Tumor Budding, p53, and DNA Mismatch Repair Markers in Sinonasal Intestinal-Type Adenocarcinoma: A Retrospective Study Supports the Adverse Prognostic Impact of Tumor Budding.

Sinonasal intestinal-type adenocarcinoma (ITAC) is a very rare, closely occupational-related tumor with strong histological similarities to colorectal cancer (CRC). In the latter, tumor budding (TB) is widely recognized as a negative prognostic parameter. The aim of this study was to evaluate the prognostic role of TB in ITAC and to correlate it with other established or emerging biomarkers of the disease, such as p53 and deficient DNA mismatch repair (MMR) system status/microsatellite instability (MSI). We retrospectively analyzed 32 consecutive specimens of patients with ITAC diagnosis treated in two institutions in Northern Italy. We reviewed surgical specimens for TB evaluation (low-intermediate/high); p53 expression and MMR proteins were evaluated via immunohistochemistry. Results were retrospectively stratified using clinical data and patients' outcomes. According to bud counts, patients were stratified into two groups: intermediate/high budding (>4 TB) and low budding (≤4 TB). Patients with high TB (>4) have an increased risk of recurrence and death compared to those with low TB, with a median survival of 13 and 54 months, respectively. On multivariate analysis, considering TB, therapy, and stage as covariates, TB emerged as an independent prognostic factor net of the stage of disease or type of therapy received. No impact of p53 status as a biomarker of prognosis was observed and no alterations regarding MMR proteins were identified. The results of the present work provide further significant evidence on the prognostic role of TB in ITAC and underline the need for larger multicenter studies to implement the use of TB in clinical practice.

HPV impact on oropharyngeal cancer radiological staging: 7th vs 8th edition of AJCC TNM classification.

PURPOSE: To evaluate the agreement between pathological and radiological staging in oropharyngeal cancer by comparing the 7th and the 8th edition of the AJCC TNM system. METHODS: This retrospective cohort study included 57 cases of oropharyngeal cancer with lymph node metastases staged with the 7th and 8th editions of the AJCC TNM system. Comparison between clinical and radiological features and differences in agreement rates were calculated between radiological and pathological staging for the primary tumor (T) and lymph nodes (N) in HPVpos and HPVneg cases. RESULTS: Comparison of HPVpos and HPVneg revealed a significantly different distribution between early and advanced stages in the 8 th edition, with a relevant number of HPVpos patients redefined from advanced stages whit the 7 th ed. to early stages with 8 th ed. (p < 0.01); no significant differences were found when comparing all diagnostic methods for T and N. CONCLUSIONS: The 8th edition of the AJCC TNM seems to lead to better pretreatment staging. For both HPVpos and HPVneg, the agreement between pretreatment radiological and pathological staging.

Multicentre study on resection margins in carcinoma of the oral cavity, oro-hypopharynx and larynx.

Objective: The prognostic significance of the resection margins is still subject of conflicting opinions. The purpose of this paper is to report the results of a study on the margins in carcinoma of the oral cavity, oro-hypopharynx and larynx. Methods: A multicentre prospective study was carried out between 2015 and 2018 with the participation of 10 Italian reference hospitals. The primary objective was to evaluate local control in patients with well-defined clinical characteristics and comprehensive histopathological information. Results: During the study period, 455 patients were enrolled; the minimum follow-up was 2 years. Previous treatment, grading and fresh specimen examination were identified as risk factors for local control in multivariate analysis. On the basis of these results, it seems possible to delineate "risk profiles" for different oncological outcomes. Discussion: The prognostic significance of the margins is reduced, and other risk factors emerge, which require diversified treatment and follow-up. Conclusions: Multidisciplinary treatment with adjuvant therapy, if indicated, reduces the prognostic importance of margins. Collaboration with a pathologist is an additional favourable prognostic factor and quality indicator.An appendix with literature review is present in the online version.

Giant Epidermoid Cyst of Posterior Fossa-Our Experience and Literature Review.

INTRODUCTION: Intracranial epidermoid cysts are the most frequent congenital intracranial lesion. They rare and benign tumors that can present in different clinical situations depending on location and extension of the disease. Diagnosis is obtained with radiological imaging with RM and non-enhanced TC as elective investigating methods. Elective treatment is surgery, based on total/subtotal excision sparring healthy neurovascular structures, considering the benign nature of this lesion. CASE REPORT: In this study we present the case of a 79-year-old woman affected by recidivist epidermal cyst of the posterior fossa. Clinical presentation was characterized by positional subjective vertigo, intense headache localized in the right part of the head increased by Valsalva maneuver and retroarticular subcutaneous swelling. Radiological investigation found a giant epidemoid cyst of the posterior fossa (8,4 x 4,8 x 5,8 cm), treated with surgery. In the postoperative, the patient was fine and no neurological deficit has been encounterd. REVIEW: In this study, we present a review of the literature regarding giant epidermoid cysts of posterior fossa. Only 11 cases were reported before ours, which actually is one of the largest ever described.

Organ preservation in locally advanced head and neck cancer of the larynx using induction chemotherapy followed by improved radiation schemes.

