirmed CUP. 17% had a benign diagnosis (of which 56% were general practitioner referrals). Of the general practitioner referrals: 55% were seen in the CUP clinic, 31% did not meet referral criteria and 14% were declined after MDM review of imaging confirmed benign appearances. ConclusionThe development of direct general practitioner referrals to CUP clinics nationally should be encouraged (as supported by the National Institute for Health and Care Excellence) – they are feasible and manageable within a tertiary CUP clinic, resulting in high rates of cancer diagnoses, with attendant early support from specialist nursing teams and oncological review.

Cancer of Unknown Primary: A Review on Clinical Guidelines in the Development and Targeted Management of Patients with the Unknown Primary Site.

Cancer of unknown primary (CUP) is a malignant widespread metastatic disease without an identifiable primary site after extensive clinical investigation. Recently, a decline is observed in the diagnosis of CUP, mainly due to improvement in detection of the primary tumors, thus decreasing the unknown primaries. Worldwide, CUP is the sixth to eighth most common malignancy, accounting for 2.3% to 5% of a new cancer diagnosis. CUP is third to fourth most common cause of death due to cancer-related mortality. The prognosis of CUP is depressing with the median survival of three to six months in the previous studies, but according to recent studies, median survival is less than one year. High risk for developing CUP is seen in heavy smokers (26 or more cigarettes/day) and individuals with the lowest quartiles of waist circumference. A weak association is observed with the use of alcohol consumption and low level of education. Human papillomavirus DNA plays a role in those with squamous cell carcinoma of unknown primaries in head and neck regions. In the diagnosis of CUP, comprehensive medical history, complete physical examination (including genitourinary, rectal exam, and breast examination in women) and necessary laboratory tests are crucial.Whole-body positron emission tomography-computed tomography (PET/CT) is the investigation of choice to assess the entire body for CUP. Multiparametric 3T-MRI (MP-MRI) is used to examine the local soft tissue status, helps in the staging of the tumor, and to determine the extent of involvement of tissue for medical as well as prognostic purposes. Immunohistochemistry outlines the specific markers, including caudal-related homeobox protein (CDX2), homeobox protein Nkx-3.1 (NKX3-1), paired box gene 8 (PAX8), special AT-rich sequence-binding protein 2 (SATB2), thyroid transcription factor 1 (TTF-1), and splicing factor 1 (SF1) with the focus on the effectiveness of lineage-restricted transcription factors. Patients response to treatment can be evaluated by the gene expression profiling (GEP) test that also predicts tissue of origin (TOO). Tumor identified through gene profiling is sensitive to platinum/taxane therapy, others that are not TOO tumors are resistant to platinum/taxane. The new therapeutic method based on molecular profiling is associated with higher treatment response. In comprehensive genomic profiling, it is observed that there is at least one clinically appropriate genomic alteration in CUP that can influence the targeted therapy. The targeted therapeutic approach will not only improve the disease outcome but will also be cost-effective and save time from finding the primary site.