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Cancer treatment is increasingly focused on targeting molecular alterations identified across different tumor histologies. While some oncogenic drivers such as microsatellite instability (MSI) and NTRK fusions are actionable with the very same approach regardless of tumor type ("histology-agnostic"), others require histology-specific therapeutic adjustment ("histology-tuned") by means of adopting specific inhibitors and ad hoc combinations. Among histology-agnostic therapies, pembrolizumab or dostarlimab demonstrated comparable activity in MSI metastatic colorectal cancer (mCRC) as in other tumors with MSI status (ORR 38% vs 40% and 36% vs 39%, respectively), while entrectinib or larotrectinib proved effective in NTRK rearranged mCRC even though less dramatically than in the overall population (ORR 20% vs 57%, and 50% vs 78%, respectively). Histology-tuned approaches in mCRC are those targeting BRAFV600E mutations and ERBB2 amplification, highlighting the need of simultaneous anti-EGFR blockade or careful choice of companion inhibitors in this tumor type. Anti-RET and anti-ALK therapies emerged as a potential histology-agnostic indications, while anti- KRASG12C strategies could develop as future histology-tuned therapies. Targeting of ERBB2 mutations and NRG1 fusion provided discrepant results. In conclusion, agnostic targets such as MSI and NTRK fusions are already exploitable in mCRC, while the plethora of emerging histology-tuned targets represent a challenging opportunity requiring concurrent evolution of molecular diagnostic tools. [ABSTRACT FROM AUTHOR]

• Making the best from standard treatments might improve mCRC patients' survival. • Anti-EGFR rechallenge emerged as an active therapeutic strategy in mCRC patients. • ctDNA safely and timely predicts patients benefitting from this clinical approach. • Further data from ongoing ctDNA-guided phase III trials are soon expected. Despite recent molecular and immunological advancements, prognosis of metastatic colorectal cancer (mCRC) patients remains poor. In this context, several retrospective and phase II studies suggested that after failure of an upfront anti-EGFR based regimen, a subset of patients can still benefit from further anti-EGFR blockade. Several translational studies involving circulating tumor DNA (ctDNA) analysis demonstrated that cancer clones harboring mutations driving anti-EGFR resistance, which can arise under anti-EGFR agents selective pressure, often decay after anti-EGFR discontinuation potentially restoring sensitivity to this therapeutic strategy. Accordingly, several retrospective analyses and a recent prospective trial demonstrated that ctDNA RAS and BRAF wild-type mCRC patients are those benefitting the most from anti-EGFR rechallenge. Indeed, in molecularly selected patients, anti-EGFR rechallenge strategy achieved up to 30 % response rate, with a progression free survival longer than 4 months and an overall survival longer than 1 year, which favorably compared with other standard therapeutic options available for heavily pretreated patients. Anti-EGFR is also well tolerated with no unexpected toxicities compared to the upfront setting. However, several open questions remain to be addressed towards a broader applicability of anti-EGFR strategy in the everyday clinical practice such as the identification of the best rechallenge regimen, the right placement in mCRC therapeutic algorithm, the best ctDNA screening panel. In our systematic review, we revised available data from clinical trials assessing anti-EGFR rechallenge activity in chemo-refractory mCRC patients, discussing as well potential future scenarios and development to implement this therapeutic approach. Particularly, we discussed the role of ctDNA as a safe, timely and comprehensive tool to refine patient's selection and the therapeutic index of anti-EGFR rechallenge. [ABSTRACT FROM AUTHOR]

Proboscis lateralis (PL) is a rare malformation, reported for the first time in 1861 by Forster in his monograph on congenital malformations of the human body. The abnormal side of the nose is represented by a tube-like rudimentary nasal structure, attached at any point along the embryonic fusion line between the anterior maxilla and the frontonasal processes. As clefts of the lip (and alveolus) are bilateral or unilateral, an arrhinia can be bilateral (total) or unilateral. In this case it is a 'hemi-arrhinia' (or heminasal agenesis. The arrhinias represent three groups of anomalies, each with different levels of clinical severity, some involving association with the labio-palatal cleft or agenesia of the premaxilla (1). In PL the nasal cavity on the affected side is replaced by a tubular appendage located off-center from the midline of the face, arising commonly from the medial aspect of the roof of the orbit (2). It is usually associated with heminasal aplasia or hypoplasia, microphthalmia, and — less commonly — with midline clefting. Associated brain and cranial vault anomalies are seen in 19% of these patients. PL is usually unilateral, with very few symmetrical/bilateral cases being reported (3). Morpho-aesthetic and psychological problems are frequent concerns for the patients and their families. In this study, the authors describe a clinical case and the chosen surgical technique, as well as reviewing the alternative techniques present in the literature. [ABSTRACT FROM AUTHOR]

