Association of tumor-infiltrating lymphocytes with recurrence score in hormone receptor-positive/HER2-negative breast cancer: Analysis of four prospective studies.

BACKGROUND: The clinical value of tumor infiltrating lymphocytes (TILs) in hormone receptor-positive (HR+)/HER2- breast cancer (BC) may be unearthed by focusing on more biologically aggressive tumors. Here we deepen and describe the correlation between RS and TILs, proposing an immuno-genomic model for HR+ /HER2- BC. METHODS: We enrolled T1-T3, N0-N1 BC patients with available RS® and TILs in the context of four multicenter, prospective studies. RS® and TILs were considered as continuous and categorical variables. RS® was categorized into: 0-10 (low risk), 11-25 (intermediate risk) and 26-100 (high risk); TILs were categorized into: low TILs (0-10%), intermediate TILs (11-59%) and high TILs (60-100%). RESULTS: 811 patients were included. RS distribution was (n = 810): low risk 22.0%, intermediate risk 61.2%, high risk 16.8%. TIL distribution was (n = 455): low TILs 84.6%, intermediate TILs 13.6% and high TILs 1.8%. A significant, weak positive, linear correlation was found between continuous TILs and RS (Pearson coefficient=0.223, p < 0.001). When considering RS and TILs categories, tumors with intermediate/high TIL levels significantly enriched the high RS subgroup (p = 0.006). This was confirmed both within Luminal A and Luminal B cohorts. Among high-RS patients, 16.7% of Luminal A and 26.7% of Luminal B tumors had intermediate/high TILs. CONCLUSIONS: We observed that RS® and TILs capture only slightly overlapping information on the biology of HR+ /HER2- tumor microenvironment. We demonstrated the feasibility of combining RS and TILs into a composite immuno-genomic model, which may serve the purpose of guiding and focalizing patient selection in the further development of immunotherapy strategies for Luminal-like disease.

Sequential Vestibular Neuritis: Report of Four Cases and Literature Review.

BACKGROUND AND OBJECTIVES: Bilateral sequential vestibular neuritis (BSVN) is a rare condition in which an inflammation or an ischemic damage of the vestibular nerve occurs bilaterally in a sequential pattern. We described four cases of BSVN. SUBJECTS AND METHODS: Every patient underwent video-head impulse test during the first and the second episode of vestibular neuritis (VN), furthermore they have been studied with radiological imaging. RESULTS: Contralateral VN occurred after a variable period from prior event. Vestibular function recovered from the first episode in one case. The other three patients developed contralateral VN. One case was due to a bilateral VN in association with a Ramsay-Hunt syndrome, in another patient clinical records strongly suggested an ischemic etiology, whereas in two cases aetiology remained uncertain. Two patients subsequently developed a benign paroxysmal positional vertigo involving the posterior canal on the side of the latest VN (Lindsay-Hemenway syndrome). CONCLUSIONS: Instrumental vestibular assessment represents a pivotal tool to confirm the diagnosis of VN and BSVN.

Upright BPPV Protocol: Feasibility of a New Diagnostic Paradigm for Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo Compared to Standard Diagnostic Maneuvers.

