Strategies to tackle RAS-mutated metastatic colorectal cancer.

The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as 'undruggable'. Recently, novel specific KRASG12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRASG12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRASG12C. In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC.

The DNA damage response pathway as a land of therapeutic opportunities for colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) represents a major cause of cancer deaths worldwide. Although significant progress has been made by molecular and immune therapeutic approaches, prognosis of advanced stage disease is still dismal. Alterations in the DNA damage response (DDR) pathways are emerging as novel targets for treatment across different cancer types. However, even though preclinical studies have shown the potential exploitation of DDR alterations in CRC, systematic and comprehensive testing is lagging and clinical development is based on analogies with other solid tumors according to a tissue-agnostic paradigm. Recently, functional evidence from patient-derived xenografts and organoids have suggested that maintenance with PARP inhibitors might represent a therapeutic opportunity in CRC patients previously responsive to platinum-based treatment. DESIGN AND RESULTS: In this review, we highlight the most promising preclinical data and systematically summarize published clinical trials in which DDR inhibitors have been used for CRC and provide evidence that disappointing results have been mainly due to a lack of clinical and molecular selection. CONCLUSIONS: Future preclinical and translational research will help in better understanding the role of DDR alterations in CRC and pave the way to novel strategies that might have a transformative impact on treatment by identifying new therapeutic options including tailored use of standard chemotherapy.

Percutaneous ablation techniques for renal cell carcinoma: current status and future trends.

Percutaneous ablation is an increasingly applied technique for the treatment of localized renal tumors, especially for elderly or co-morbid patients, where co-morbidities increase the risk of traditional nephrectomy. Ablative techniques are technically suited for the treatment of tumors generally not exceeding 4 cm, which has been set as general consensus cutoff and is described as the upper threshold of T1a kidney tumors. This threshold cutoff is being challenged, but with still limited evidence. Percutaneous ablation techniques for the treatment of renal cell carcinoma (RCC) include radiofrequency ablation, cryoablation, laser or microwave ablation; the main advantage of all these techniques over surgery is less invasiveness, lower complication rates and better patient tolerability. Currently, international guidelines recommend percutaneous ablation either as intervention for frail patients or as a first line tool, provided that the tumor can be radically ablated. The purpose of this article is to describe the basic concepts of percutaneous ablation in the treatment of RCC. Controversies concerning techniques and products and the need for patient-centered tailored approaches during selection among the different techniques available will be discussed.

Increased incidence of colon cancer among individuals younger than 50 years: A 17 years analysis from the cancer registry of the municipality of Milan, Italy.

BACKGROUND: Colorectal cancer (CRC) overall incidence has been decreasing in the last decade. However, there is evidence of an increasing frequency of early-onset CRC in young individuals in several countries. The aim of this study is to evaluate the trends of CRC occurrence over 17 years in the municipality of Milan, Italy, focusing on early-onset CRC. POPULATION AND METHODS: This retrospective study was performed using the Cancer Registry of the municipality of Milan, including all cases of CRC diagnosed 1999-2015. Incidence rates were stratified by age and anatomic subsite, and trends over time were measured using the estimated annual percentage change. Age-period-cohort modelling was used to disentangle the different effects. RESULTS: 18,783 cases of CRC were included. CRC incidence rates among individuals aged 50-60 years declined annually by 3% both in colon and in rectal cancer. Conversely, in adults younger than 50 years, overall CRC occurrence increased annually by 0.7%, with a diverging trend for colon (+2.6%) and rectal (-5.3%) cancer. Among individuals aged 60 years and older, CRC incidence rates increased by 1.0% annually up to 2007, and decrease thereafter by 4% per year, both for colon and rectal cancer. Age-period-cohort models showed a reduction of CRC risk for the cohorts born up to 1979, followed by an increase in younger cohorts. In contrast, rectal cancer among women showed a systematic risk decrease for all birth cohorts. CONCLUSIONS: The study highlights increasing incidence of colon cancer in younger subjects and a decrease in incidence rates for rectal cancer in females.

Treatments for colorectal liver metastases: A new focus on a familiar concept.

A major challenge for the management of advanced-colorectal-cancer is the multidisciplinary approach required for the treatment of liver metastases. Reducing the burden of liver metastases with liver-directed therapy has an important impact on both survival and health-related quality of life. This paper debates the rationale and current liver-directed approaches for colorectal liver metastases based on the evidence of literature and new clinical trials. Surgery is the gold standard, when feasible, and it's the main treatment goal for patients with potentially-resectable disease as a means of prolonging progression-free survival. Better tumor response rates with modern systemic therapy mean that more unresectable patients are now down-staged for radical resection following conversion therapy but for other patients, additional procedures are needed. In multiple unilobar disease, when the projected remnant liver is <30% of the total liver, portal embolization or selective-internal-radiation-therapy (SIRT) can induce hypertrophy of the healthy liver, leading to resectability. In multiple bilobar disease, in situ destruction of non-resectable lesions by minimally invasive techniques may be associated with liver resection to achieve potential curative intent. Other palliative liver-directed approaches, such as SIRT or intra-hepatic chemotherapy (HAI), which are associated with higher response rates, may also have role in down-staging patients for resection. Until recently, such technologies have not been validated in prospective controlled trials. However in the light of new Phase 3 data for SIRT as well as for HAI combined with modern therapies or radiofrequency ablation in the first- and second-line setting, the clinical value of these treatments needs to be re-appraised.