Background: Despite advances in precision oncology and immunotherapy of tumors, little progress has been made in metastatic colorectal cancer (mCRC) in recent years. Therefore, making the most of available therapies is a necessity. Several studies, based on the pulsatile behavior of RAS clones under EGFR blockade, investigated whether readministration of EGFR-targeted agents is effective beyond second line.Methods: A systematic review of studies of retreatment with anti-EGFR monoclonal antibodies has been performed from January 2005 to December 2018 according to PRISMA criteria from PubMed, ESMO and ASCO meetings libraries and Clinicaltrial.gov. Efficacy has been evaluated as objective response rate and survival in available publications. In addition, type and incidence of side effects occurring during on anti-EGFR retreatment have been considered.Results: 26 publications have been retrieved, of which 20 full-text articles and 6 abstracts and categorized as for the retreatment strategy into five groups: rechallenge (n = 10), reintroduction (n = 4), sequence (n = 5), dose escalation (n = 1) and mixed (n = 6). Data of efficacy displayed high heterogeneity across different strategies (objective response rate, ORR = 0.0-53.8%; disease control rate, DCR = 24.0-89.7%), with best results in the setting of rechallenge (ORR = 2.9-53.8%; DCR = 40.0-89.7%).Conclusions: Rechallenge with anti-EGFR provides clinical benefit in molecularly selected mCRC patients beyond second line. Further ctDNA-guided studies comparing this option of treatment with current approved advanced line treatments are warranted. [ABSTRACT FROM AUTHOR]

Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC. [Display omitted] [ABSTRACT FROM AUTHOR]

Background O(6)-methylguanine-DNA-methyltransferase (MGMT) is a repair protein, and its deficiency makes tumours more susceptible to the cytotoxic effect of alkylating agents. Five clinical trials with temozolomide or dacarbazine have been performed in metastatic colorectal cancer (mCRC) with selection based on methyl-specific PCR (MSP) testing with modest results. We hypothesised that mitigated results are consequences of unspecific patient selection and that alternative methodologies for MGMT testing such as immunohistochemistry (IHC) and digital polymerase chain reaction (PCR) could enhance patient enrolment. Patients and methods Formalin-fixed paraffin embedded archival tumour tissue samples from four phase II studies of temozolomide or dacarbazine in MGMT MSP-positive mCRCs were analysed by IHC for MGMT protein expression and by methyl-BEAMing (MB) for percentage of promoter methylation. Pooled data were then retrospectively analysed according to objective response rate, progression-free survival (PFS) and overall survival (OS). Results One hundred and five patients were included in the study. Twelve had achieved partial response (PR) (11.4%), 24 stable disease (SD; 22.9%) and 69 progressive disease (PD; 65.7%). Patients with PR/SD had lower IHC scores and higher MB levels than those with PD. MGMT expression by IHC was negatively and MB levels positively associated with PFS (p < 0.001 and 0.004, respectively), but not with OS. By combining both assays, IHC low/MB high patients displayed an 87% reduction in the hazard of progression (p < 0.001) and a 77% in the hazard for death (p = 0.001). Conclusion In mCRC selected for MGMT deficiency by MSP, IHC and MB testing improve clinical outcome to alkylating agents. Their combination could enhance patient selection in this setting. [ABSTRACT FROM AUTHOR]

In metastatic colorectal cancer (mCRC), fluorouracil-based combination therapy with oxaliplatin or irinotecan is the mainstay of first-line treatment. Patient survival has been significantly improved with the introduction of monoclonal antibodies against VEGF (bevacizumab), VEGFR2 (ramucirumab) or EGFR (cetuximab or panitumumab) in first- and second-line therapies. However, all patients treated with chemotherapy and targeted therapies will eventually relapse, and recently the emergence of alterations in EGFR, RAS, BRAF, ERB-B2, MET and possibly in other genes has been shown to jeopardize response to EGFR blockade. In chemorefractory patients, multikinase inhibition with regorafenib has proved to be effective and rechallenge with chemotherapy or anti-EGFR agents is empirically pursued. This review will critically discuss how the evolving knowledge of mechanisms of resistance driven by intratumoural dynamic molecular heterogeneity can impact on rational choice of treatments in this setting. [ABSTRACT FROM AUTHOR]