Background: The diagnosis of benign paroxysmal positional vertigo (BPPV) involving the lateral semicircular canal (LSC) is traditionally entrusted to the supine head roll test, also known as supine head yaw test (SHYT), which usually allows identification of the pathologic side and BPPV form (geotropic vs. apogeotropic). Nevertheless, SHYT may not always allow easy detection of the affected canal, resulting in similar responses on both sides and intense autonomic symptoms in patients with recent onset of vertigo. The newly introduced upright head roll test (UHRT) represents a diagnostic maneuver for LSC-BPPV, supplementing the already-known head pitch test (HPT) in the sitting position. The combination of these two tests should enable clinicians to determine the precise location of debris within LSC, avoiding disturbing symptoms related to supine positionings. Therefore, we proposed the upright BPPV protocol (UBP), a test battery exclusively performed in the upright position, including the evaluation of pseudo-spontaneous nystagmus (PSN), HPT and UHRT. The purpose of this multicenter study is to determine the feasibility of UBP in the diagnosis of LSC-BPPV. Methods: We retrospectively reviewed the clinical data of 134 consecutive patients diagnosed with LSC-BPPV. All of them received both UBP and the complete diagnostic protocol (CDP), including the evaluation of PSN and data resulting from HPT, UHRT, seated-supine positioning test (SSPT), and SHYT. Results: A correct diagnosis for LSC-BPPV was achieved in 95.5% of cases using exclusively the UBP, with a highly significant concordance with the CDP (p < 0.000, Cohen's kappa = 0.94), regardless of the time elapsed from symptom onset to diagnosis. The concordance between UBP and CDP was not impaired even when cases in which HPT and/or UHRT provided incomplete results were included (p < 0.000). Correct diagnosis using the supine diagnostic protocol (SDP, including SSPT + SHYT) or the sole SHYT was achieved in 85.1% of cases, with similar statistical concordance (p < 0.000) and weaker strength of relationship (Cohen's kappa = 0.80). Conclusion: UBP allows correct diagnosis in LSC-BPPV from the sitting position in most cases, sparing the patient supine positionings and related symptoms. UBP could also allow clinicians to proceed directly with repositioning maneuvers from the upright position.

Impact of 21-Gene Breast Cancer Assay on Treatment Decision for Patients with T1-T3, N0-N1, Estrogen Receptor-Positive/Human Epidermal Growth Receptor 2-Negative Breast Cancer: Final Results of the Prospective Multicenter ROXANE Study.

BACKGROUND: The ROXANE Italian prospective study evaluated the impact of the 21-gene Recurrence Score (RS) results on adjuvant treatment decision for patients with early breast cancer. MATERIALS AND METHODS: Nine centers participated. Physicians used the RS test whenever unsure about adjuvant treatment recommendation for patients with estrogen receptor-positive/human epidermal growth receptor 2-negative, T1-T3, N0-N1 early breast cancer. Pre-RS and post-RS treatment recommendations were collected. RESULTS: A total of 251 patients were included. N0 patients (61%) showed higher grade (p < .001) and higher Ki67 (p = .001) and were more frequently progesterone receptor negative (p = .012) as compared with N1 patients. RS results were as follows: <11, n = 63 (25.1%); 11-25, n = 143 (57%); and ≥26, n = 45 (17.9%). Higher RS was found in N0 vs. N1 patients (p = .001) and in cases of G3 (p < .001) and higher Ki67 (p < .001). The rate of change in treatment decision was 30% (n = 75), mostly from chemotherapy (CT) plus hormone therapy (CT + HT) to hormone therapy (HT; 76%, n = 57/75). The proportion of patients recommended to CT + HT was significantly reduced from pre-RS to post-RS (52% to 36%, p < .0001). CT use reduction was more evident for N1 patients (55% to 27%) than for N0 patients (50% to 42%) and was observed only in cases of RS ≤17. CONCLUSION: Physicians predominantly used the 21-gene assay in N0 patients with a more aggressive biology or in N1 patients showing more indolent biology. In this selected patient population, the use of RS testing led to a 30% rate of change in treatment decision. In the N1 patient subgroup, the use of RS testing contributed to reduce CT use by more than half. IMPLICATIONS FOR PRACTICE: This study shows that, even in a context in which physicians recommend a high proportion of patients to endocrine treatment alone before knowing the results of the Recurrence Score (RS) assay, the use of the RS test, whenever uncertainty regarding adjuvant treatment recommendation is present, significantly contributes in further reducing the use of chemotherapy, especially for N1 patients.

Pneumolabyrinth and Recurrent Paroxysmal Positional Vertigo After Traumatic Stapes Fracture.

