Management and prognosis of patients with cancer of unknown primary: 20 years of experience.

Background/aim: Cancer of unknown primary (CUP) is a difficult clinical entity to manage. The aim of the study was to investigate the sociodemographic and pathological characteristics, treatment options, and factors affecting overall survival (OS) in CUP patients whose primary tumor was not detected during follow-up. Materials and methods: A total of 243 CUP patients whose primary tumors could not be detected during follow-up were included in the study. Their demographic characteristics, survival outcomes, and prognostic factors were investigated. Results: Of the 243 patients included in this study, 61.7% were male and 38.3% were female, and the median age was 61 (range: 19-90) years. The most common histological type was adenocarcinoma (79%). The median follow-up time of the patients was 30.3 months (95% CI: 11.4-49.3), the median OS time was 9.1 months (95% CI: 7.2-11.0), and 72.4% of the patients received at least 1 line of chemotherapy (CT). The difference in survival between the patients who did and did not receive CT was statistically significant (median OS: 10.1 vs. 4.2 months, p = 0.003). According to the multivariate analysis, the presence of cholestasis (HR: 0.48, 95% CI: 0.29-0.79, p = 0.004), lung metastasis (HR: 0.69, 95% CI: 0.51-0.95, p = 0.001), second-line chemotherapy (HR: 1.69, 95% CI: 1.14-2.49, p < 0.001), and Eastern Cooperative Oncology Group (ECOG) performance status (HR: 0.20, 95% CI: 0.10-0.40, p < 0.001) were independent prognostic factors influencing OS. Conclusion: CUP patients who receive multiple lines of chemotherapy tend to have longer survival. This is the first study to report cholestasis as a prognostic factor in CUP patients. In addition, the presence of lung metastases, not receiving second-line chemotherapy, and ECOG performance status (≥2) were found to be independent poor prognostic factors.

Improved prognosis and evidence of enhanced immunogenicity in tumor and circulation of high-risk melanoma patients with unknown primary.

BACKGROUND: Melanoma of unknown primary (MUP) represents a poorly understood group of patients both clinically and immunologically. We investigated differences in prognosis and candidate immune biomarkers in patients with unknown compared with those with known primary melanoma enrolled in the E1609 adjuvant trial that tested ipilimumab at 3 and 10 mg/kg vs high-dose interferon-alfa (HDI). PATIENTS AND METHODS: MUP status was defined as initial presentation with cutaneous, nodal or distant metastasis without a known primary. Relapse-free survival (RFS) and overall survival (OS) rates were estimated by the Kaplan-Meier method. Stratified (by stage) log-rank test was used to compare RFS and OS by primary tumor status. Gene expression profiling (GEP) was performed on the tumor biopsies of a subset of patients. Similarly, peripheral blood samples were tested for candidate soluble and cellular immune biomarkers. RESULTS: MUP cases represented 12.8% of the total population (N=1699) including 11.7% on the ipilimumab arms and 14.7% on the HDI arm. Stratifying by stage, RFS (p=0.001) and overall survival (OS) (p=0.009) showed outcomes significantly better for patients with unknown primary. The primary tumor status remained prognostically significant after adjusting for treatment and stage in multivariate Cox proportional hazards models. Including only ipilimumab-treated patients, RFS (p=0.005) and OS (p=0.023) were significantly better in favor of those with unknown primary. Among patients with GEP data (n=718; 102 MUP, 616 known), GEP identified pathways and genes related to autoimmunity, inflammation, immune cell infiltration and immune activation that were significantly enriched in the MUP tumors compared with known primaries. Further investigation into infiltrating immune cell types estimated significant enrichment with CD8 +and CD4+T cells, B cells and NK cells as well as significantly higher major histocompatibility complex (MHC)-I and MHC-II scores in MUP compared with known primary. Among patients tested for circulating biomarkers (n=321; 66 unknown and 255 known), patients with MUP had significantly higher circulating levels of IL-2R (p=0.04). CONCLUSION: Patients with MUP and high-risk melanoma had significantly better prognosis and evidence of significantly enhanced immune activation within the TME and the circulation, supporting the designation of MUP as a distinct prognostic marker in patients with high-risk melanoma.

