Clinical relevance of gene mutations and rearrangements in advanced differentiated thyroid cancer.

BACKGROUND: Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making. MATERIALS AND METHODS: We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development. RESULTS: A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006). CONCLUSIONS: Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC.

Standard versus personalized schedule of regorafenib in metastatic gastrointestinal stromal tumors: a retrospective, multicenter, real-world study.

BACKGROUND: Despite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off). PATIENTS AND METHODS: Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan-Meier method was used to estimate survival and the log-rank test to make comparisons. RESULTS: Of a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16). CONCLUSIONS: Regorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy.

Granular cell tumor of the trachea as a rare cause of dyspnea in a young woman.

Tracheal granular cell tumors are rare neurogenic neoplasms characterized by an indolent behavior. We report the case of a young woman affected by this tumor with non-specific clinical presentation. We performed a literature search in order to identify all the cases of tracheal granular cell tumor and to summarize the current state of knowledge about this rare disease.

Assessing the feasibility of community health insurance in Uganda: A mixed-methods exploratory analysis.

Community health insurance (CHI) aims to provide financial protection and facilitate health care access among poor rural populations. Given common operational challenges that hamper the full development of the scheme, there is need to undertake systematic feasibility studies. These are scarce in the literature and usually they do not provide a comprehensive analysis of the local context. The present research intends to adopt a mixed-methods approach to assess ex-ante the feasibility of CHI. In particular, eight preconditions are proposed to inform the viability of introducing the micro insurance. A case study located in rural northern Uganda is presented to test the effectiveness of the mixed-methods procedure for the feasibility purpose. A household survey covering 180 households, 8 structured focus group discussions, and 40 key informant interviews were performed between October and December 2016 in order to provide a complete and integrated analysis of the feasibility preconditions. Through the data collected at the household level, the population health seeking behaviours and the potential insurance design were examined; econometric analyses were carried out to investigate the perception of health as a priority need and the willingness to pay for the scheme. The latter component, in particular, was analysed through a contingent valuation method. The results validated the relevant feasibility preconditions. Econometric estimates demonstrated that awareness of catastrophic health expenditures and the distance to the hospital play a critical influence on household priorities and willingness to pay. Willingness is also significantly affected by socio-economic status and basic knowledge of insurance principles. Overall, the mixed-methods investigation showed that a comprehensive feasibility analysis can shape a viable CHI model to be implemented in the local context.

Radiotherapy in the management of gist: state of the art and new potential scenarios.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. The main treatment for localized gastrointestinal stromal tumors is surgical resection. Unresectable or advanced GIST are poorly responsive to conventional cytotoxic chemotherapy but the introduction of tyrosine kinase inhibitors (TKIs) marked a revolutionary step in the treatment of these patients, radically improving prognosis and clinical benefit. Historically GIST has been considered radiation-resistant, and the role of radiotherapy in the management of patients with GIST is currently restricted to symptomatic palliation in current treatment guidelines. CASE PRESENTATION: Here we report two patients affected by metastatic GIST, treated with radiotherapy and radiosurgery in combination with TKIs, achieving an unexpected objective response in the first case and a significant clinical benefit associated with a local tumor control of several months in the second case. CONCLUSIONS: These and other successful experiences that are progressively accumulating, open up new scenarios of use of radiation therapy in various settings of treatment. GIST is not universally radioresistant and radiotherapy, especially if combined with molecularly targeted therapy, can improve the outcomes for patients diagnosed with GIST.

Successful selective arterial embolizations for bone metastases in renal cell carcinoma integrated with systemic therapies: A case report.

Herein is described the case of a 64-year-old patient affected by metastatic clear-cell carcinoma, with exclusive bone disease, subjected after the initial cytoreductive nephrectomy to 3 successive lines of medical treatment (sunitinib, everolimus, and sorafenib) and multiple locoregional treatments (spinal surgery, radiation therapy, and selective arterial embolization), resulting in a surprisingly long survival of over 75 months. In the era of target therapy, integration strategies, including additional locoregional treatment to medical therapy, are essential to optimize the clinical benefit, to maximize treatment duration overcoming focal progressive disease, and to improve the quality of life. In this context, we would highlight that selective transcatheter embolization of bone metastases from renal cell carcinoma should be considered as an effective and safe option in the palliative setting for patients with bone metastasis, especially for pain relief.