Purpose: The literature reports that flapless compared with traditional implant surgery can be associated with several advantages, including the maintenance of peri-implant hard tissues. This study investigated vertical bone resorption during long-term follow-up after implant placement with flapless versus traditional surgery.Material and Methods: In this prospective, randomized controlled clinical trial, 40 patients underwent implant placement at the Maxillofacial Department Surgery of the Istituto Stomatologico Italiano Hospital in Milan, Italy. Patients were randomly assigned to the control or experimental group. The control group had implants placed with open flap surgery (traditional surgery), whereas the experimental group had implants placed with flapless surgery. The distance between the first implant thread and the marginal crestal bone level was measured at the basal, loading, and long-term control points. The basal recording was performed just after implant placement. The loading measurement was recorded at the time of implant loading, after 2 months of healing for the lower jaw and after 3 months of healing for the upper jaw, and the long-term control record was registered 36 months after implant placement. Statistical analysis was performed using mean values and standard deviations based on bone resorption in the 2 groups. To detect statistical differences, the Student t test was applied. Differences were considered significant if P values were less than .05.Results: The control group (open flap surgery) was comprised of 19 patients, and the experimental group (flapless surgery) was comprised of 21 patients. No statistical differences were found in peri-implant bone resorption between the 2 groups at the basal, implant loading, and 3-year control recordings.Conclusion: According to this study, the approach to implant surgery does not seem to influence peri-implant bone resorption in humans, at least for the period measured in this study. [ABSTRACT FROM AUTHOR]

Background: We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2-amplified metastatic colorectal cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer.Methods: HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33.Findings: Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51-127), eight (30%, 95% CI 14-50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI -3 to 11) achieving a complete response, and seven (26%, 95% CI 9-43) achieving partial responses; 12 (44%, 95% CI 25-63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events.Interpretation: The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer.Funding: Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche. [ABSTRACT FROM AUTHOR]

ERBB2 amplification is a driver oncogenic alteration in many cancers and it has recently been incorporated among therapeutically actionable biomarkers also in metastatic colorectal cancer (mCRC). In contrast, the role of ERBB2 point mutations, which are detectable in up to 3% of CRC patients, remains to be assessed. In this systematic review, we collected preclinical and clinical data addressing the role of ERBB2 point mutations in mCRC patients as a predictive biomarker for anti-EGFR and anti-HER2 targeted agents, and as mechanism of acquired resistance to ERBB2 amplified mCRC treated with any anti-HER2 regimen. In both preclinical and clinical studies, most ERBB2 point mutations were associated with resistance to anti-EGFR agents, particularly L755S and R784G, which occur in the HER2 protein kinase domain. No ERBB2 mutation was associated with tumor response to HER2-targeted agents in mCRC patients, although signals of activity were observed in preclinical models. Eight ongoing clinical trials are underway to test different anti-HER2 treatments in ERBB2 mutant mCRC. Several reports documented the emergence of ERBB2 mutations in the circulating tumor DNA (ctDNA) of ERBB2 amplified mCRC progressing to anti-HER2 agents, thus hinting a role in acquired resistance. [ABSTRACT FROM AUTHOR]

Abstract: Highly ordered A–B–A block copolymer arrangements in the submicrometric scale, resulting from dewetting and solvent evaporation of thin films, have inspired a variety of new applications in the nanometric world. Despite the progress observed in the control of such structures, the intricate scientific phenomena related to regular patterns formation are still not completely elucidated. SEBS is a standard example of a triblock copolymer that forms spontaneously impressive pattern arrangements. From macroscopic thin liquid films of SEBS solution, several physical effects and phenomena act synergistically to achieve well-arranged patterns of stripes and/or droplets. That is, concomitant with dewetting, solvent evaporation, and Marangoni effect, Rayleigh instability and phase separation also play important role in the pattern formation. These two last effects are difficult to be followed experimentally in the nanoscale, which render difficulties to the comprehension of the whole phenomenon. In this paper, we use computational methods for image analysis, which provide quantitative morphometric data of the patterns, specifically comprising stripes fragmentation into droplets. With the help of these computational techniques, we developed an explanation for the final part of the pattern formation, i.e. structural dynamics related to the stripes fragmentation. [ABSTRACT FROM AUTHOR]

Purpose: HER2 alterations are potential candidates for targeted treatments in metastatic urothelial/bladder cancer (mUC). ERBB2 gene amplification and mutations are found in around 6% and 4% of mUC, respectively.Methods: This is a systematic review of clinical trials evaluating HER2-targeting (amplification and mutations) in mUC. We assigned each study to one of the following strategies: HER2-targeting with single agents, anti-HER2 agents in combination with cytotoxic chemotherapy, dual HER2 blockade, HER2-targeted antibody-drug conjugates (ADCs), and other novel therapeutic approaches.Results: 36 clinical trials (17 with results and 19 ongoing) were included. As for ERBB2 amplification, anti-HER2 single agents (5 studies) and combinations with chemotherapy (4 studies) failed to provide any benefit, whereas dual HER2 blockade through monoclonal antibodies proved active in one trial in pretreated patients. Two studies assessed single-agent targeting for ERBB2 mutations with negative results. Most promising data come from 2 studies with ADCs in ERBB2 amplified tumors (disitamab-vedotin and trastuzumab-duocarmazine), while 2 other studies with TDM-1 and ADCT-502 was discontinued due to toxicity. In this category, trastuzumab-deruxtecan and other ADCs are still under investigation for either ERBB2-amplified or mutated mUC. Novel approaches include ADCs with immunotherapy (1 study with results), CAR-T cells, and HER2-sensitising vaccines.Conclusions: ERBB2 amplification could become a novel target in mUC, although the magnitude of clinical benefit remains to be clarified. To this regard, novel ADCs are the most promising strategy. ERBB2 mutations are still at very early stage of clinical study. [ABSTRACT FROM AUTHOR]