Therapeutic Actionability of Circulating Cell-Free DNA Alterations in Carcinoma of Unknown Primary.

Cancer of unknown primary (CUP) is a metastatic disease with unidentifiable primary tumor. Somatic alterations can be assessed noninvasively via liquid biopsies interrogating cell-free DNA (cfDNA). METHODS: We evaluated 1,931 patients with CUP with a cfDNA next-generation sequencing panel (73-74 genes). RESULTS: Overall, 1,739 patients (90%) had ≥ 1 cfDNA alteration. We then explored alteration actionability (per the levels of evidence from the OncoKB database); 825 patients (47.4% of 1,739) had level 1, level 2, or resistance/R1 alterations. Among 40 clinically annotated patients with CUP who had cfDNA evaluated, higher degrees of matching treatment to alterations (Matching Score > 50% v ≤ 50%) was the only variable predicting improved outcome: longer median progression-free survival (10.4 v 2.5 months; P = .002), overall survival (13.4 v 5.7 months; P = .07, trend), and higher clinical benefit rate (stable disease ≥ 6 months/partial response/complete response; 83% v 25%; P = .003). CONCLUSION: In summary, cfDNA frequently reveals strong level-of-evidence actionable alterations in CUP, and high degrees of matching to therapy correlates with better outcomes.

Relevance of the time interval between surgery and adjuvant radio (chemo) therapy in HPV-negative and advanced head and neck carcinoma of unknown primary (CUP).

INTRODUCTION: In contrast to head and neck squamous cell carcinoma (HNSCC), the effect of treatment duration in HNSCC-CUP has not been thoroughly investigated. Thus, this study aimed to assess the impact of the time interval between surgery and adjuvant therapy on the oncologic outcome, in particular the 5-year overall survival rate (OS), in advanced stage, HPV-negative CUPs at a tertiary referral hospital. 5-year disease specific survival rate (DSS) and progression free survival rate (PFS) are defined as secondary objectives. MATERIAL AND METHODS: Between January 1st, 2007, and March 31st, 2020 a total of 131 patients with CUP were treated. Out of these, 59 patients with a confirmed negative p16 analysis were referred to a so-called CUP-panendoscopy with simultaneous unilateral neck dissection followed by adjuvant therapy. The cut-off between tumor removal and delivery of adjuvant therapy was set at the median, i.e. patients receiving adjuvant therapy below or above the median time interval. RESULTS: Depending on the median time interval of 55 days (d) (95% CI 51.42-84.52), 30 patients received adjuvant therapy within 55 d (mean 41.69 d, SD = 9.03) after surgery in contrast to 29 patients at least after 55 d (mean 73.21 d, SD = 19.16). All patients involved in the study were diagnosed in advanced tumor stages UICC III (n = 4; 6.8%), IVA (n = 27; 45.8%) and IVB (n = 28; 47.5%). Every patient was treated with curative neck dissection. Adjuvant chemo (immune) radiation was performed in 55 patients (93.2%), 4 patients (6.8%) underwent adjuvant radiation only. The mean follow-up time was 43.6 months (SD = 36.7 months). The 5-year OS rate for all patients involved was 71% (95% CI 0.55-0.86). For those patients receiving adjuvant therapy within 55 d (77, 95% CI 0.48-1.06) the OS rate was higher, yet not significantly different from those with delayed treatment (64, 95% CI 0.42-0.80; X2(1) = 1.16, p = 0.281). Regarding all patients, the 5-year DSS rate was 86% (95% CI 0.75-0.96). Patients submitted to adjuvant treatment in less than 55 d the DSS rate was 95% (95% CI 0.89-1.01) compared to patients submitted to adjuvant treatment equal or later than 55 d (76% (95% CI 0.57-0.95; X2(1) = 2.32, p = 0.128). The 5-year PFS rate of the entire cohort was 72% (95% CI 0.59-0.85). In the group < 55 d the PFS rate was 78% (95% CI 0.63-0.94) and thus not significantly different from 65% (95% CI 0.45-0.85) of the group ≥55 d; (X2(1) = 0.29, p = 0.589). CONCLUSIONS: The results presented suggest that the oncologic outcome of patients with advanced, HPV-negative CUP of the head and neck was not significantly affected by a prolonged period between surgery and adjuvant therapy. Nevertheless, oncologic outcome tends to be superior for early adjuvant therapy.

