Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study.

BACKGROUND: Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study. MATERIALS AND METHODS: Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability. RESULTS: Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAFV600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities. CONCLUSIONS: Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.

A signature of circulating microRNAs predicts the response to treatment with FOLFIRI plus aflibercept in metastatic colorectal cancer patients.

The benefit of adding the antiangiogenic drug aflibercept to FOLFIRI regime in metastatic colorectal cancer (CRC) patients resistant to or progressive on an oxaliplatin-based therapy has been previously demonstrated. However, the absence of validated biomarkers to predict greater outcomes is a major challenge encountered when using antiangiogenic therapies. In this study we investigated profiles of circulating microRNAs (miRNAs) to build predictive models of response to treatment and survival. Plasma was obtained from 98 metastatic CRC patients enrolled in a clinical phase II trial before receiving FOLFIRI plus aflibercept treatment, and the circulating levels of 754 individual miRNAs were quantified using real-time PCR. A distinct signature of circulating miRNAs differentiated responder from non-responder patients. Remarkably, most of these miRNAs were found to target genes that are involved in angiogenic processes. Accordingly, some of these miRNAs had predictive value and entered in predictive models of response to therapy, progression of disease, and survival of patients treated with FOLFIRI plus aflibercept. Among these miRNAs, circulating levels of hsa-miR-33b-5p efficiently discriminated between responder and non-responder patients and predicted the risk of disease progression. Moreover, the combination of circulating VEGF-A and miR-33b-5p levels improved clinical stratification of metastatic CRC patients who were to receive FOLFIRI plus aflibercept treatment. In conclusion, our study supports circulating miRNAs as valuable biomarkers for predicting better outcomes in metastatic CRC patients treated with FOLFIRI plus aflibercept.

Short-course radiotherapy in stage IV rectal cancer with resectable disease.

INTRODUCTION: Stage IV rectal cancer with resectable disease presents challenging issues, as the radical treatment of the whole disease is difficult. Surgery and chemotherapy (CT) play an unquestionable role, but the contribution of pelvic radiotherapy (RT) is not very clear. METHODS: In 2009, we established a prospective treatment protocol that included CT, short-course preoperative radiotherapy (SCRT) with surgery of the primary tumour and all metastatic locations. RESULTS: Forty patients were included. Eight (20%) patients did not receive CT due to significant comorbidities. Radical surgery treatment was possible in 22 (55%) patients. The mean follow-up was 42.81 months (3.63-105.97). Overall survival at 24 and 36 months was 71.4% and 58.2%, respectively. There was good local control of the disease, as 97.2% of pelvic surgeries were R0 and there were no local recurrences. CONCLUSION: In stage IV with resectable metastatic disease, the proposed therapeutic regimen seems very appropriate in well selected patients able to tolerate the treatment. We bet on the role of pelvic RT, due to the good local control of the disease in our series.

Effect of a multi-ingredient based food supplement on sexual function in women with low sexual desire.

BACKGROUND: Studies have demonstrated that women with low desire and low excitement have negative feelings regarding their physical and emotional satisfaction, as well as their happiness. In this study, we evaluate the efficacy of Libicare® - a multi-ingredient food supplement - to improve sexual function in postmenopausal women. METHODS: This was an exploratory, prospective, non-controlled, observational study. Postmenopausal women aged 45-65 with a risk of sexual dysfunction (Female Sexual Function Index (FSFI) < 25.83) were included during routine clinical visits and treated with 2 tablets of Libicare® daily for 2 months. Libicare® is an oral food supplement containing Trigonella foenum graecum, Turnera diffusa, Tribulus terrestris, and Ginkgo biloba dry extracts. Primary endpoint: change vs. baseline in FSFI score. Secondary endpoints: 1) changes in testosterone and serum steroid levels of free testosterone and sex hormone-binding globulin (SHBG) levels and 2) tolerability. RESULTS: A total of 29 patients (mean age: 54.69 years) were included. FSFI mean (SD) score showed a significant increase: 20.15 (4.48) vs 25.03 (6.94), baseline vs final; p = 0.0011, paired t-test. Most patients (86.2%) increased their FSFI score. All FSFI domains, except dyspareunia, showed significant increases. The highest increase was observed in the desire domain (p = 0.0004). Testosterone and SHBG levels were assessed in 21 patients. A significant increase in testosterone level was observed: 0.41 (0.26) vs. 0.50 (0.34) pg/mL, baseline vs. final; p = 0.038, Wilcoxon test. 52.4% of patients increased their testosterone levels. Finally, a significant decrease was observed in SHBG level: 85 (32.9) vs. 73 (26.8) nmol/L, baseline vs. final; p = 0.0001; paired t-test. 95.2% of patients decreased their SHBG levels. CONCLUSION: In this pilot study, a significant improvement in sexual function and related hormone levels was observed with Libicare®. Further studies must be conducted to confirm these exciting results. TRIAL REGISTRATION: Current Controlled Trial ISRCTN12928573 . Date of registration: 28/March/2019. Retrospectively registered.

Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy.

BACKGROUND: Extended RAS analysis is mandatory in metastatic colorectal cancer (mCRC) patients. The optimal threshold of RAS mutated subclones to identify patients most likely to benefit from antiepidermal growth factor receptor (EGFR) therapy is controversial. Our aim was to assess the clinical impact of detecting mutations in RAS, BRAF, PIK3CA and EGFRS492R in basal tissue tumour samples by using a highly sensitive next-generation sequencing (NGS) technology in mCRC patients treated with chemotherapy plus anti-EGFR or anti-vascular endothelial growth factor. PATIENTS AND METHODS: Five hundred and eighty-one tumour samples from untreated mCRC patients from 7 clinical studies were collected. Mutational analysis was carried out by standard-of-care (therascreen pyro) with a sensitivity detection of 5% mutant allele fraction (MAF), and compared with NGS technology using 454GS Junior platform (Roche Applied Science, Germany) with a sensitivity of 1%. Molecular results were correlated with clinical outcomes. RESULTS: After quality assessment, 380 samples were evaluable for molecular analysis. Standard-of-care mutational analysis detected RAS, BRAFV600E or PIK3CA mutations in 56.05% of samples compared with 69.21% by NGS (P = 0.00018). NGS identified coexistence of multiple low-frequency mutant alleles in 96 of the 263 mutated cases (36.5%; range 2-7). Response rate (RR), progression-free survival (PFS) and overall survival (OS) were increasingly improved in patients with RAS wild-type, RAS/BRAF wild-type or quadruple (KRAS/NRAS/BRAF/PIK3CA) wild-type tumours treated with anti-EGFR, assessed by standard-of-care. No additional benefit in RR, PFS or OS was observed by increasing the detection threshold to 1% by NGS. An inverse correlation between the MAF of the most prevalent mutation detected by NGS and anti-EGFR response was observed (P = 0.039). EGFRS492Rmutation was not detected in untreated samples. CONCLUSIONS: No improvement in the selection of patients for anti-EGFR therapy was obtained by adjusting the mutation detection threshold in tissue samples from 5% to 1% MAF. Response to anti-EGFR was significantly better in patients with quadruple wild-type tumours.

2018 consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary.

Cancer of unknown primary (CUP) is defined as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They differ from other primary tumours in their biological features and how they spread, which means that they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, CUP can account for 2-9% of all cancer patients, mostly 60-75 years old. This article reviews the main clinical, pathological, and molecular studies conducted to analyse and determine the origin of CUP. The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed.

SEOM clinical guideline on unknown primary cancer (2017).

Cancer of unknown primary site is a histologically confirmed cancer that manifests in advanced stage, with no identifiable primary site following standard diagnostic procedures. Patients are initially categorized based on the findings of the initial biopsy: adenocarcinoma, squamous-cell carcinoma, neuroendocrine carcinoma, and poorly differentiated carcinoma. Appropriate patient management requires understanding several clinical and pathological features that aid in identifying several subsets of patients with more responsive tumors.

SEOM Clinical Guideline of localized rectal cancer (2016).

Localized rectal adenocarcinoma is a heterogeneous disease and current treatment recommendations are based on a preoperative multidisciplinary evaluation. High-resolution magnetic resonance imaging and endoscopic ultrasound are complementary to do a locoregional accurate staging. Surgery remains the mainstay of treatment and preoperative therapies with chemoradiation (CRT) or short-course radiation (SCRT) must be considered in more locally advanced cases. Novel strategies with induction chemotherapy alone or preceding or after CRT (SCRT) and surgery are in development.

Recommendations in the management of epithelial appendiceal neoplasms and peritoneal dissemination from mucinous tumours (pseudomyxoma peritonei).

The epithelial appendiceal neoplasms are uncommon and are usually detected as an unexpected surgical finding. The general surgeon should be aware of the diversity of its clinical manifestations and biological behaviors along with the significance of the surgical treatment on the progression of the illness and the prognosis of the patients. The operative findings and, especially, tumor histology, determine the type of surgery. Intestinal histologic subtype behaves and should be treated similarly to the right colon neoplasms; while mucinous tumors, often discordant between histology and its aggressiveness, can be treated with a simple appendectomy or require complex oncological surgeries. Mucinous tumors are often associated with the presence of mucin or tumor implants in the abdominal cavity, being the clinical syndrome known as pseudomyxoma peritonei (PMP). PMP tends to present an indolent but deadly evolution and requires a multimodal approach as a single treatment with curative potential: complete cytoreductive surgery plus hyperthermic Intra-peritoneal chemotherapy (CCRS + HIPEC) now considered the standard of care in this pathology. The general surgeon should be aware of the governing principles of the treatment of appendiceal neoplasms with or without peritoneal dissemination, know the therapeutic frontiers in every situation (avoiding unnecessary or counterproductive surgeries) and sending early these patients to specialised centres in the radical management of malignant diseases of the peritoneum in the conditions and with the necessary information to facilitate a possible radical treatment.