Objective: This article shows the in vitro and in vivo characterization of a new biomimetic treatment developed to enhance the osseointegration of titanium dental implants. Study design: A novel biomimetic treatment of titanium was developed. Its physicochemical properties and biologic and in vivo performance were considered and studied. Mineralization capability was assessed by soaking test in simulated body fluid solution, and cytocompatibility was assessed using osteoblast-like MG63 cell culture. Histomorphometric analysis was performed at 3 time points using a sheep animal model. Results: In vitro tests confirmed the biomimetic potential of the considered novel treatment. Histomorphometric analysis indicated its potential for rapid and good-quality osseointegration. Conclusion: The in vitro and in vivo test results indicated that the proposed novel treatment possesses a significant potential to increase the rate of osteointegration of titanium for endosseous dental implants. [Copyright &y& Elsevier]

Background: Oxaliplatin represents a main component of cytotoxic treatment regimens in colorectal cancer (CRC). Given its efficacy, oxaliplatin is frequently re-administered in the context of the continuum of care in metastatic CRC (mCRC). However, efficacy and tolerability of this therapeutic strategy has not been comprehensively assessed.Methods: We performed a systematic review of the literature on September 19th 2020, according to PRISMA criteria 2009. The research was performed on PubMed, ASCO Meeting Library, ESMO library and ClinicalTrials.gov for citations or ongoing trials.Results: 64 records were retrieved and 13 included in the systematic review: 8 full-text articles, 4 abstracts and 1 ongoing clinical trial. According to readministration timing, studies were classified as rechallenge/reintroduction (n = 8) or stop & go/intermittent therapeutic strategies (n = 4). The studies presented wide heterogeneity in terms of efficacy (Response Rate 6-31%; Disease Control Rate 39-79%; median Progression-Free Survival 3.1-7 months). Those patients who received retreatment after prior adjuvant oxaliplatin or exploiting a stop-&-go strategy appeared to achieve better outcomes. However, no formal comparisons on treatment outcomes were feasible. The most frequent grade 3 or higher adverse events were hematologic toxicities (5-27%), peripheral neuropathy (5-14%) and hypersensitivity reactions (5-20%).Conclusions: Retreatment with oxaliplatin for mCRC is practiced based on scarce and heterogeneous data indicating efficacy and manageable toxicity. The best strategy to exploit this approach remains to be defined, and the most promising research avenue to improve therapeutic index of oxaliplatin is represented by selection of responder patients whose tumors harbor molecular defects in the DNA damage repair pathway. [ABSTRACT FROM AUTHOR]

Background: The management of locally advanced rectal cancer (RC) is an evolving clinical field where the multidisciplinary approach can reach its best, and liquid biopsy for obtaining tumor-derived component such as circulating tumor DNA (ctDNA) might provide complementary informations.Methods: A systematic review of studies available in literature of liquid biopsy in non-metastatic RC has been performed according to PRISMA criteria to assess the role of ctDNA as a diagnostic, predictive and prognostic biomarker in this setting.Results: Twenty-five publications have been retrieved, of which 8 full-text articles, 7 abstracts and 10 clinical trials. Results have been categorized into three groups: diagnostic, predictive and prognostic. Few but promising data are available about the use of liquid biopsy for early diagnosis of RC, with the main limitation of sensitivity due to low concentrations of ctDNA in this setting. In terms of prediction of response to chemoradiation, still inconclusive data are available about the utility of a pre-treatment liquid biopsy, whereas some studies report a positive correlation with a dynamic (pre/post-treatment) monitoring. The presence of minimal residual disease by ctDNA was consistently associated with worse prognosis across studies.Conclusions: The use of liquid biopsy for monitoring response to chemoradiation and assess the risk of disease recurrence are the most advanced potential applications for liquid biopsy in RC, with implications also in the context of non-operative management strategies. [ABSTRACT FROM AUTHOR]