Local ablative treatment with surgery and/or radiotherapy in single-site and oligometastatic carcinoma of unknown primary.

BACKGROUND: Single-site carcinoma of unknown primary (CUP) is recognised as a distinct favourable subtype in the European Society of Medical Oncology (ESMO) classification. There is broad consensus that these patients are candidates for local ablative treatment strategies with surgery and/or radiotherapy, but data on their outcomes are scarce. PATIENTS AND METHODS: In this study, we have addressed the prospects of cure and prognostic factors in a retrospective cohort of 63 patients who were eligible for local treatment at our centre. RESULTS: Median event-free (EFS) and overall survival (OS) were 15.6 months and 52.5 months, respectively. Of 61 patients who received local treatment, 20 (32.8%) remained event-free over a median follow-up of 28 months. Baseline clinical parameters including affected organ, number, volume and histology of metastases had no significant impact on prognosis, whereas deleterious TP53 mutations and DNA copy number loss emerged as independent adverse risk factors with respect to EFS. Surgical treatment was associated with improved OS as compared to radiation-based therapy. CONCLUSION: Our study advocates to pursue localised treatment with surgery and/or radiotherapy whenever feasible and implies that genetic parameters might additionally determine the clinical course of single-site CUP patients.

Comparative genomic characterization of melanoma of known and unknown primary.

BACKGROUND: This study aims to genomically characterize melanoma of unknown primary (MUP) in comparison to melanomas of cutaneous primary (MCP). METHODS: Eligible cases were collected from the MSK-IMPACT™ Clinical Sequencing Cohort published in the cBioPortal database. Genomic analysis was performed using a hybridization-capture-based next-generation sequencing assay designed to detect mutations, small insertions and deletions, copy number alterations, and genomic rearrangements. RESULTS: Among 462 patients of whom 18.4% had MUP, brain metastasis was more common among patients with MUP (23% vs 7.1%). The differences in genomic profiling between MCP and MUP did not reach statistical significance. The 187 MCP and 44 MUP patients treated with immune checkpoint inhibitors had a median overall survival of 49 and 44 months, respectively (p = 0.705). CONCLUSIONS: The differences in somatic mutation patterns and survival outcomes were not statistically significant. These findings may allude to similar carcinogenic processes but should be considered exploratory and interpreted with caution.

Clinical outcome of patients with metastatic melanoma of unknown primary in the era of novel therapy.

Melanoma of unknown primary (MUP) is considered different from melanoma of known primary (MKP), and it is unclear whether these patients benefit equally from novel therapies. In the current study, characteristics and overall survival (OS) of patients with advanced and metastatic MUP and MKP were compared in the era of novel therapy. Patients were selected from the prospective nation-wide Dutch Melanoma Treatment Registry (DMTR). The following criteria were applied: diagnosis of stage IIIc unresectable or IV cutaneous MKP (cMKP) or MUP between July 2012 and July 2017 and treatment with immune checkpoint inhibition and/or targeted therapy. OS was estimated using the Kaplan-Meier method. The stratified multivariable Cox regression model was used for adjusted analysis. A total of 2706 patients were eligible including 2321 (85.8%) patients with cMKP and 385 (14.2%) with MUP. In comparative analysis, MUP patients more often presented with advanced and metastatic disease at primary diagnosis with poorer performance status, higher LDH, and central nervous system metastases. In crude analysis, median OS of cMKP or MUP patients was 12 months (interquartile range [IQR] 5 - 44) and 14 months (IQR 5 - not reached), respectively (P = 0.278). In adjusted analysis, OS in MUP patients was superior (hazard rate 0.70, 95% confidence interval 0.58-0.85; P < 0.001). As compared to patients with advanced and metastatic cMKP, MUP patients have superior survival in adjusted analysis, but usually present with poorer prognostic characteristics. In crude analysis, OS was comparable indicating that patients with MUP benefit at least equally from treatment with novel therapies.

Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas.

PURPOSE: Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown. EXPERIMENTAL DESIGN: Patients with melanoma were prospectively offered tumor sequencing of 341-468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables. RESULTS: A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months. CONCLUSIONS: Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor-refractory melanoma.

Extensive diagnostic work-up for patients with carcinoma of unknown primary.

Patients with carcinoma of unknown primary (CUP) present with metastatic disease without an identified primary tumour. The unknown site of origin makes the diagnostic work-up and treatment challenging. Since little information is available regarding diagnostic work-up and treatment in daily practice, we collected and analysed these in a patient cohort with regard to the recommendations of the national CUP guideline. Data of 161 patients diagnosed with CUP in 2014 or 2015 were extracted from the Netherlands Cancer Registry (NCR) and supplemented with diagnostic work-up information from patient files and analysed. Patients underwent an average of five imaging studies during the diagnostic phase (range 1-17). From the tests as recommended in the national guideline on CUP, a chest X-ray was most commonly performed (73%), whereas a PET-CT was done in one out of four patients (24%). Biopsies were taken in 86% of the study population, with Cytokeratin 7 being the most frequently tested histopathological marker (73%). Less than half of patients received therapy (42%). CUP patients undergo extensive diagnostic work-up. The performance status did not influence the extent of the diagnostic work-up in CUP patients, but it was an important factor for receiving treatment.

Cancer of Unknown Primary in the Molecular Era.

Cancer of unknown primary (CUP) is a rare malignancy that presents with metastatic disease and no identifiable site of origin. Most patients have unfavorable features and attempts to treat based on tissue-of-origin identification have not yielded a survival advantage compared with empiric chemotherapy. Next-generation sequencing has revealed genomic alterations that can be targeted in selected cases, suggesting that CUP represents a unique malignancy in which the genomic aberrations may be integral to the diagnosis. Recent trials focusing on tailored combination therapy matched to the genomic alterations in each cancer are providing new avenues of clinical investigation. Here, we discuss recent findings on molecular aberrations in CUP and how the genomic and immune landscape can be leveraged to optimize therapy.

Differences in outcomes of bilateral adrenalectomy in patients with ectopic ACTH producing tumor of known and unknown origin.

BACKGROUND: Endogenous Cushing syndrome (CS) can be caused by ectopic corticotropin-producing tumors of known (EK) and unknown origin (EU). Bilateral adrenalectomy (BA) can be used as definite treatment of hypercortisolism in such cases. This study compared patients undergoing BA for CS secondary to EK vs EU. METHODS: Retrospective review (1995-2017) of patients undergoing BA due to EK or EU. We analyzed demographic characteristics, laboratory values, intraoperative variables, surgical outcomes, and survival. RESULTS: 48 patients (26 EU, 22 EK) were identified. Serum cortisol and ACTH concentrations were similar. 92% of BA for EU were performed minimally invasively vs 77% for EK, P = 0.22. Complications occurred in 19% of EU and 4.5% EK, P = 0.2. Mean survival was 4.3 years for EU and 4.0 years for EK without difference in all-cause mortality P = 0.63. CONCLUSION: BA cure rate was 100% for CS in EU and EK. Morbidity, long term and all-cause mortality differences were not statistically significant between EK and EU.

Alcohol consumption, cigarette smoking and cancer of unknown primary risk: Results from the Netherlands Cohort Study.