Healthy and tumoral tissue resistivity in wild-type and sparc-/- animal models.

Despite the technological improvement of radiologic, endoscopic and nuclear imaging, the accuracy of diagnostic procedures for tumors can be limited whenever a mass-forming lesion is identified. This is true also because bioptical sampling cannot be properly guided into the lesions so as to puncture neoplastic tissue and to avoid necrotic areas. Under these circumstances, invasive and expensive procedures are still required to obtain diagnosis which is mandatory to plan the most appropriate therapeutic strategy. In order to test if electrical impedance spectroscopy may be helpful in providing further evidence for cancer detection, resistivity measurements were taken on 22 mice, 11 wild-type and 11 sparc-/- (knock out for the protein SPARC: secreted protein acidic and rich in cysteine), bearing mammary carcinomas, by placing a needle-probe into tumor, peritumoral and contralateral healthy fat areas. Tumor resistivity was significantly lower than both peritumoral fat and contralateral fat tissues. Resistivity in sparc-/- mice was lower than wild-type animals. A significant frequency dependence of resistivity was present in tissues analyzed. We conclude that accurate measurements of resistivity may allow to discriminate between tissues with different pathological and/or structural characteristics. Therefore, resistivity measurements could be considered for in vivo detection and differential diagnosis of tumor masses.

Outcomes and Risk Factors for Complications of Laser Ablation for Thyroid Nodules: A Multicenter Study on 1531 Patients.

BACKGROUND: Image-guided laser ablation therapy (LAT) of benign thyroid nodules demonstrated favorable results in randomized trials with fixed modalities of treatment. The aim of this retrospective multicenter study was to assess the effectiveness, tolerability, and complications of LAT in a large consecutive series of patients from centers using this technique in their routine clinical activity. PATIENTS: Clinical records of 1534 consecutive laser-treated nodules in 1531 patients from eight Italian thyroid referral centers were assessed. Inclusion criteria were as follows: solid or mixed nodules with fluid component up to 40%; benign cytological findings; and normal thyroid function. METHODS: LAT was performed with a fixed-power protocol, whereas the number of applicators and illumination times were different according to target size. From one to three illuminations with pullback technique and with a total energy delivery based on the nodule volume were performed during the same session. Patients were evaluated during LAT, within 30 days, and 12 months after the procedure. RESULTS: Total number of treatments was 1837; 1280 (83%) of nodules had a single LAT session. Mean nodule volume decreased from 27 ± 24 mL at baseline to 8 ± 8 mL 12 months after treatment (P < .001). Mean nodule volume reduction was 72% ± 11% (range 48%-96%). This figure was significantly greater in mixed nodules (79% ± 7%; range 70%-92%) because they were drained immediately before laser illumination. Symptoms improved from 49% to 10% of cases (P < .001) and evidence of cosmetic signs from 86% to 8% of cases (P < .001). Seventeen complications (0.9%) were registered. Eight patients (0.5%) experienced transitory voice changes that completely resolved at the ear-nose-throat examination within 2-84 days. Nine minor complications (0.5%) were reported. No changes in thyroid function or autoimmunity were observed. CONCLUSIONS: Real practice confirmed LAT as a clinically effective, reproducible, and rapid outpatient procedure. Treatments were well tolerated and risk of major complications was very low.

PET/CT-guided percutaneous liver mass biopsies and ablations: targeting accuracy of a single 20 s breath-hold PET acquisition.

AIM: To determine whether a single 20 s breath-hold positron-emission tomography (PET) acquisition obtained during combined PET/computed tomography (CT)-guided percutaneous liver biopsy or ablation procedures has the potential to target 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG)-avid liver masses as accurately as up to 180 s breath-hold PET acquisitions. MATERIALS AND METHODS: This retrospective study included 10 adult patients with 13 liver masses who underwent FDG PET/CT-guided percutaneous biopsies (n = 5) or ablations (n = 5). PET was acquired as nine sequential 20 s, monitored, same-level breath-hold frames and CT was acquired in one monitored breath-hold. Twenty, 40, 60, and 180 s PET datasets were reconstructed. Two blinded readers marked tumour centres on randomized PET and CT datasets. Three-dimensional spatial localization differences between PET datasets and either 180 s PET or CT were analysed using multiple regression analyses. Statistical tests were two-sided and p < 0.05 was considered significant. RESULTS: Targeting differences between 20 s PET and 180 s PET ranged from 0.7-20.3 mm (mean 5.3 ± 4.4 mm; median 4.3) and were not statistically different from 40 or 60 s PET (p = 0.74 and 0.91, respectively). Targeting differences between 20 s PET and CT ranged from 1.4-36 mm (mean 9.6 ± 7.1 mm; median 8.2 mm) and were not statistically different from 40, 60, or 180 s PET (p = 0.84, 0.77, and 0.35, respectively). CONCLUSION: Single 20 s breath-hold PET acquisitions from PET/CT-guided percutaneous liver procedures have the potential to target FDG-avid liver masses with equivalent accuracy to 180 s summed, breath-hold PET acquisitions and may facilitate strategies that improve image registration and shorten procedure times.