Oculomeningovascular amyloidosis is a variant of transthyretin (TTR) amyloidotic polyneuropathy, which is associated with blindness and brain ischemia, microhemorrages, and siderosis due to prominent production of the abnormal TTR in the eye and in the choroid plexuses. Tafamidis is a TTR stabilizer that is orally administered and, by interfering with amyloid fibril formation and deposition, is capable of slowing progression of TTR polyneuropathy and of early-stage cardiomyopathy. However, the ocular manifestations of amyloid deposition progressed despite tafamidis therapy in Val30Met TTR amyloidosis, and the effects of tafamidis on meningovascular amyloidosis are unknown. We observed failure of tafamidis to halt progression of oculomeningovascular amyloid deposition in a patient with familial Ala36Pro TTR amyloidosis. She received molecular diagnosis at age 24 and presented at age 26 with paresthesias of the lower limbs and bowel dysfunction. Echography showed minimal amyloid opacities in the corpus vitreum. Treatment with tafamidis meglumine was started. Sixteen months later, she complained of severe headache followed by left hemiparesthesias and numbness lasting 20 minutes. Magnetic resonance imaging showed multiple focal and diffuse hemosiderin deposits compatible with microbleeds and early siderosis. Echography showed a marked increase of "vitreal opacities." Our observation confirms that tafamidis fails in halting increase of vitreal amyloid deposits and indicates that it is presumably ineffective in preventing clinical onset due to progression of meningovascular amyloidosis. These failures may be due to the incapability of tafamidis to cross the blood-retina and blood-brain barriers. Therapeutic options targeting oculomeningovascular TTR amyloidoses in humans are required. [ABSTRACT FROM AUTHOR]

Leukoencephalopathy with calcifications and cysts (LCC) is an uncommon condition of unknown etiology occurring in children and adults. Pathological findings include obliterative hyalinosis of the small vessels, myelin loss, intense gliosis, Rosenthal fiber formation, microcalcifications, and hemosiderin deposits. Herein we report a 55-year-old man with LCC documented 10 years ago, in whom we examined brain perfusion by pseudocontinuous arterial spin labeling technique. We demonstrated diffused hypoperfusion of the affected white matter (WM) and of the subcortical gray matter (GM) and cortical GM in the patient in comparison to a group of healthy control subjects, using both qualitative evaluation and region of interest analysis. WM and subcortical GM hypoperfusion reflects the known distribution of LCC microangiopathy. We speculate that cortical hypoperfusion may be related to cerebral atrophy or may reflect deafferentation secondary to severe leukoencephalopathy, and may possibly contribute to severe motor and cognitive impairment. Further studies addressing cerebral blood flow in LCC are necessary. [ABSTRACT FROM AUTHOR]

Unexplained focal neurologic episodes (FNEs) can occur in patients with transthyretin-related familial amyloidotic polyneuropathy (TTR-FAP) after orthotopic liver transplantation (OLT). A patient with Val30Met FAP underwent OLT at age 34 years. Twelve years after transplantation, she presented with recurrent FNEs lasting from 10 minutes to 8 hours each, with nonuniform deficitary clinical features and variably associated with headache. Magnetic resonance imaging showed multiple brain microbleeds and diffuse contrast enhancement of the craniospinal leptomeninges consistent with amyloid deposits. Our observation suggests that microbleeds associated with meningovascular amyloidosis can underlie FNEs in TTR-FAP. Moreover, it confirms that OLT does not halt progression of leptomeningeal and vascular amyloid deposition due to TTR production in the choroid plexuses. Such a progression might compromise the good long-term prognosis of patients with TTR-FAP due to increased risk of intracranial hemorrhages. Pharmacologic therapies targeting brain TTR production may modify this scenario. [ABSTRACT FROM AUTHOR]

Treatment with the immunoconjugate trastuzumab deruxtecan leads to unprecedented improvements in response and overall survival in patients with HER2-positive (HER2+) metastatic gastroesophageal carcinoma (GEA), according to a study published in the New England Journal of Medicine. Until now, no HER2-targeted drugs other than trastuzumab have shown significant benefit in patients with HER2+ GEA. [ABSTRACT FROM AUTHOR]

The critical role of different adjuncts in improving the neurological outcome in intrinsic brain lesions affecting eloquent areas is demonstrated by their more diffuse utilization. Neurosurgeons often rely on preoperative and intraoperative diffusion tensor imaging tractography to improve the operative strategy and prognosis. We aimed to identify and validate a diffusion tensor imaging–based classification considering the relationship between the brain lesion and the corticospinal tract to predict a >50% reduction of motor evoked potentials (MEPs) during surgical excision of lesions involving the motor pathways. We included patients consecutively enrolled at our institution between April 2020 and September 2022 with 3 patterns of increasing complexity according to the relationship between the lesion and the corticospinal tract as identified on preoperative diffusion tensor imaging. Outcome measures were >50% reduction in intraoperative MEPs and neurological outcome defined as unchanged, improved, or worsened. The study included 83 patients. A statistically significant linear trend between higher rates of reduction of MEPs and higher classification grades was observed (P = 0.001), with sensitivity 0.60, specificity 0.88, accuracy 0.83, and area under the curve 0.75. Higher grades were associated with worse neurological outcomes (P = 0.02). The classification proved reliable in anticipating reduction in intraoperative MEPs and in predicting neurological outcome. Using this classification in patients undergoing surgery for lesions involving the motor pathways could help in counseling the patient, surgical planning, enhancing teamwork of operating room personnel, and improving the patient's prognosis. [ABSTRACT FROM AUTHOR]