OBJECTIVES:: The development of pneumolabyrinth without previous head trauma is a rare event; the associated symptoms may be nonspecific, and they can simulate various cochleo-vestibular pathological entities. The aim of the present study is to describe one of these rare occurrences, characterized by a peculiar onset. METHODS:: We report a case of stapes fracture secondary to ear pick penetration into the middle ear with a pneumolabyrinth that caused a recurrent paroxysmal positional vertigo (PPV) mimicking a canalolithiasis. RESULTS:: The patient developed a profound left sensorineural hearing loss and an intractable PPV with "migrant" features. A pneumolabyrinth was visualized with high-resolution computed tomography. A perilymphatic fistula (PLF) with stapes fracture was found while performing an explorative tympanotomy. After the surgical treatment of the PLF, the patient no longer complained of vestibular symptoms. CONCLUSIONS:: To our knowledge, this is the fifth case of traumatic pneumolabyrinth simulating a canalolithiasis without previous history of temporal bone trauma and/or middle ear surgery. A pneumolabyrinth should be suspected in case of patients presenting recurrent intractable PPV after ear trauma.

Spontaneous Canalith Jam and Apogeotropic Horizontal Canal Benign Paroxysmal Positional Vertigo: Considerations on a Particular Case Mimicking an Acute Vestibular Deficit.

OBJECTIVE: Canalith jam refers to a condition caused by an otolithic clump blocked inside a semicircular canal, generally provoked by canalith repositioning procedure. We describe the first case of spontaneous canalith jam mimicking an acute vestibular deficit. PATIENT: We report the case of an 82-year-old woman who suffered a sudden episode of persistent rotational vertigo with nausea and vomiting, not provoked by head movements. INTERVENTIONS: Videonystagmography revealed a horizontal right-beating spontaneous nystagmus, inhibited by visual fixation. Surprisingly, the positional test showed a direction changing apogeotropic horizontal nystagmus weaker in the left side, compatible with a left side horizontal canal canalolithiasis of the apogetropic type. Returning to the sitting position, a spontaneous nystagmus was observed again, not tilt sensitive. A left side caloric paresis was found. RESULTS: After performing liberatory maneuvers, the spontaneous nystagmus disappeared and a horizontal canal benign paroxysmal positional vertigo of geotropic type was documented. The canal paresis also disappeared. CONCLUSIONS: Canalith jam is rarely described and is overall observed as a repositioning manoeuvre complication, not as a mimicker of a vestibular neuritis. Furthermore, our case represents the first observation of a recurrent canalith jam and apogeotropic variant of horizontal canal benign paroxysmal positional vertigo.

Sneezing and Perilymphatic Fistula of the Round Window: Case Report and Systematic Review of the Literature.

The goal of the present study was to describe a case of perilymphatic fistula (PLF) of the round window (RW) that occurred after sneezing, along with a review of the literature. We report a case of PLF of RW, which was provoked by sneezing, and its consequent medical and surgical treatments. With respect to the review of the literature, articles were initially selected based on their titles or abstracts, followed by methodological evaluation. The patient underwent an explorative tympanotomy (ET) with packaging of RW with the pericondrium, following which the patient's complaints regarding vertigo and imbalance disappeared, but the severe sensorineural hearing loss persisted. For the literature review, five references were selected. These studies showed a great variety in the clinical presentation and healing of symptoms. Sneezing represents a rare but well-recognized cause of PLF, as reported in our case. The correct selection of patients who should undergo ET and an early surgical repair of PLF are mandatory for better outcomes, especially in case of hearing.

First Prospective Multicenter Italian Study on the Impact of the 21-Gene Recurrence Score in Adjuvant Clinical Decisions for Patients with ER Positive/HER2 Negative Breast Cancer.

