Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies.

BACKGROUND: Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. METHODS: This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. RESULTS: Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. CONCLUSIONS: Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Soluble PD-L1 and Circulating CD8+PD-1+ and NK Cells Enclose a Prognostic and Predictive Immune Effector Score in Immunotherapy Treated NSCLC patients.

INTRODUCTION: Upfront criteria to foresee immune checkpoint inhibitors (ICIs) efficacy are far from being identified. Thus, we integrated blood descriptors of pro-inflammatory/immunosuppressive or effective anti-tumor response to non-invasively define predictive immune profiles in ICI-treated advanced non-small cell lung cancer (NSCLC). METHODS: Peripheral blood (PB) was prospectively collected at baseline from 109 consecutive NSCLC patients undergoing ICIs as first or more line treatment. Soluble PD-L1 (sPD-L1) (immunoassay), CD8+PD-1+ and NK (FACS) cells were assessed and interlaced to generate an Immune effector Score (IeffS). Lung Immune Prognostic Index (LIPI) was computed by LDH levels and derived Neutrophil-to-Lymphocyte Ratio (dNLR). All these parameters were correlated with survival outcome and treatment response. RESULTS: High sPD-L1 and low CD8+PD-1+ and NK number had negative impact on PFS (P < 0.001), OS (P < 0.01) and ICI-response (P < 0.05). Thus, sPD-L1high, CD8+PD-1+low and NKlow were considered as risk factors encompassing IeffS, whose prognostic power outperformed that of individual features and slightly exceeded that of LIPI. Accordingly, the absence of these risk factors portrayed a favorable IeffS characterizing patients with significantly (P < 0.001) prolonged PFS (median NR vs 2.3 months) and OS (median NR vs 4.1) and greater benefit from ICIs (P < 0.01). We then combined each risk parameter composing IeffS and LIPI (LDHhigh, dNLRhigh), thus defining three distinct prognostic classes. A remarkable impact of IeffS-LIPI integration was documented on survival outcome (PFS, HR = 4.61; 95%CI = 2.32-9.18; P < 0.001; OS, HR=4.03; 95%CI=1.91-8.67; P < 0.001) and ICI-response (AUC=0.90, 95%CI=0.81-0.97, P < 0.001). CONCLUSION: Composite risk models based on blood parameters featuring the tumor-host interaction might provide accurate prognostic scores able to predict ICI benefit in NSCLC patients.

The CBCL 1.5-5 and the identification of preschoolers with autism in Italy.

AIMS: To study the potential use of child behaviour checklist (CBCL) 1.5-5 scales for the early identification of preschoolers at risk of autism. METHODS: CBCL scores of three groups of preschoolers were compared: (1) an experimental group of 101 preschoolers with autism spectrum disorder (ASD); (2) a control group of 95 preschoolers with other psychiatric disorders (OPD); (3) a control group of 117 preschoolers with typical development (TD). One-way analysis of variance (ANOVA), logistic regression with odds ratio (OR) and receiver operating characteristic (ROC) analyses were performed. RESULTS: ANOVA revealed that ASD and OPD had significantly higher scores in almost all CBCL scales than TD. ASD presented significantly higher scores than OPD on Withdrawn, Attention Problems and Pervasive Developmental Problems (PDP) scales. Logistic regression analysis demonstrated that these same CBCL scales have validity in predicting the presence of an ASD towards both TD and OPD. ROC analysis indicated high sensitivity and specificity for PDP (0.85 and 0.90) and Withdrawn (0.89 and 0.92) scales when ASD is compared to TD. Specificity (0.60 for PDP and 0.65 for Withdrawn) decreases when comparing ASD and OPD CONCLUSIONS: The PDP and Withdrawn scales have a good predictive validity so that they could be proposed as a first-level tool to identify preschoolers at risk of autism in primary care settings. Problems regarding the lower specificity when comparing ASD v. OPD are discussed.

The effect of esophageal myotomy and myectomy on the lower esophageal sphincter pressure profile: intraoperative computerized manometry study.