Patients with solid tumours have high COVID-19 mortality. Limited and heterogeneous data are available regarding the immunogenicity of SARS-CoV-2 mRNA vaccines in this population. This is a prospective, single-centre cohort study aiming at evaluating seroconversion in terms of anti-spike antibodies in a population of patients with solid tumours undergoing cancer therapy within 2 months before the second vaccine dose, as compared with a cohort of controls. Subjects who were not SARS-CoV-2 naïve were excluded, and 171 patients were included in the final study population (150 vaccinated with BNT162b2, 87.7%; 21 with mRNA-1273, 12.3%) and compared with 2406 controls. The median follow-up time from the second dose of vaccination was 30 days (12–42; IQR: 26–34). Most patients had metastatic disease (138, 80.7%). Seroconversion rate was significantly lower in cancer patients than in controls (94.2% versus 99.8%, p < 0.001). At univariate logistic regression analysis, Odds ratio (OR) for seroconversion was also reduced in older individuals (>70 years). A multivariate logistic model confirmed cancer as the only significant variable in impairing seroconversion (OR 0.03, p < 0.001). In the cancer population, a multivariate analysis among clinical variables, including the type of cancer treatment, showed ECOG PS > 2 as the only one of impact (OR 0.07, p = 0.012). There is a fraction of 6% of patients with solid tumours undergoing cancer treatment, mainly with poorer performance status, who fail to obtain seroconversion after SARS-CoV-2 mRNA vaccines. These patients should be considered for enhanced vaccination strategies and carefully monitored for SARS-CoV-2 infection during cancer treatment. • Cancer patients have high COVID-19 mortality and were prioritised for vaccination. • About 6% of cancer patients do not develop protective antibodies after vaccination. • Cancer in active treatment is the main factor impairing seroconversion. • Enhanced vaccination strategies warrant consideration in such a setting of care. [ABSTRACT FROM AUTHOR]

The Pap test is a preventive approach that requires specialized and labor-intensive examination of cytological preparations to track potentially cancerous cells from the internal and external cervix surface. A cytopathologist must analyze many microscopic fields while screening for abnormal cells. Therefore there is hope that a support decision system could assist with clinical diagnosis, for example, by identifying sub-cellular abnormalities, such as changes in the nuclei features. This work proposes an ensemble method for cervical nuclei detection aiming to reduce the workload of cytopathologists. First, a preprocessing phase divides the original image into superpixels, which are input to feature extraction and selection algorithms. The proposed ensemble method combines three classifiers: Decision Tree (DT), Nearest Centroid (NC), and k-Nearest Neighbors (k-NN), which are evaluated against the ISBI'14 Overlapping Cervical Cytology Image Segmentation Challenge dataset. Experiments show that the proposed method is the state-of-the-art algorithm of the literature for recall (0.999) and F1 values (0.993). It produced a recall very close to the optimum value and also kept high precision (0.988). [Display omitted] • Ensemble of classifiers to provide a more assertive cervical cell nuclei segmentation. • Automatic inspection of Pap smear test to reduce the human workload in cervical cell analysis. • Superpixel computation and feature extraction to improve cell characterization and classification. [ABSTRACT FROM AUTHOR]

Background: HER2 amplification has been identified in 2-3% of patients with colorectal cancer, although there are currently no approved HER2-targeted therapies for colorectal cancer. We aimed to study the antitumour activity and safety of trastuzumab deruxtecan (an antibody-drug conjugate of humanised anti-HER2 antibody with topoisomerase I inhibitor payloads) in patients with HER2-expressing metastatic colorectal cancer.Methods: DESTINY-CRC01 is an open-label, phase 2 study that recruited patients from 25 clinics and hospitals in Italy, Japan, Spain, the UK, and the USA. Eligible patients had centrally confirmed HER2-expressing metastatic colorectal cancer that had progressed on two or more previous regimens (HER2-targeted therapies other than trastuzumab deruxtecan permitted), were aged 18 years or older (≥20 years in Japan), had an Eastern Cooperative Oncology Group score of 0 or 1, and had RAS and BRAFV600E wild-type tumours. Patients were enrolled into one of three cohorts by HER2 expression level: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC2+ and in-situ hybridisation [ISH]-positive), cohort B (IHC2+ and ISH-negative), or cohort C (IHC1+). Patients received 6·4 mg/kg trastuzumab deruxtecan intravenously every 3 weeks until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate in cohort A by independent central review which was assessed in the full analysis set and safety was assessed in the safety analysis set. Both the full analysis set and the safety analysis set included all patients who received one or more doses of trastuzumab deruxtecan. This ongoing trial is registered with ClinicalTrials.gov, number NCT03384940.Findings: Between Feb 23, 2018, and July 3, 2019, 78 patients were enrolled in the study (53 in cohort A, seven in cohort B, and 18 in cohort C), all of whom received at least one dose of study drug. For the 53 (68%) patients with HER2-positive tumours (cohort A), a confirmed objective response was reported in 24 (45·3%, 95% CI 31·6-59·6) patients after a median follow-up of 27·1 weeks (IQR 19·3-40·1). Grade 3 or worse treatment-emergent adverse events that occurred in at least 10% of all participants were decreased neutrophil count (17 [22%] of 78) and anaemia (11 [14%]). Five patients (6%) had adjudicated interstitial lung disease or pneumonitis (two grade 2; one grade 3; two grade 5, the only treatment-related deaths).Interpretation: Trastuzumab deruxtecan showed promising and durable activity in HER2-positive metastatic colorectal cancer refractory to standard treatment, with a safety profile consistent with that reported in previous trastuzumab deruxtecan trials. Interstitial lung disease and pneumonitis are important risks requiring careful monitoring and prompt intervention.Funding: Daiichi Sankyo. [ABSTRACT FROM AUTHOR]