Cytoreductive surgery and intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis from colorectal origin.

Peritoneal carcinomatosis (PC) is a common form of tumour metastasis stemming from gastrointestinal and colorectal cancers. For a long time, PC has been considered a terminal clinical condition treated only with palliative systemic chemotherapy and associated with very limited results. During the last decade, the treatment of advanced colorectal disease has greatly improved with the emergence of new chemotherapy drugs and biological agents. However, the median survival rates still do not surpass 24 months, even though most of these studies correspond to groups of patients with metastatic disease to the liver and/or lung. The approach and development of cytoreductive radical surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) are based on performing radical surgery of the entire visible tumour within the abdomen/peritoneum, followed immediately by HIPEC, which acts upon microscopic tumour that remains present after surgery and which is responsible for the persistence or relapse of peritoneal disease. Peritonectomy procedures are demanding surgical techniques that permit elimination of the tumour present in the peritoneal lining and any other organs and/or structures that are infiltrated. The synergistic effect of hyperthermia and chemotherapy has been well documented. Hyperthermia increases the cytotoxicity of some cytostatic agents and increases the penetration of certain drugs into the neoplastic cells. The prognosis for patients with PC who undergo combined treatment correlates with the volume of PC (tumour burden) measured as the Peritoneal Cancer Index (PCI) and the ability to perform a CRS, to completely eliminate the gross tumour. At least one phase III study and an important number of phase II studies have shown that CRS + HIPEC provides important survival benefits for patients with PC of colorectal origin. The combination of CRS + HIPEC is indicated for patients with good general health, a low PCI, absence of extra-abdominal metastasis and who can, technically, undergo CRS. The early identification of this group of patients, rapid referral to centres specialised in CRS + HIPEC, together with the correct application of this treatment, are key in achieving the best results.

Allergen profile of Protophormia terraenovae, other species of calliphoridae, and Lumbricus terrestris in anglers allergic to maggots in Cáceres, Spain.

BACKGROUND: Our group previously found that up to 7% of amateur anglers in Caceres, Spain may be allergic to the larvae of Protophormia terraenovae (order Diptera, family Calliphoridae) used as live bait for fishing. OBJECTIVE: To identify the pattern of major allergens in P terraenovae and other species of Calliphoridae. MATERIALS AND METHODS: Extracts of P terraenovae, Calliphora vomitoria, Lucilia sericata and Lumbricus terrestris were characterized using sodium dodecyl sulfate polyacrylamide gel electrophoresis and IgE-immunoblotting techniques in individual sera from 24 patients with a positive skin test result and/or specific IgE determination (enzyme-linked immunosorbent assay [ELISA]) to P terraenovae. ELISA and IgE-immunoblotting inhibition studies were also performed to identify potential cross-reactive allergens between these species. RESULTS: IgE-immunoblotting with P terraenovae showed a band of 15.3 kDa recognized by 15 patients, in addition to 2 further allergens of 22.8 kDa and 69 kDa. For C vomitoria, 5 bands of 73, 46, 40, 28, and 14 kDa were observed. For L sericata, 2 major allergens of 73 kDa and 14 kDa were observed. In the case of L terrestris, IgE from 13 patients recognized 1 allergen of around 15.5 kDa. IgE-immunoblotting and ELISA inhibition revealed the presence of cross-reactivity, mainly between L terrestris and P terraenovae. CONCLUSIONS: P terraenovae appears to have species-specific allergens and allergens shared with C vomitoria and L sericata. Striking immunological cross-reactivity was observed between P terraenovae and L terrestris. An allergen of 15-16 kDa could be involved in this phenomenon.

Panitumumab and irinotecan every 3 weeks is an active and convenient regimen for second-line treatment of patients with wild-type K-RAS metastatic colorectal cancer.

PURPOSE: To evaluate the efficacy and safety profile of the combination of panitumumab and irinotecan every 3 weeks in a phase II trial as second-line treatment in patients with advanced wild-type (WT) K-RAS colorectal cancer (CRC). METHODS: Fifty-three patients received 9 mg/kg of panitumumab followed by 350 mg/m(2) of irinotecan every 21 days until disease progression, unacceptable toxicity or consent withdrawal. RESULTS: Median age of patients included was 67 years. All patients had previously received 5-fluorouracil, 84 % oxaliplatin and 8 % irinotecan as first-line treatment. Patients received a median of five infusions of panitumumab and irinotecan. On an intention-to-treat analysis, 12 patients (23 %) achieved partial responses and 22 patients (41 %) achieved disease stabilization. Median progression-free survival and overall survival were 4.5 and 15.1 months, respectively. The most frequent treatment-related severe toxicities per patient were diarrhoea (35.8 %), followed by skin rash (32.1 %), asthenia (18.9 %) and neutropenia (13.2 %). A significant association between clinical response and incidence and grade of skin toxicity was observed (p = 0.0032). CONCLUSION: This study shows that the administration of panitumumab plus irinotecan every 3 weeks is safe, active and feasible as second-line treatment in patients with advanced WT K-RAS CRC.