BACKGROUND: The Breast DX Italy prospective study evaluated the impact of the 21-gene recurrence score (RS) result on adjuvant treatment decisions for patients with early breast cancer. MATERIALS AND METHODS: Nine centers (two Hub and seven Spoke centers of the Veneto Oncology Network) participated. Consecutive patients with estrogen receptor positive, human epidermal growth receptor negative, T1-T3, N0-N1 early breast cancer were prospectively registered; only those meeting protocol-defined clinicopathological "intermediate risk" criteria were eligible for the RS test. Pre-RS and post-RS physicians' treatment recommendations and treatment actually received were collected. RESULTS: A total of n = 124 N0 and n = 126 N1 patients underwent the RS assay. The majority had Grade 2 tumors (71%); median age was 55 years, median tumor size was 16 mm, and median Ki67 expression was 20%. Patients enrolled at Hub centers presented higher-risk features. The distribution of RS results was <18 (60.8%), 18-30 (32.4%), and >30 (6.8%). The indication before RS was hormonal therapy (HT) alone in 52% of cases. An indication before RS of chemotherapy (CT)+HT was more frequent for patients with N1 versus N0 tumors (57% vs. 39%, p = .0035) and for patients enrolled at Hub versus Spoke centers (54% vs. 36%, p = .007).The overall rate of change in treatment decision was 16% (n = 40), mostly from CT+HT to HT (n = 30). According to nodal status, rate of change in treatment decision was 12% for the N0 cohort and 20% for the N1 cohort. The proportion of patients recommended to CT+HT was significantly reduced from before to after RS (48% to 40%, p < .0016), especially in the N1 cohort (57% to 45%, p = .0027) and at Hub centers (54% to 44%, p = .001). CONCLUSION: Despite frequent indication of HT before RS, the use of the RS assay further contributed to sparing CT, especially for patients with N1 tumors and at Hub centers. IMPLICATIONS FOR PRACTICE: This study shows that, although a high proportion of patients were recommended to receive endocrine treatment alone before knowing the recurrence score (RS) assay, the RS test further contributed in sparing chemotherapy for some of these patients, especially in case of the N1 stage or for patients enrolled at referral centers. These data highlight the need for further work in collaboration with health authorities and companies in order to define strategies for the implementation of the use of RS testing in clinical practice in the Italian setting.

From "Circe's Root" to "Spongia Soporifera": The Role of the Mandrake as True Anesthetic of Ancient Times.

Several ancient authors cited mandrake as a powerful and well-known narcotic drug: from Homer to Dioscorides, from Plato to Aristotle, passing from Hippocrates, Demosthenes, Theophrastus, Celsus, and Apuleius. Their detailed studies included the concrete appearance of the plant, the related recipes including mandrake as essential ingredient, the right dosages, how to administer the obtained medication, and the possible collateral effects. Even in the Middle Ages, the success of this root continued: Isidore of Seville, Theodoric of Cervia, Gilbertus Anglicus, and William from Varignana extensively reported their researches on sponges soaked with mandrake juice, which were used before surgical interventions as soporific tools. This article represents a travelogue among ancient ages to discover the anesthetic properties of the mandrake.

Retraction pocket excision with cartilage grafting as a preventive surgery for cholesteatoma.

Aims: The goal of the present study is to summarize our experience on surgical management of retraction pockets (RP) as a preventive tool against cholesteatomas. Methods: Twenty-five ears have been followed up for a mean period of 6.16 ± 4.35 years (from 1 to 17 years). The sample presented a mean age of 47.56 ± 19.11 years (from 16 to 73 years). All patients underwent cartilage graft surgery. Furthermore 10 (40%) underwent tympanoplasty (TPL) type I, 14 (56%) TPL type II and 1 (4%) TPL type V. Results: Eleven ears (44%) showed cholesteatoma: all these cases were stage III according to Charachon staging, and stage IV or V according to Gersdorff classification. Twelve patients (48%) showed erosion of the ossicular chain. Of these, five were associated with cholesteatoma and seven only with retraction. The recurrence rate of cholesteatoma was 12%. None of the patients with a stage II or III RP (according to Gersdorff classification) developed cholesteatoma. The recurrence of RP was 0%.In regards to literature review, seven references were selected. These studies showed a success rate ranging from 79.1% to 88%, while recurrences of RP varied from 6.4% to 13%. Only one study specified a recurrence rate of cholesteatoma of 28%. Conclusions: Surgical treatment of stages II and III RP is an effective tool to prevent cholesteatoma formation. The presence of keratin accumulation and cholesteatoma at the RP (stages IV and V, according to Gersdorff) are the real predictors of poor prognosis.

Congenital Intratympanic Cholesteatoma in an Adult Patient: A Case Report and Review of the Literature.