Rat sarcoma (RAS) oncogenes have intensively been investigated during the last decades. Taking into account all human tumours, Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene is the most frequently mutated (about 22%) among the three isoforms, followed by Neuroblastoma RAS Viral Oncogene Homolog (NRAS) (8%) and Harvey Rat Sarcoma Viral Oncogene Homolog (HRAS) (3%). In the last years, careful attention has been paid on KRAS and NRAS gene mutations in non–small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients because of their prognostic and predictive roles. In particular, a large body of literature data has been generated investigating clinical outcomes of targeted treatments in NSCLC and CRC KRAS - and NRAS -mutated patients. The latest evidences are here reviewed, providing also an overview of the real-world RAS mutation testing practice across different Italian laboratories. On this basis, we propose a knowledge-based system, www.rasatlas.com , to support the healthcare personnel in the management of patients featuring RAS gene mutations in the landscape of precision oncology. • KRAS exon 2 p.G12C point mutation plays a predictive value in NSCLC patients. • Novel anti- KRAS exon 2 p.G12C agents have been developed. • We reported a KRAS and NRAS mutation rate of 23.8% and 0.8% in NSCLC patients. • In our Italian survey, K - and NRAS mutations were reported in 47.8% of CRC patients. [ABSTRACT FROM AUTHOR]

Quality of life (QoL) patient-reported outcomes (PROs) data from pivotal first-line trials in metastatic colorectal cancer (mCRC) are poor. The Valentino study showed that de-escalation to single-agent panitumumab after 4-month induction with panitumumab-FOLFOX is inferior to panitumumab-5-FU/LV in patients with RAS wild-type mCRC, although slightly reducing toxicity. We report QoL, a secondary end-point. PROs were assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 (QLQ-C30), EORTC QLQ-CR29, EuroQol EQ-5D questionnaires, at baseline and every 8 weeks until disease progression. First two evaluations correspond to induction treatment (identical in both arms), while subsequent to maintenance. To describe QoL changes over time, mean changes from baseline at each time point were calculated in overall population. To compare maintenance between two arms, mean changes and proportion of improved/stable/worse patients versus baseline were compared for each item. In arm A/B, 91.5%/92.0% of enrolled patients completed questionnaires at baseline. No significant differences in the two arms were reported in compliance, baseline scores and mean changes versus baseline for the three questionnaires during maintenance (24/32/40 weeks). Overall, mean changes versus baseline showed an early deterioration during induction with partial recovering during maintenance for global QoL, functional scales and several symptoms/items of QLQ-C30 (fatigue, nausea/vomiting, appetite loss, diarrhoea) and QLQ-CR29 (body image, dry mouth, hair loss, taste, faecal incontinence, sore skin), and EQ-5D Visual Analogue Scale (VAS) score. In patients with RAS wild-type mCRC, induction with oxaliplatin-containing chemotherapy plus anti-EGFRs induces a transient significant QoL deterioration. After induction phase, treatment deintensification determines an overall recovery of health-related QoL, besides the expected prevention of oxaliplatin-related neurotoxicity. • This study reports on a pre-specified secondary analysis of the randomized open-label phase II Valentino trial. • Quality of Life (QoL) changes are reported through patient-reported outcomes. • Patients affected by RAS wild type metastatic colorectal cancer were treated in first-line with panitumumab (pan) plus/minus fluorouracil/leucovorin maintenance after FOLFOX-pan induction. • The results of this study showed an early deterioration of QoL during induction with partial recovery during maintenance. • No significant QoL differences between the two maintenance treatment arms are reported. [ABSTRACT FROM AUTHOR]