NATIVE LARVAL PARASITOIDS ASSOCIATED WITH TUTA ABSOLUTA (MEYRICK) IN GREENHOUSE TOMATO CROPS OF SOUTHERN SARDINIA.

Since its first detection in Sardinia (Italy), Tuta absoluta (Meyrick) has been reported as a major pest of greenhouse tomatoes. In recent years, however, a tendency toward a progressive reduction of tomato borer infestation levels has been observed. The reasons behind this decline are probably diverse, including both the increase in growers' ability to manage the pest and the adaptation of native predators and parasitoids to the new prey/host. In order to assess the species composition of the parasitoid complex associated with T. absoluta larvae in Sardinian greenhouse tomatoes, a two-year (2010/11) survey was conducted in one of the island's major horticultural areas (Pula, Cagliari). An estimate of the levels of parasitism caused by native wasps was also carried out. The occurrence of larval parasitoids of T. absoluta was detected in approximately half of the crops monitored. The average parasitism rate recorded in tomato plants infested by tomato borer larvae was 1.3%. Moreover, while no parasitism was observed in 76.4% of the samples collected, only 3.0% of the samples showed a parasitism rate exceeding 10%. The highest rates were recorded in spring and summer, with a peak in July (4.8%). Of 159 adult parasitoids recovered from infested leaves, 62.9% were found to belong to a Necremnus sp. near artynes (Walker), 34.6% to a Necremnus sp. near tidius (Walker), and 2.5% to Neochrysocharis formosa (Westwood) (Hymenoptera: Eulophidae). These results show that some native parasitoids have adapted to T. absoluta in the study area. Although parasitoid abundance in tomato crops appeared to be low, their contribution for the control of tomato borer infestation could possibly be enhanced through the application of conservation biological control measures.

The influence of selection for vulnerability to angling on foraging ecology in largemouth bass Micropterus salmoides.

Several traits related to foraging behaviour were assessed in young-of-the-year produced from largemouth bass Micropterus salmoides that had been exposed to four generations of artificial selection for vulnerability to angling. As recreational angling may target foraging ability, this study tested the hypothesis that selection for vulnerability to angling would affect behaviours associated with foraging ecology and prey capture success. Fish selected for low vulnerability to angling captured more prey and attempted more captures than high vulnerability fish. The higher capture attempts, however, ultimately resulted in a lower capture success for low vulnerability fish. Low vulnerability fish also had higher prey rejection rates, marginally shorter reactive distance and were more efficient at converting prey consumed into growth than their high vulnerability counterparts. Selection due to recreational fishing has the potential to affect many aspects of the foraging ecology of the targeted population and highlights the importance of understanding evolutionary effects and how these need to be considered when managing populations.

Molecular detection of epidermal growth factor receptor in colorectal cancer: does it still make sense?

AIM: The aim of the study was to detect and compare the epidermal growth factor receptor (EGFr) content using different methods, to establish whether the quantitative detection and functional study of EGFr in colorectal cancer, using methods other than immunohistochemistry (IHC), are appropriate. METHOD: Analysis of EGFr by IHC was performed in 230 colorectal cancer patients using monoclonal anti-EGFr. Total and activated EGFr (pY1068) contents were determined in 92 patients and real-time PCR, to determine the level of EGFr messenger RNA, was carried out in 60 patients. RESULTS: There was no association between EGFr IHC groups and the mean total EGFr levels measured using ELISA. CONCLUSION: The study shows that the results of different EGFr detection methods do not correlate with each other. Hence, the real role of EGFr in colorectal cancer remains unsettled. Clinically, the receptor itself does not seem to be important and it would be better to focus on EGFr signalling in downstream pathways.

Experimental results and related clinical implications of PET detection of epidermal growth factor receptor (EGFr) in cancer.

The epidermal growth factor receptor (EGFr) is one of the most studied molecules as a target for cancer therapy. Over these last few years, several studies attempting to identify predictive biomarkers of treatment response, such as the receptor status or other molecules related to the downstream signalling pathway, have been conducted. However, from a clinical point of view, the information obtained from ex vivo analyses still has various limitations that may be overcome by the combination with molecular imaging technologies which may provide a noninvasive, global, in vivo evaluation of the molecular tumour background. The aim of this review is to report the preclinical results of all positron emission tomography (PET) tracers synthesized until now for in vivo detection of EGFr in cancer. Two classes of PET compounds have been developed: labelled small molecules such as tyrosine kinase inhibitors and labelled monoclonal antibodies. The in vitro and in vivo results of these PET tracers are very different depending on the chemical properties, positron emission radionuclide, or animal models. As a consequence, various critical questions are still open, and the implications of a translation in the clinical setting for EGFr imaging in cancer patients is discussed.