Cancer of unknown primary (CUP) is a metastasised malignancy with no identifiable primary tumour origin. Despite the frequent occurrence and bleak prognosis of CUP, research into its aetiology is scarce. Our study investigates alcohol consumption, tobacco smoking and CUP risk. We used data from the Netherlands Cohort Study, a cohort that includes 120 852 participants aged 55 to 69 years, who completed a self-administered questionnaire on cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and Dutch Pathology Registry. After 20.3 years of follow-up, 963 CUP cases and 4288 subcohort members were available for case-cohort analyses. Multivariable-adjusted hazard ratios (HRs) were calculated using proportional hazard models. In general, CUP risk increased with higher levels of alcohol intake (Ptrend = .02). The association was more pronounced in participants who drank ≥30 g of ethanol per day (HR: 1.57, 95% confidence interval [CI]: 1.20-2.05) compared to abstainers. Current smokers were at an increased CUP risk (HR: 1.59, 95% CI: 1.29-1.97) compared to never smokers. We observed that the more the cigarettes or the longer a participant smoked, the higher the CUP risk was (Ptrend = .003 and Ptrend = .02, respectively). Interaction on additive scale was found for participants with the highest exposure categories of alcohol consumption and cigarette smoking frequency and CUP risk. Our findings demonstrate that alcohol consumption and cigarette smoking are associated with increased CUP risk. Lifestyle recommendations for cancer prevention regarding not drinking alcohol and avoiding exposure to smoking are therefore also valid for CUP.

Retrospective Analysis of Survival in Patients with Brain Metastases from an Unknown Primary Tumor.

AIM: To evaluate the patients with brain metastases from unknown primary (BMUP) cancers, and to analyze the prognostic factors and survival rates. MATERIAL AND METHODS: We conducted a retrospective study with 110 patients (mean age: 62.8 years [range 23?90], n=85- 77.3% male and n=25-22.7% female) with BMUP cancers at the time of diagnosis, who presented to our outpatient oncology clinic between January 2015 and December 2019. We employed the following variables as significant prognostic factors for a prominent index of patients? survival: age, gender, Karnofsky performance score (KPS), number of metastatic lesions, primary site, and type of treatment were analyzed for their prognostic effects on survival outcomes. Patients? survival was evaluated from plotted Kaplan? Meier curves, and the log-rank test was used for univariate analysis. RESULTS: The mean follow-up was 13 months (range 4?60 months). The means of survival after the diagnosis of brain metastasis was 18.7 months for the study group. Lung cancer was the most common primary tumor (74, 5%). The KPS and number of lesions were found to have a prognostic effect on survival. Survival analysis showed no statistical significance with age and gender, primary site, type of treatment. CONCLUSION: This study showed that KPS, and the number of lesions affect the survival outcomes but both the other variables. Therefore, BMUP cancer is indeed related to poor prognosis.

Comparative cohort study of volumetric modulated arc therapy for squamous cell cancer of unknown primary in the head and neck-Involved neck only versus mucosal irradiation.

OBJECTIVES: Target volumes for irradiation remain ill-defined for squamous cell cancer of unknown primary in the head and neck (SCCUP). The aim of this study was to compare involved neck only (INO) radiotherapy (RT) with irradiating involved neck plus potential mucosal primary sites and contralateral neck (MUC) in patients diagnosed and treated with modern diagnostics and techniques. DESIGN: This is a retrospective cohort study. Patients with a diagnosis of SCCUP with unilateral neck disease were included. RESULTS: Thirty patients were identified. All underwent FDG PET-CT. 47% of patients had HPV-positive SCC. 20 patients received RT to INO, 10 patients to MUC, all with volumetric modulated arc therapy (VMAT). A significantly lower dose for each organ at risk was delivered in INO-treated patients, with mean dose to contralateral parotid gland 57% less. The proportion of patients with late grade 2 or worse xerostomia was higher in MUC patients. The incidence of grade 2-3 mucositis (89% vs 45%) and grade 3 or worse dysphagia (50% vs 10%) was higher in MUC patients. Median follow-up was 31 months. No mucosal primaries emerged. Progression-free survival at 2 years was 74.7% for INO patients, 70% in the MUC group. Overall survival at 2 years was 79.7% in the INO group and 70% in the MUC patients. CONCLUSION: INO radiotherapy for patients with SCCUP of the head and neck is a safe treatment strategy resulting in clinically significant lower RT doses to OARS. Acute and late toxicities are reduced without detriment to patient survival.