Background: Many procedures and different osteotomies have been described for percutaneous hallux valgus correction. Percutaneous techniques may lead to reduced morbidity, surgery, and recovery time. The aim of this study is to evaluate the clinical and radiographic outcome of a new percutaneous procedure (PBS-Percutaneous Bianchi System).Methods: Fifty-eight cases were treated with Percutaneous Bianchi System procedure for correction of mild, moderate or severe hallux valgus deformity. All patients were clinically assessed preoperatively and then followed up by weight-bearing x-rays, AOFAS (American Orthopedic Foot and Ankle Score), VAS (Visual Analog Scale) pain score, and patient satisfaction.Results: AOFAS scores improved from 28.6 at the preoperative assessment to 91.7 at the latest follow-up. The VAS pain score improved from 6.7 before surgery to 0.6 at the latest follow-up. The mean Hallux valgus angle (HVA), Intermetatarsal angle (IMA) and Distal metatarsal articular angle (DMAA) significatively decreased from the preoperative assessment to the latest follow-up.Conclusions: The PBS technique is a safe, reliable, and effective procedure for the correction of symptomatic mild-to-severe hallux valgus. [ABSTRACT FROM AUTHOR]

Despite the well-known negative prognostic value of the V600E BRAF mutation in patients with metastatic colorectal cancer (mCRC), its outcome is quite heterogeneous, and the basis for this prognostic heterogeneity should be better defined. Two large retrospective series of V600E BRAF -mutated mCRC from 22 institutions served as an exploratory and validation set to develop a prognostic score. The model was internally and externally validated. A total of 395 V600E BRAF -mutated mCRCs were included in the exploratory set. Performance status, CA19.9, lactate dehydrogenase, neutrophil/lymphocyte ratio, grading and liver, lung and nodal involvement emerged as independent prognostic factors for overall survival (OS). Two different scoring systems were built: a 'complete' score (0–16) including all significant covariates and a 'simplified' score (0–9), based only on clinicopathological covariates, and excluding laboratory values. Adopting the complete score, proportions of patients with a low (0–4), intermediate (5–8) and high (9–16) score were 44.7%, 42.6% and 12.6%, respectively. The median OS was 29.6, 15.5 (hazard ratio [HR] for intermediate vs low risk: 2.16, 95% confidence interval [CI]: 1.44–3.22, p <.001) and 6.6 months (HR for high vs low risk: 4.72, 95% CI: 2.72–8.20, p <.001). Similar results were observed also after adjusting for the type of first-line treatment and adopting the simplified score. The simplified prognostic score derived from the exploratory set was then applied to the validation set for external confirmation. These scoring systems are based on easy-to-collect data and defined specific subgroups with relevant differences in their life expectancy. These tools could be useful in clinical practice, would allow better stratification of patients in clinical trials and may be adopted for proper adjustments in exploratory translational analyses. • The V600E BRAF mutation occurs in roughly 10% of metastatic colorectal cancer (mCRC). • It leads to a peculiar clinicopathological phenotype and worse prognosis. • Nevertheless, great heterogeneity in the outcome is evident among BRAF-mutated mCRC. • The present study developed and validated prognostic classifiers for BRAF-mutated mCRC. • These data are informative for clinical, methodological and translational purposes. [ABSTRACT FROM AUTHOR]

Highlights • A methodology capable of segmenting both free-lying and clumps of abnormal cells with high overlapping rate from digitized images of conventional Pap smears. • The segmentation algorithm applies a convolutional neural network trained with more than a million patch-images to identify abnormal cell regions. • We used the average area of segmented regions to rank images according to the probability that they contain abnormal cells. • Results showed that the proposed methodology achieved more accurate results and performed faster when compared with other existing methods. • All the codes and the database will be published upon paper acceptance. Abstract Ninety years after its invention, the Pap test continues to be the most used method for the early identification of cervical precancerous lesions. In this test, the cytopathologists look for microscopic abnormalities in and around the cells, which is a time-consuming and prone to human error task. This paper introduces computational tools for cytological analysis that incorporate cell segmentation deep learning techniques. These techniques are capable of processing both free-lying and clumps of abnormal cells with a high overlapping rate from digitized images of conventional Pap smears. Our methodology employs a preprocessing step that discards images with a low probability of containing abnormal cells without prior segmentation and, therefore, performs faster when compared with the existing methods. Also, it ranks outputs based on the likelihood of the images to contain abnormal cells. We evaluate our methodology on an image database of conventional Pap smears from real scenarios, with 108 fields-of-view containing at least one abnormal cell and 86 containing only normal cells, corresponding to millions of cells. Our results show that the proposed approach achieves accurate results (MAP = 0.936), runs faster than existing methods, and it is robust to the presence of white blood cells, and other contaminants. [ABSTRACT FROM AUTHOR]