SUMMARY: The surgical treatment of achalasia, based on Heller's myotomy is the procedure of choice to reduce the sphincterial high pressure zone, either by laparotomy or, most recently, by laparoscopy. What is the right length of the myotomy? Many authors have reported 10-15% postoperative residual dysphagia, due to the incomplete gastric myotomy and not to esophageal pouring. The aim of this study is to experimentally determine the modifications induced by Heller's myotomy and myectomy of the esophago-gastric junction on lower esophageal sphincter (LES) pressure profile, using a computerized manometric system. Myotomy of the esophageal portion of the LES (i.e. without dissection of the gastric fibers) has not modified the parameters considered, while the dissection of gastric fibers for at least 2-3 cm on the anterior gastric wall has created a significant modification of the LES pressure profile. Our observations seem to confirm and more clearly demonstrate the important role played by gastric fibers in sustaining the sphincteric HPZ. Moreover, analysis of our data, showed the need to always perform a complete myotomy. This was objectively shown during the intervention by means of intraoperative manometry, in order to significantly reduce the possibility of a dysphagic relapse, caused by inadequate treatment.

[Total gastrectomy for gastric cancer: can the type of lymphadenectomy condition the long-term results?]. / Gastrectomia totale per cancro gastrico: può il tipo di linfadenectomia condizionare i risultati a distanza?

INTRODUCTION: Gastric cancer is the second tumor for frequency in the world. Surgery is still the only curative treatment. Good results in terms of long distance survival, postoperative morbidity and mortality have been achieved in the last years. The extension of lymphadenectomy is an important and discussed matter and it is not clear if lymphadenectomy may contribute to improve the surgical results. The Japanese surgeons were the first ones, in the 60's, to introduce a D2-D3 extended lymphadenectomy, but the real benefits of this technique are still being discussed. Indeed lymphonodal metastasis seem to be one of the most important prognostic factors in the gastric cancer and the level and the number of metastatic nodes are useful to predict the patients' survival. The aim of this study is to value the D2 lymphadenectomy in the patients who were treated with total gastrectomy for gastric adenocarcinoma, comparing the results both with the D1 lymphadenectomy and the D3-D4, paying attention to the survival rates related with the lymphonodal dissection. PATIENTS AND METHOD: From 1998 to 2004, we studied 87 patients with gastric cancer. Out of 78 patients treated surgically, 9 were judged unresectable. Out of 69 patients treated surgically, one died before surgery and so he was put away by this study. All the patients were treated with total gastrectomy and a GI tract reconstruction by Roux's Y termino-lateral esophageal-jejunal anastomosis. In 20 patients we also made a splenectomy. We followed the Japanese Research Society for Gastric Cancer guidelines, according to which nodes are gathered into 16 levels and divided in 4 groups (N1-N4) depending on the cancer localization. The extension of the lymphadenectomy has been classified according to the level of the removed nods. The patients were divided into 3 groups. First group: patients undergone a total gastrectomy with D1 lymphadenectomy. Second group: patients undergone D2 lymphadenectomy. Third group: patients undergone D3 and D4 lymphadenectomy. The data we obtained let us value the survival rate. RESULTS: Out of the 78 patients treated, 69 were resected with a 88.5% resection rate (69/78). Perioperatory mortality was 1.4% (1/69). Global survival was 53.8% (44/68). The 5 years survival for the Ia stage was 82.6%, 89.3% for the Ib stage, 67.8% for the II stage, 56.6% for the IIIa, 16.8% for the IIIb and 0% for the IV stage. In addition the 5 years survival in the patients without lymphnodal metastasis was 79%, much higher than the 30.6% obtained in the patients with lymphonodal metastasis (p <0.0001). In the patients who underwent D1 lymphadenectomy, survival was 73.4%, while we obtained a result of 70.4% and 13.8% respectively in the D2 and D3-D4 (p <0.05). In the advanced stages (IIIa, IIIb, IV), the survival rate in the patients with lymphadenectomy D2 vs D1 vs D3-D4 was 38.9% vs 0% vs 36.3% (p <0.0001). The survival rate based on the extension of the lymphadenectomy in the patients with lymphonodal metastasis resulted to be much higher in those patients who underwent a D2 lymphadenectomy (43.5% in 5 years) compared both to D1 (0% in 6 months) and (29.5% in 5 years) D3-D4 lymphadenectomy. CONCLUSIONS: The relation between long distance survival and extension of the lymphadenectomy in the patients with gastric adenocarcinoma is still being discussed. Different studies show the importance of a careful lymphadenectomy as the main mean for a better long distance survival in the patients with gastric cancer. Other studies showed a link between gastric cancer prognosis and number of positive nodes. If more than 7-8 nodes are affected with metastasis, prognosis is usually poor. Therefore the presence of nod metastasis has a negative influence in the prognosis of this tumor; for this reason D2 lymphadenectomy is the technique to be used for the treatment of the gastric adenocarcinoma, both for a good staging and a better long distance survival, but particularly in the advanced cancers which are, at the moment, the highest number of cases that reach the surgeon's attention.