Surveillance of hospital-acquired infections in Liguria, Italy: results from a regional prevalence study in adult and paediatric acute-care hospitals.

A multi-hospital prevalence study of hospital-acquired infections (HAIs) was carried out between 19 March and 6 April 2007 in Liguria, Italy, being the first to be performed in this region. Of the 29 existing public acute hospitals, 25 took part in the investigation (86.2%). In total, 3176 patients were enrolled in the study, representing a regional average bed-occupancy rate of nearly 70%. Three-hundred and ten HAIs were diagnosed from 283 patients, with an overall prevalence of infections and cases of 9.8% and 8.9%, respectively. Prevalence varied considerably between hospitals, ranging from 0 to 24.4% [95% confidence interval (CI): 15.53-33.27]. Urinary tract infections (UTIs) (30.0%) and respiratory tract infections (RTIs) (26.1%) presented the highest relative frequency, followed by bloodstream infections (BSIs) (14.8%), surgical site infections (11.6%) and gastrointestinal infections (6.5%). Intensive care units (ICUs) and haemato-oncological units showed the highest specific prevalence of HAI, respectively 42.5% (95% CI: 34.48-50.52) and 13.3% (6.28-20.32), with RTI and BSI as the predominant infections. Spinal units (33.3%; 13.14-53.46) and functional-rehabilitation units (18.9%; 17.75-24.06) demonstrated a high rate of urinary tract infections. Uni- and multivariate analyses were performed to assess the main risk factors and conditions associated with HAI, both overall and by site. Our study provides an overall picture of the epidemiology of HAI in Liguria, which may be usefully employed as a starting point to plan and organise future surveillance and control programmes.

Integrated approach to TYLCD management in Sardinia (Italy).

In Sardinia (Italy) Tomato yellow leaf curl disease (TYLCD) re-emerged in 2003, after a period of decline, producing severe yield losses in protected tomato crops. This epidemic outbreak highlighted the inadequacy of the approach to TYLCD management based chiefly on the chemical control of its vector, the whitefly Bemisia tabaci, and the use of 40-mesh nets for greenhouse screening. To evaluate the reliability of alternative practices for implementation within IP&DM programmes, in 2007 and 2008 we carried out two field experiments on greenhouse tomato crops planted in summer. In both trials we tested the use of UV-reflective mulches (UVRM) or floating row covers (NWRC), against an uncovered control on clear mulch. Furthermore, we assessed the effectiveness of acibenzolar-S-methyl, a SAR elicitor, as subplot factor in a split plot design. In 2007 because of the low incidence of the disease it was not possible to assess differences among the treatments. However a significant increase in plant growth, and production was observed in UVRM plots. By contrast, in 2008 the study crop was seriously affected by TYLCD. In the plots not treated with acibenzolar-S-methyl, the disease progression was initially slowed down in NWRC and, to a lesser extent, in UVRM plots compared to control plots but, during the second month of the cropping period, the differences among treatments became statistically not significant. In the plots treated with acibenzolar-S-methyl the dynamics of TYLCD infection during the first five weeks exhibited the same trend as in the untreated plots. Thereafter, the combination of UVRM and, to a lesser extent, of NWRC with the SAR elicitor resulted in a reduction of disease incidence with respect to the control. In conclusion, all the control measures tested in the present work showed the potential for TYLCD management in greenhouse tomatoes. However, the most promising results were achieved using UV-reflective mulch and non-woven row cover in combination with acibenzolar-S-methyl. In view of its positive impact on plant growth and yield in summer planted tomato crops, as well as on TYLCD infection, the use of UV-reflective mulch warrants further investigation.

An epidemiological survey of TYLCD in southern Sardinia (Italy).