The present prospective study seeks to evaluate overall and disease free survival, response and organ preservation rate, and toxicity of an intensive chemotherapy regimen (CT) followed by unconventional radiotherapy (RT) in patients with locally advanced operable head and neck cancer. Between January 1998 and December 2006 (June 2005), 115 patients with locally advanced, operable head and neck cancer were evaluated. A total of 333 cycles of neoadjuvant CT (cisplatin-5FU, days 1, 14, 28) followed by hyperfractionated/accelerated radiotherapy were given to 108 patients. A total of 108 patients were evaluable and received the planned CT-RT treatment. Two months after the end of RT, 97.2% of patients had a clinical complete remission of the primary and 67.5% of the neck node site. The overall survival was 55% and cause-specific survival was 73% at 5 years. Of the 33 relapsed patients, 12 recurred only at the primary site and 10 patients had distant metastases. The overall organ preservation rate was 73.5%. The chemotherapy regimen reported an overall cardiotoxicity from 5FU in 14% of patients, with severe toxicity in 3%. The radiotherapy schedule developed 84% of Grade 3-4 mucositis in the observed patients. The accelerated CT-RT regimen is able to achieve a high rate of larynx preservation, a good tolerability, and a satisfactory cause-specific overall survival.

The watch-pat in pediatrics sleep disordered breathing: Pilot study on children with negative nocturnal pulse oximetry.

OBJECTIVES: The main purpose of this study was to determine the efficacy of Watch-PAT in Pediatric Sleep Disordered Breathing (PSDB) diagnosis in children with symptoms suggestive of PSDB, in which the nocturnal pulse oximetry was negative according to the Brouilette criteria. METHODS: We enrolled 28 patients aged between 5 and 12 years (mean age: 7.75 ± 1.69), who underwent the registration with Watch-PAT, that utilizes the Peripheral Arterial Tone (PAT), AHI, RDI, body position, snoring, pulse oximetry and actigraphy. RESULTS: Recording Watch-PAT was indicative of PSDB in 10/28 (35.7%) patients; when it was placed the threshold of AHI > 1 the number of positive patients for PSDB increased to 17/28 (60.7%). Exists a positive correlation between pat-RDI (rho = 0.798, p = 0.005) and the snoring > 40% of the time (rho = 0.656, p < 0.001) were correlated with the pat-AHI values. CONCLUSION: The recording Watch-PAT appears to permit the defection of a certain number of SDB that might escape to the clinical evaluation and pulse oximetry only.

Multicenter research into the quality of life of patients with advanced oropharyngeal carcinoma with long-term survival associated with human papilloma virus.

The treatment of advanced-stage oropharyngeal squamous cell carcinoma may utilize various modes, including combining surgery with chemoradiotherapy (CTRT), or primary CTRT followed by rescue surgery. In previous literature it has been revealed how patients treated with combined modes report a low quality of life (QoL) and severe consequences following surgery, radiotherapy and chemotherapy, in the short and in the long-term. The decrease in the QoL of patients treated with high-intensity multi-modal strategies highlights the necessity of modifying treatments, particularly for young HPV-positive patients, where an increased survival rate has already been reported. The modified treatment for HPV-positive tumors in the tonsils and at the base of the tongue is based on the deintensification of therapies aiming to reduce toxicity and thereby improve QoL in the long term, whilst still maintaining therapeutic effectiveness. The aim of the present study was to evaluate the QoL in patients with a long-term survival, who were treated with combined therapy for squamous cell tumors in the tonsils and at the base of the tongue, and to compare the results observed in HPV-positive and HPV-negative patients. According to statistical analysis, differences in the general QoL and in the single scales of the European Organization for the Research and Treatment of Cancer questionnaires were not correlated with the type of therapy selected for the particular patient. QoL considered the presence of HPV, the type of treatment, the subregion of the tonsils vs. the base of the tongue and the disease stage at the time of diagnosis, and was determined to be non-influential with regard to these specific variables.

Neoadjuvant accelerated chemotherapy followed by hyperfractionated radiation therapy in patients with operable, locally advanced head and neck carcinoma.

A prospective phase II trial was carried out to evaluate an accelerated chemotherapy (CT) regimen followed by hyperfractionated radiation therapy (RT) in previously untreated Stage III-IV, operable (total laryngectomy), head and neck cancer patients. The current study evaluates overall survival, loco-regional control, organ preservation rates and toxicity. Between April 1997 and December 2002, 68 patients with advanced head and neck cancer were treated with 3 cycles of induction CT (cisplatin and 5-fluorouracil; days 1, 14, and 28) followed by hyperfractionated RT (7440 cGy/62 fractions). Sixty patients received the planned RT-CT treatment. Two months after the end of RT, 96% of patients had a clinical complete remission of the primary and 66% of the neck disease. At a median follow-up of 32 months, the 3-year overall and disease-free survival rates were 66% and 76%, respectively. Seven patients recurred on the primary site, 1 on the neck and 2 patients only had distant metastases. The organ preservation rate was 73%. Acute grade 3-4 mucositis occurred in 75% of patients and an 18% rate of CT-related cardiotoxicity was reported. The accelerated CT-RT regimen achieves a high rate of larynx preservation albeit with considerable toxicity. The current prospective clinical trial was approved by the Ethics Committee of the Centro di Riferimento Oncologico (C.R.O.) on May 27, 1996, # CRO-02-96. Written informed consent was required from all patients entering the study.