Gastric cancer in the elderly patient.

The incidence of gastric cancer is increasing in elderly patients, unlike what it's being observed in the younger patients. The aim of this study is to evaluate the impact of the age on the resecability, resection type (R0-R1-2), morbidity, mortality and survival rate. The higher mortality observed in the elderly patients, the discussed role of an extended lymphadenectomy and the poor survival rate, would lead to a surgical approach which mostly tends to the palliation of the symptoms than the obtainment of a curative resection. But, on the other hand, the impossibility of making chemotherapy in most of the over 75 year old patients, lead us to a R0 surgery treatment.

Open trial of risperidone in 24 young children with pervasive developmental disorders.

OBJECTIVE: To describe tolerability and efficacy of risperidone in very young children with pervasive developmental disorders. METHOD: Twenty-four children aged 3.6 to 6.6 years (mean 4.6 years +/- 8 months) enrolled during 1999 and 2000 participated in a 16-week open-label trial with risperidone monotherapy. Outcome measures included the Children's Psychiatric Rating Scale (CPRS), Childhood Autism Rating Scale (CARS), Clinical Global Impression-Improvement (CGI-I), and Children's Global Assessment Scale (C-GAS). RESULTS: Two subjects did not complete the trial because of side effects. The optimal dose was 0.5 mg/day. After the treatment a 21% improvement in CPRS and a 14% improvement in CARS total scores was found. Items related to behavioral control (hyperactivity, fidgetiness, rhythmic motions) and affect regulation (lability of affect, angry affect) improved more than 25%. Based on improvement of at least 25% on the CPRS and a score of 1 or 2 on the CGI-I, eight subjects were considered responders. Functional impairment (C-GAS) improved more than 25%. Thirteen subjects (54%) were free of any side effects; in the other participants risperidone was well tolerated. Only three subjects had a weight gain greater than 10%. CONCLUSIONS: Low-dose risperidone may positively affect symptoms in young autistic children, improving disruptive/hyperactive behavior and affective dysregulation. Further controlled studies in this age group are warranted.

Risperidone monotherapy in preschool children with pervasive developmental disorders.

The aim of this preliminary study was to examine the short-term efficacy and safety of the atypical antipsychotic risperidone in preschool autistic children. The sample consisted of 10 subjects (7 males and 3 females) aged 3 9/12 to 6 6/12 years (mean age 4.7 years). A 16-week open-label trial with risperidone monotherapy was initiated at a starting dose of 0.25 mg daily and was increased to a maximum dose of 0.50 mg (0.027 mg/kg daily). Outcome measures were the Childhood Autism Rating Scale, the Children's Psychiatric Rating Scale, Clinical Global Impression (improvement score), and the Children's Global Assessment of Functioning. Two subjects did not complete the trial because of side effects (tachycardia and flushes, fever and hyporexia). After the 16-week treatment, data from the eight children who completed the trial indicated a modest improvement in the Childhood Autism Rating Scale total score, Children's Psychiatric Rating Scale total score, and Children's Global Assessment of Functioning. According to the Clinical Global Impression, the global improvement score for four subjects was much improved or very much improved; the score for the other four children was minimally improved. None of the children exhibited behavioral deterioration. The side effects in the eight children were not severe.