Tomato yellow leaf curl Sardinia virus (TYLCSV) and Tomato yellow leaf curl virus (TYLCV) are among the most virulent pathogens of greenhouse tomatoes in Sardinia (Italy). To investigate the relationship between seasonal population trends of the vector Bemisia tabaci and the dynamics of TYLCD spread to susceptible crops, between May and October 2007 we carried out a survey in a tomato growing area located in the south of the island. On three farms specialized in the production of fresh market tomatoes we monitored, outside commercial greenhouses, the following parameters related to TYLCD epidemiology: mean weekly catches of the whiteflies B. tabaci and Trialeurodes voporariorum on yellow sticky traps, ratio between the two whitefly species and proportion of B. tabaci adults carrying TYLCSV/TYLCV in adult samples collected on hosts not susceptible to the disease, proportion of tomato plants infected by TYLCSV/TYLCV after a two-week exposure to open field conditions. Generally speaking, the flight activity of whiteflies increased during spring, reached a peak in May or June and gradually declined in summer. At the beginning of the survey, T. vaporariorum was found to be the prevalent species, but after a shift in composition of whitefly populations during July, B. tabaci became predominant. While the percentage of vector adults carrying the viral agents of the disease was relatively high up to July, with maximum values ranging between 14 and 25%, during the following months it decreased to less than 5%. The incidence of TYLCD in the plants exposed outside the greenhouses showed a similar trend in the sites surveyed, with two peaks roughly coinciding with the beginning and end of summer. Therefore, two distinct phases of TYLCD spread were observed: from spring to midsummer when the disease was transmitted by low 8. tabaci populations with relatively high proportions of virus carriers; from midsummer to autumn, when the disease was spread by larger vector populations with low percentages of individuals carrying the viruses. Further studies are necessary to gain a better understanding of the interactions among B. tabaci biotypes, TYLCSV/TYLCV and their hosts.

Seasonal trends of whitefly populations in a Mediterranean tomato growing area.

The whiteflies Bemisia tabaci and Trialeurodes vaporariorum and their associated viruses constitute a major threat to tomato crops in the Mediterranean region. Continuous host availability and mild climate are thought to be among the factors contributing to the outbreaks of whitefly-related problems in this area. We carried out a year-long survey to investigate the relative contribution of different plants, agricultural and not, and indoor/outdoor crops as hosts of the two whiteflies and the tomato yellow leaf curl disease (TYLCD) in a multi-crop system typical of tomato growing areas in southern Sardinia (S. Margherita di Pula, Cagliari, Italy). For this purpose, during 2005 we monitored whitefly population trends in different plots of a horticulture farm, evaluated seasonal changes in the infestation density of the two pests on the most represented host species and assessed the incidence of TYLCD on tomato crops and susceptible weeds. Whitefly catches on yellow sticky traps were found to be higher inside et along the external perimeter of greenhouses compared to open field crops or uncultivated areas, thus suggesting significant adult movement between indoor and outdoor patches. In most plots flight activity increased between late spring and late summer, peaking in July. The number of immatures of the two whitefly species showed similar dynamics, but while T. vaporariorum reached the highest densities in greenhouse tomato crops in June, peak levels of 8. tabaci were recorded between July and August in outdoor horticultural crops and weeds. The occurrence of TYLCD was detected all year round on weed hosts, but the highest number of infected plants was observed in June on long cycle tomato crops. The present survey has demonstrated the contribution of non-agricultural plants the maintenance of tomato yellow leaf curl disease in the study site. However, tomato crops established in summer as major reservoirs of TYLCD-associated viruses and presumably played a key role in the spread of the disease to autumn tomato crops. The implementation of a crop-free period between successive susceptible crops, or at least the avoiding of whitefly movement through greenhouse openings and the complete destruction of plants after final harvest, would probably reduce the severity of TYLCD epidemics in this area.

Biological agents for whitefly control in Sardinian greenhouse tomatoes.