Evaluation of radiation treatment volumes for unknown primaries of the head and neck in the era of FDG PET.

OBJECTIVES: Positron-emission tomography (PET) has improved identification of the primary tumor as well as occult nodal burden in cancer of the head and neck. Nevertheless, there are still patients where the primary tumor cannot be located. In these situations, the standard of care is comprehensive head and neck radiation therapy however it is unclear whether this is necessary. This study examines the effects of radiation treatment volume on outcomes among using data from two cancer centers in unknown primary carcinoma of the head and neck. METHODS: Patients received unilateral (n = 34), or bilateral radiation (n = 28). Patient factors such as age, gender, smoking history, and patterns of failure were compared using Mann Whitney U and Chi Square. Overall survival (OS) and disease free survival (DFS) trends were estimated using Kaplan-Meier survival curves. Effect of treatment volume on survival was examined using multivariate cox proportional hazard regression model. RESULTS: No significant differences were observed in the frequency of local (p = 0.32), regional (p = 0.50), or distant (p = 0.76) failures between unilateral and bilateral radiation therapy. By Kaplan-Meier estimates, OS (3-year OS bilateral = 71.67%, unilateral = 77.90%, p = 0.50) and DFS (3-year DFS bilateral = 77.92%, unilateral = 69.43%, p = 0.63) were similar between the two treatment approaches. Lastly, multivariate analysis did not demonstrate any significant differences in outcome by treatment volumes (OS: HR = 0.74, 95% CI: 0.31, 1.81, p = 0.51; DFS: HR: 0.68, 95% CI: 0.24, 1.93, p = 0.47). CONCLUSIONS: Unilateral radiation therapy compared with bilateral produced similar survival.

Long-term results of elective mucosal irradiation for head and neck cancer of unknown primary in Chinese population: The EMICUP study.

OBJECTIVE: Controversy still exists regarding the volume of radiation for head and neck cancer of unknown primary (HNCUP). Theoretically, elective mucosal irradiation (EMI) should achieve a balance between survival and toxicity. This prospective study was conducted to evaluate the long-term benefit of EMI in Chinese HNCUP patients. METHODS: A phase II, single-arm trial was performed at two centers in China. HNCUP patients with pathologically confirmed metastatic squamous cell carcinoma or poorly differentiated carcinoma were enrolled. Patients with metastatic lymph nodes limited to level IV and/or the supraclavicular fossa were excluded. The EMI approach was specifically customized to Chinese patients by differentiating HNCUP as putative nasopharyngeal carcinoma (NPC) or non-putative NPC. The primary endpoint was 3-year mucosal recurrence-free survival (MRFS). RESULTS: A total of 48 patients were enrolled between 02/02/2010 and 08/01/2018; 46 patients were analyzed, including 24 putative NPC and 22 non-putative NPC patients. No primary recurrence was observed during a median follow-up period of 70 months, and only 1 patient experienced out of field recurrence in the contralateral neck. The 3-year MRFS was 90.6% (95%CI: 76.4%-96.4%). The 5-year MRFS, regional-recurrence free survival (RRFS) and overall survival (OS) were 90.6% (95%CI: 76.4%-96.4%), 86.0% (95%CI: 71.1%-93.7%), and 90.6% (95%CI: 76.4%-96.4%), respectively. No grade 4 acute or late toxicities occurred, and the most frequent grade 3 acute toxicity was oral mucositis (45.7%). CONCLUSION: To the best of our knowledge, this is the first prospective study to evaluate the long-term outcomes of EMI in Chinese HNCUP patients. Excellent MRFS and OS rates were observed. Further randomized studies are warranted.

Survival and therapeutic response in patients with melanoma of unknown and known primary: a single-centre retrospective analysis.