Congenital cholesteatoma within the tympanic membrane is an uncommon entity, with only few cases being documented. The aetiopathogenesis of this lesion is still unknown; however, when cholesteatoma develops in subjects without any history of previous ear inflammation, as in the case we report here, an embryologic origin is deeply suspected. An acquired origin is hypothesized in patients with a previous history of an inflammatory process of the external or middle ear because of the proliferation of the basal cell layer of the tympanic membrane epithelium. We report a rare case of congenital cholesteatoma of the tympanic membrane in an adult patient and review the literature.

Anatomically Based Outcome Predictors of Treatment for Obstructive Sleep Apnea with Intraoral Splint Devices: A Systematic Review of Cephalometric Studies.

AIMS: The aim of this review is to summarize data from the literature on the predictive value of anatomy-based parameters, as identified by cephalometry, for the efficacy of mandibular advancement devices (MAD) for the treatment of obstructive sleep apnea (OSA). METHODS: Articles were initially selected based on their titles or abstracts. Full articles were then retrieved and further scrutinized according to predetermined criteria. Reference lists of selected articles were searched for any missed publications. The selected articles were methodologically evaluated. RESULTS: Of an initial 311 references, 13 were selected that assessed correlations between polysomnographic and cephalometric variables. The majority of studies demonstrated a correlation between treatment effectiveness and features as determined by cephalometric analysis, such as the mandibular plane angle, hyoid bone distance to mandible, antero-posterior diameter of the maxilla, tongue area, cranial base, and soft palate. CONCLUSIONS: The mandibular plane angle and the distance between hyoid bone and mandibular plane was found to have a predictive value for MAD effectiveness in OSA patients. However, the relative weak and somewhat inconsistent cephalometric data suggest that decisions based solely on these factors cannot be recommended, especially because an integrated analysis of other risk factors (e.g., age, sex, BMI) should also be taken into account.

Oral appliances for the treatment of obstructive sleep apnea in patients with low C-PAP compliance: a long-term case series.

OBJECTIVES: To assess the effectiveness of mandibular advancement devices (MADs) for the treatment of obstructive sleep apnea syndrome (OSAS) over a long-term follow-up in patients non-compliant with continuous positive airway pressure (CPAP) and to identify potential predictive factors of response to MADs. METHODS: Fifteen OSAS patients were enrolled. Apnea-hypopnea index (AHI) and daytime sleepiness were assessed at baseline and at the end of follow-up. Potential baseline predictors of treatment effectiveness were assessed. RESULTS: AHI and Epworth Sleepiness Scale (ESS) scores improved significantly with MADs. Sixty per cent of patients were 'responders', of whom 33% were 'full responders'. Sixty-seven per cent of patients showed total compliance. No correlations between the potential predictors and the response to MAD therapy were found. DISCUSSION: Effectiveness of MAD therapy was shown over a long-term follow-up in OSAS patients with low compliance to CPAP. Efforts to identify predictive success factors fell short.

Disseminating the WHO International Classification of Functioning Health and Disability (ICF) in the Veneto region of Italy.

PURPOSE: To show the feasibility and effect of a large formation effort focused on the International Classification of Functioning, Disability and Health (ICF), which may introduce a revolutionary new conceptual framework for people involved in rehabilitation services. METHODS: We here describe the large information/formation project launched by the Regional Direction for Social Services of the Veneto region (Italy). Here we describe the first of the two steps of the project, aimed to reach 900 health professionals throughout the whole region. They were exposed to a structured modular course consisting of a mix of frontal lectures and workshop sessions. During the workshop sessions the participants were confronted with questions referring to the actual application of ICF in their services. RESULTS: The results show that the attendance (90%) was very high. The workshop sessions provided interesting indications on the possible applications of ICF in the clinical settings, as well as points of strength and potential problems that the implementation of ICF may have in the Regional Health Service. CONCLUSIONS: To our knowledge this is the largest alphabetization effort on ICF attempted in a public health system, and it indicates a possible effective approach to its controlled diffusion and future implementation.