Prolactin levels in young children with pervasive developmental disorders during risperidone treatment.

Although hyperprolactinemia is a common side effect during risperidone treatment in adult patients, no information is available on young children. The aim of this study is to report on serum prolactin levels in 25 young autistic children (22 males and 3 females, age range 3.9-7 years, mean age 4.10 years) during treatment with risperidone (dosage range 0.25-0.90 mg/day, mean dosage 0.52 mg/day). Prolactin levels were measured at baseline and after 10 weeks of treatment. The clinical outcome measure used was the Clinical Global Impression-Improvement. Serum prolactin was 9.77 +/- 3.94 ng/mL at baseline and 25.92 +/- 13.9 ng/mL during the 10th week of treatment (p < 0.001). Six children (24%) showed prolactin levels lower than 15 ng/mL, which is the upper normal level; eight children (28%) had prolactin levels higher than two times the upper limit (30 ng/mL). Hyperprolactinemia did not show significant correlations with age, weight, or risperidone dosage. There was no relation with clinical outcome. Dose reduction of risperidone resulted in a decrease of prolactin levels. None of the children showed clinical signs of hyperprolactinemia. Given the paucity of available data on potential effects of long-term hyperprolactinemia, a monitoring of prolactin during treatment with risperidone and other typical and atypical antipsychotics may be warranted.

Increased density of the platelet serotonin transporter in autism.

BACKGROUND: Various data have shown the involvement of serotonin (5-HT) in autism. The presence of the 5-HT transporter in platelets, similar to the same structure located in presynaptic serotonergic neurons, has produced a series of studies aimed at assessing its functionality in this disorder, but the ensuing findings are quite controversial. For this reason, we investigated the 5-HT transporter by means of the specific binding of [3H]-Paroxetine ([3H]-Par), which is currently considered the first-choice ligand for labeling it, in platelets of 20 autistic children and adolescents, as compared with healthy control subjects. METHODS: Twenty children and adolescents of both sexes suffering from autism according to DSM IV criteria were included in the study and compared with a similar group of healthy control subjects. Platelet membranes and the binding of [3H]-Par were carried out according to standardized protocols. RESULTS: The results showed a significantly higher density of [3H]-Par binding sites in autistic children than in healthy control subjects. CONCLUSIONS: These findings support the presence of a serotonergic dysfunction in autism and would suggest that the 5-HT transporter may have a specific role in this disorder, also in the light of its recently proposed role in brain development.

CO2 laser subtotal arytenoidectomy and posterior true and false cordotomy in the treatment of post-thyroidectomy bilateral laryngeal fixation in adduction.

A total of 39 patients with bilateral post-thyroidectomy vocal cord paralysis in adduction underwent CO2 laser subtotal arytenoidectomies with removal of the posterior third of the false and true vocal cords. Total airway resistance (Rtot) evaluated before and 4-10 months after surgery showed marked preoperative impairment before and significant improvement after surgery (P < 0.05). In five patients revision surgery was performed due to a progressive impairment of respiratory function. A variable degree of voice breathiness was observed after surgery; the maximum phonation time mean values were lower than normal and peak sound pressure levels 63 +/- 5 dB. In three cases aspiration was present in the first postoperative days, but swallowing dysfunctions disappeared within 1 week. Subtotal arytenoidectomy with removal of the posterior third of the true and false vocal folds was found to be a satisfactory surgical treatment for bilateral vocal cord paralysis in adduction. However, further research is still needed to define the surgical procedure able to balance respiratory, phonatory and sphincteric functions optimally.

The use of dynamic posturography to detect neurosensorial disorder in IDDM without clinical neuropathy.