BACKGROUND: The survival of patients with melanoma of unknown primary (MUP) is proposed to be more favourable than that for melanoma of known primary (MKP). This may be due to an enhanced initial immune response in patients with MUP, which could also affect the efficacy of immunotherapy in advanced disease. OBJECTIVES: The present study compared therapeutic outcome and survival in Stage III and IV MUP and MKP. RESULTS: Medical records of 67 MUP and 536 MKP patients were reviewed. Median overall survival (OS) in Stage III patients was 77 months versus 54 months in patients with MUP and MKP, respectively (p = 0.11). Median OS was prolonged in MUP patients receiving adjuvant first-line ipilimumab (p = 0.14). In contrast, OS tended to be more favourable in patients with MKP after palliative first-line ipilimumab treatment (p = 0.16). Yet, no statistically significant differences in OS were detected between the groups. Moreover, survival after anti-PD-1-antibody treatment was similar in patients with MUP and MKP. CONCLUSION: Overall, we observed similar survival outcomes after immunotherapy in patients with MUP and MKP. These findings provide no evidence of difference in responsiveness to immunotherapy between patients with MUP and MKP.

Rheumatic syndromes and occult tumor: 10-year experience in a teaching hospital. / Síndromes reumáticos y tumor oculto, experiencia de 10 años en un hospital universitario.

OBJECTIVE: To describe the different clinical characteristics of patients admitted to the Rheumatology Department due to rheumatic manifestations as the first expression of an unknown malignant process. PATIENTS AND METHODS: Retrospective and descriptive observational study involving the review of the medical records of those admitted to rheumatology in the University Hospital of Ciudad Real between January 2007 and August 2017 for initial rheumatic manifestations with a suspicion at discharge of an unknown tumor. RESULTS: In all, 64 patients were identified from more than 500 admissions. The most common rheumatic manifestations were inflammatory low back pain, polyarthralgia, hip pain, thoracic spine pain, cervical pain, polyarthritis and polymyalgia rheumatica. Forty-four percent had low hemoglobin, 70% had elevation of acute-phase reactants, 62% had abnormal tumor markers, 76% had metastatic lesions. In 20% the primary tumor was of pulmonary origin and only 26.56% received palliative treatment; 64% died. DISCUSSION: It is important to consider the possibility of an underlying malignant process in the differential diagnosis since its early identification can be determinant for prognosis.

Identification of Areas for Improvement in the Management of Bone Metastases in Patients with Neuroendocrine Neoplasms.

BACKGROUND: There is no global consensus on the optimal management of bone metastases (BMs) in neuroendocrine neoplasms (NENs). OBJECTIVES: To review current management and outcomes of patients with BMs in NENs, in order to identify areas for improvement. METHODS: A retrospective study of all patients with NENs, except Grade 3 lung NENs (April 2002 to March 2018) was conducted. Baseline characteristics, nature of BMs, treatment received and overall survival (OS) were evaluated. Statistical analyses were performed using SPSS version 23.0/STATA v12. RESULTS: Of 1,212 patients, 85 (7%) had BMs; median age 58 years. The majority had a gastro-entero-pancreatic primary (49%, n = 42) followed by lung (25%, n = 21), unknown primary (20%, n = 17), and "others" (6%, n = 5). Two-thirds (n = 57) had G1-2 neuroendocrine tumours, and 41% (n = 35) had functional tumours. Overall, 28% (n = 24) presented with synchronous BMs at first NEN diagnosis, and 55% (n = 47) developed BMs at the same time as other distant metastases. For the subpopulation of patients in whom BMs developed metachronously to other distant metastases (45%, n = 38), median time to development of BMs was 14.0 months. BMs were "widespread" in 61% (n = 52). Although only 22% (n = 19) reported symptoms at initial diagnosis of BMs, most (78%) developed symptoms at some time during the follow-up period (pain/hypercalcaemia 64%, skeletal-related events 20%). BMs were mainly managed with analgesia (44%, n = 37). Radiotherapy and bisphosphonates were used in 34% (n = 29) and 22% (n = 19) respectively. Surgery was rarely performed (2%, n = 2). Median OS from identification of BMs was 31.0, and 18.9 months from development of BMs-related symptoms. CONCLUSIONS: In this cohort study, most patients with BMs developed symptoms. The utility of radiotherapy and/or bisphosphonates should be prospectively and systematically explored further for its potential impact on patients' quality of life and survival outcomes.