To evaluate the effectiveness of alternative options for biocontrol of whiteflies in greenhouse tomatoes, an experiment was carried out during the cropping season 2005-2006 in one of Sardinia's major horticultural districts (S. Margherita di Pula, Cagliari, Italy). Twelve long-cycle and 17 short-cycle tomato crops (8 autumn and 9 spring crops) were surveyed. All of them were treated for insect pest control at the beginning of the growing season, but in 19 out of 29 cases whitefly natural enemies were also released (BCA greenhouses), at least four weeks after the last treatment. The following release programmes were tested: on autumn crops, 1 Macrolophus caliginosus and 12 Eretmocerus mundus/m2; on long-cycle crops, 1 M. caliginosus (released in autumn or spring) and 24 Encarsia formosa/m2 or 48 E. formosa/m2; on spring crops, 1 M. caliginosus and 24 E. formosa/m2 or 48 E. formosa/m2. The cost of each option was fixed at approximately 0.25 Euros/m2. The remaining greenhouses were maintained as controls (no BCA greenhouses). While whitefly and mirid populations were monitored monthly, whitefly species composition and mortality of immature stages were estimated at least twice during the growing season. On short-cycle autumn crops, the release of M. caliginosus and E. mundus produced negligible results in terms of Bemisia tabaci control. On long-cycle and spring crops, even though in June mortality rates in BCA greenhouses were found to be 2- to 3-fold higher than in no-BCA greenhouses, Trialeurodes vaporariorum population growth was not significantly affected by natural enemies. Among the beneficials tested, E. formosa proved to be the most effective; E. mundus and M. caliginosus did not establish well, probably owing to the persistence of insecticide residues, scarce prey availability and intense plant de-leafing. The presence of indigenous natural enemies of whiteflies was observed in most sites, but in general they contributed little to biological control. The present experiment showed that in Sardinian tomato greenhouses the use of beneficial insects may result in inadequate biocontrol of whiteflies. In particular, the application of cultural practices which may disrupt the establishment and development of predator and parasitoid populations should be critically reexamined.

Molecular imaging suggests efficacy of bevacizumab beyond the second line in advanced colorectal cancer patients.

We report the clinical history of a female affected by advanced colorectal cancer (CRC). The patient was treated with five subsequent therapeutic schedules (FOLFIRI, FOLFOXIRI, FOLFIRI, FOLFOX4, FOLFOX4 plus cetuximab) because of the progression of the disease. The sixth treatment was bevacizumab in combination with 5-fluorouracil and irinotecan (FOLFIRI). The CT scan and the FDG-PET/CT performed 3 months after the beginning of the treatment showed that some, even if not all, lesions had a reduction of both size and metabolic activity. After the second revaluation the disease progressed. This short report suggests that the response of CRC to antiangiogenetic therapy may also occur after several unsuccessful antineoplastic treatments. Different biological features may explain the nonhomogeneous objective response of the metastatic lesions. Molecular imaging techniques seem to be mandatory in the era of tailored therapy since it is useful to have an in vivo 'biological picture' of the neoplastic disease.

Gene expression profiling of liver metastases from colorectal cancer as potential basis for treatment choice.

At present no reports on gene expression profiling of liver metastases from colorectal cancer are available. We identified two different signatures using Affymetrix platform: epidermal growth factor receptor pathway was upregulated in metachronous lesions, whereas the pathway mainly related to angiogenesis was in synchronous lesions. Synchronous or metachronous liver metastases could be treated differently on the basis of different molecular pathways.

Molecular imaging and targeted therapies in oncology: new concepts in treatment response assessment. a collection of cases.

The widespread use of several new non-cytotoxic drugs and the significant improvements in functional imaging highlights a number of difficulties in monitoring, interpreting and predicting treatment response in clinical practice. Certain guidelines for disease assessment after therapy are already available: the traditional Response Evaluation Criteria in Solid Tumours guidelines based on tumour size variations using conventional imaging technologies, the recent combined method developed by Choi and colleagues in gastrointestinal stromal tumour treated with tyrosine kinase inhibitors based on tumour density variations using computed tomography (CT), and the European Organization for Research and Treatment of Cancer criteria based on tumour glucose metabolism variations using fluorodeoxyglucose (FDG) positron emission tomography (PET). At the moment combined PET/CT response criteria are still not available. A number of new PET compounds other than FDG are also currently being developed to visualize specific cellular and molecular tumour pathways but their role in assessment and prediction of cancer treatment response has not yet been thoroughly investigated in a large series. However, in clinical practice many oncologists treat cancer patients with targeted therapies or chemotherapy and evaluate the response using conventional or functional imaging without appropriate and standardized guidelines. The aim of this study was to present a selection of clinical cases that illustrate the usefulness of new PET tracers and efficacy evaluation of new drugs. In the era of molecular imaging and molecular therapies, these cases highlight the urgency to develop new criteria for treatment assessment and the exigency of correctly interpreting the biological information obtained from new technologies, and introduce new concepts that require further investigation in clinical trials.