The main aim was to evaluate the relative importance of sensory interactions for postural stability in 45 patients with insulin-dependent diabetes mellitus (IDDM) with and without peripheral neuropathy. All subjects had normal electronystagmography. Dynamic posturography provides functional, selective testing of three sensory modalities in maintenance of balance, i.e., vestibular, visual, and somatosensory. The Sensory Organization Test (SOT) includes six test conditions during which the subject tries to maintain an upright stance with as little sway as possible. The subject stands on a movable platform facing a square visual surrounding, which can be rotated independently. The test is performed first with the eyes open, then with the eyes closed. The second component of posturography testing consists of the Motor Control Test (MCT) concerning motor responses routinely used in balance maintenance. Compared to control subjects, IDDM patients with peripheral neuropathy but not patients without neuropathy showed lower scores for test conditions SOT 1 (analysis of variance, ANOVA F = 8.3; Scheffe test: p = 0.0007), SOT 2 (F = 6.6; p = 0.004), SOT 3 (F = 3.4; p = 0.04), and SOT 6 (F = 3.4; p = 0.04). The muscle response latencies in MCT were prolonged for small forward perturbations (F = 4.6; p = 0.02) in neuropathic patients (148.3+/-14.2 ms) with respect to control subjects, but not in non-neuropathic patients with respect to control subjects (135.2+/-13.3 ms). Sural (r = 0.2; p = 0.002) and peroneal (r = 0.12; p = 0.02) nerve conduction velocities showed significant correlations with muscle response latencies of MCT for small forward perturbations. Our results suggest a subclinical dysequilibrium in IDDM patients with peripheral neuropathy. The results of dynamic posturography may reflect the impairment of the somatosensory system, rather than a specific lesion of vestibular and/or visual modalities.

The role of vision on postural strategy evaluated in patients affected by congenital nystagmus as an experimental model.

The role of vision in postural control is crucial and is strictly related to the characteristics of the visual stimulus and to the performance of the visual system. The purpose of this investigation was to evaluate the effects of chronically reduced visual cues upon postural control in patients affected by Congenital Nystagmus (CN). These patients have developed since birth a postural strategy mainly based on vestibular and somatosensorial cues. Fifteen patients affected by CN and 15 normal controls (NC) were enrolled in the study and evaluated by means of dynamic posturography. The overall postural control in CN patients was impaired as demonstrated by the equilibrium score and by the changes of the postural strategy. This impairment was even more enhanced in CN than in NC group when somatosensorial cues were experimentally reduced. An aspecific pattern of visual impairment and a pathological composite score were also present. Our data outline that in patients affected by CN an impairment of the postural balance is present especially when the postural control relies mainly on visual cues. Moreover, a decrease in accuracy of the somatosensory cues has a proportionally greater effect on balance than it has on normal subjects.

Postural control in benign paroxysmal positional vertigo before and after recovery.

Thirty-two patients affected by idiopathic benign paroxysmal positional vertigo (BPPV) of the posterior semicircular canal were studied before, 3 days and I month after a resolutive Semont manoeuvre by means of dynamic posturography. The overall postural control in BPPV patients was shown to be impaired, as demonstrated by the pathological equilibrium scores. Data obtained before treatment showed a specific pattern of vestibular involvement and a pathological composite score. After the liberatory manoeuvre the Sensory Organization Test indicated a significant improvement in the pathological composite and vestibular scores. However, significant differences from controls were still detected 3 days and 1 month after clinical recovery from BPPV. The results clearly show that, in BPPV patients, there is an impairment of the vestibular system, which seems unable to maintain a normal postural balance. This deficit can be particularly detected when dynamic posturography evaluates the vestibular cues. After the liberatory manoeuvre a consistent improvement in the overall postural control has been observed but the residual differences from controls seem to suggest that damage to the otoconial maculae influences postural control, even when there is significant improvement in the clinical signs.

[Current views and controversies about reconstruction after esophagectomy]. / Attualità e controversie nelle ricostruzioni dopo esofagectomia.

The Authors examine the reconstructive procedures following total or partial esophagectomy, reporting advantages and disadvantages related to stomach, colon or jejunum transposition. The stomach is certainly the organ most widely employed for its adaptability and excellent vascularization; furthermore, only one anastomosis is needed. After a short note on pathophysiology of the most common complications, the Authors point out the advantages of using stapling devices, with special attention to the low incidence of anastomotic dehiscence.