Tips and tricks for a correct "endo approach".

The world is facing an epidemic of diabetes, consequently in the next years critical limb ischemia due to diabetic artery disease will become a major issue for vascular and endovascular operators. Revascularization is a key therapy in these patients because reestablishing an adequate blood supply to the wound is essential for healing avoiding a major amputation. In this paper, we summarize our experience in endovascular treatment of diabetic critical limb ischemia, focusing of the main technical challenges in treating below-the-knee vessels. We describe the following topics: 1) targets of the revascularization therapy: "complete" versus "partial" revascularization and the concept of wound related artery. Every procedure must be tailored on technically realistic strategies and on the general patient status; 2) the antegrade femoral access using both, the X-ray and the ultrasound guided techniques; 3) the chronic total occlusions crossing strategy proposing a step-by-step approach: endoluminal, subintimal, retrograde approaches. Particular attention has been given to the different retrograde approaches: pedal-plantar loop technique, trans-collateral approaches and the different types of retrograde puncture. For each step we provide a complete description of the technical details and of the suitable devices. Eventually we in brief describe: 3) acute result optimization and 4) prevention of restenosis.

Combination of gene expression and genome copy number alteration has a prognostic value for breast cancer.

Specific genome copy number alterations, such as deletions and amplifications are an important factor in tumor development and progression, and are also associated with changes in gene expression. By combining analyses of gene expression and genome copy number we identified genes as candidate biomarkers of BC which were validated as prognostic factors of the disease progression. These results suggest that the proposed combined approach may become a valuable method for BC prognosis.

Percutaneous laser ablation of metastatic lymph nodes in the neck from papillary thyroid carcinoma: preliminary results.

CONTEXT: Percutaneous laser ablation (PLA) may be useful in treating patients with metachronous metastatic lymph nodes in the neck. OBJECTIVE: Our objective was to assess PLA as a treatment of difficult-to-treat metachronous cervical lymph node metastases from papillary thyroid carcinoma. DESIGN AND SETTING: We conducted a retrospective analysis of prospectively collected data at a public hospital. PATIENTS: Fifteen patients with previous resection of papillary thyroid carcinoma with elevated serum levels of thyroglobulin (Tg) or anti-Tg antibodies (TgAbs) and 24 metachronous nodal metastases treated between September 2010 and April 2012 were followed with [¹8F]fluorodeoxyglucose (¹8FDG) positron emission tomography (PET)/computed tomography (CT) and contrast-enhanced ultrasound (CEUS). INTERVENTION: Intervention was PLA. OUTCOME MEASURES: Technique feasibility and technical success were evaluated. Tg/TgAb serum levels and ¹8FDG-PET/CT, and CEUS appearance were assessed at 6 and 12 months and compared with baseline. Complications were recorded. RESULTS: PLA was always feasible, and technical success was achieved in all patients. At 6 months, local control was achieved in 11 of 15 patients (73%), with 6 (40%) having serum Tg/TgAb normalized (P = .017 vs baseline). Whereas 20 of 24 (83%) nodes were negative at ¹8FDG-PET/CT and CEUS (P < .001 vs baseline), 4 were ¹8FDG-PET/CT-positive (3 also CEUS-positive). At the 12-month follow-up, local control was achieved in 10 of 14 patients (71.4%). Sixteen of 20 nodes (80%) were negative at ¹8FDG-PET/CT and CEUS (P < .001 vs baseline), 4 were ¹8FDG-PET/CT-positive (2 also CEUS-positive). Four of 10 (40%) patients had normalization of serum Tg/TgAb (P = .098 vs baseline). No major complications occurred. CONCLUSIONS: PLA is potentially feasible, safe, and effective for the treatment of metachronous cervical nodal metastases from papillary thyroid carcinoma. This procedure may reduce or delay a large number of highly invasive repeat neck dissections.

[Osteopetrosis ( Albers-Schönberg disease ). II. Personal contribution]. / L'osteopetrosi (malattia di Albers-Schönberg). Nota II Contributo personale

Five cases of marble bones in two families living near Brescia are presented. Case 1 (42-yr-old female) was a typical malignant form with deep and extensive eburnation, many pathological fractures, concomitant osteitis and the formation of many fistulae, massive spleen enlargement and infarct, and marked anaemia with clear signs of extra-medullary haemopoiesis. The patient died 5 yr after her first admission. Two of her brothers had had an identical, fatal form. Case 4 (28-yr-old male) was much the same: virtually general osteosclerosis despite the difference in age, marked spleen enlargement, a history of fractures, serious anaemia and extramedullary haemopoiesis. Benign pictures were seen in cases 2 and 3 (73- and 68-yr-old females). In case 5 (25-yr-old male), typical bone condensation was the only significant pathological sign. It is suggested that this, too, may be seen as a "benign" form.