Gamma probe accuracy in detecting the sentinel lymph node in clinically N0 squamous cell carcinoma of the head and neck.

The sentinel node, which is not always located at the first-echelon nodal area close to the primary tumor, is the initial recipient of possible metastasis. In order to verify the usefulness of the sentinel lymph node technique in the staging of head and neck cancers, we studied 31 untreated patients with squamous cell carcinoma of the upper airways by injecting them around the primary tumor with technetium 99m albumin microcolloid (99mTc) and submitting them to selective neck dissection with en bloc tumor removal. The nodes were examined after gamma-probe identification of the sentinel node(s). No patients were found to have microscopic tumor spread outside the level(s) containing the gamma-probe-identified sentinel node(s). In only 1 case was the metastatic node not the gamma-probe-positive one, but an adjacent one. Lymphoscintigraphy with 99mTc seems reliable in identifying the sentinel node(s) and might contribute to the reduction of surgical morbidity by reserving therapeutic neck dissection for cases with histologically confirmed nodal metastasis.

Intensity-modulated radiotherapy (IMRT)/Tomotherapy following neoadjuvant chemotherapy in stage IIB-IVA/B undifferentiated nasopharyngeal carcinomas (UCNT): a mono-institutional experience.

To evaluate the outcome of Undifferentiated Nasopharyngeal Carcinomas (UCNT) treated with intensity-modulated radiation therapy with Simultaneous Integrated Boost (SIB), following induction chemotherapy. Between January 2006 and June 2009, 52 patients with stage II B-IVA/B UCNT were treated either with linac-IMRT or Tomotherapy. All patients were scheduled to receive three cycles of cisplatin based neoadjuvant chemotherapy. With a median follow-up of 38.5 months (range 12.3-64.1), 3 year overall survival (OS), disease-free survival (DFS), and DFS by T2a-2b and T3-T4-stage were 95.0%, 84.6%, 89.0%, and 78.0%, respectively. At multivariate analysis, none of the examined prognostic factors reported statistical significance. N-classification was not a significant predictive factor for either OS or development of distant metastases. T-stage alone had a borderline effect on DFS and development of metastases. No difference between Tomotherapy and linac-IMRT emerged in terms of loco-regional control and development of severe, acute, and late toxicities. The most significant severe, acute toxicities were grade 3 (32.7%) and grade 4 (7.7%) mucositis. No grades 3 and 4 late toxicities were observed. The most commonly observed late effect was xerostomia, 11.5% patients complained grade 2 xerostomia. The severity of grade 2 xerostomia diminished over time with only four patients not improving salivation. IMRT-SIB following neoadjuvant chemotherapy was very satisfactory in terms of local control, regional control, DFS and OS rates in patients with stage IIB to IVB UCNT. In our experience, adding concurrent chemotherapy to IMRT after neoadjuvant chemotherapy in loco-regional widespread disease resulted to be the indicated approach.

Postoperative reduced dose of cisplatin concomitant with radiation therapy in high- risk head and neck squamous cell carcinoma.

BACKGROUND: The role of low doses of cisplatin and concomitant postoperative radiotherapy in high risk head and neck squamous cell carcinoma has not yet been defined. METHODS: Patients treated with definitive surgery, who had histological evidence of involvement of more than 2 lymph nodes, extracapsular extension of disease, perineural and/or intravascular invasion, involved or close surgical margins, received postoperative radiotherapy plus 75 mg/m(2) of cisplatin every 3 weeks during the radiotherapy cycle. The primary endpoints were to evaluate treatment compliance and overall, cause-specific, and disease-free survival. RESULTS: A total of 142 patients were enrolled. With a median follow-up of 40 months, 5-year overall survival was 68%, cause-specific survival 78% and disease-free survival 82%. At multivariate analysis surgical margins status and extracapsular lymph node invasion were the only statistically significant prognostic factors. Fifty-three percent of the patients developed severe mucositis and 14% hematologic toxicity of grade 3. The 3 planned concomitant chemotherapy cycles were delivered to 48% of the patients. CONCLUSIONS: Postoperative radiotherapy and concomitant low-dose cisplatin was an effective treatment in high risk head and neck patients. The total toxicity observed was lower compared with that reported with higher doses of cisplatin, although the delivery of all the 3 planned chemotherapy cycles was challenging. The distant failure rate was high, which was an unsatisfactory result.

Changes in presentation and survival of head and neck carcinomas in Northeastern Italy, 1975-1998.

BACKGROUND: During the last 20 years, survival rates of head and neck carcinoma patients in the United States and Europe have plateaued. To determine the factors that can reduce mortality rates, we examined changes in clinical presentation and survival rates across 24 years of treatment of head and neck carcinoma patients. METHODS: A retrospective study of patients with head and neck carcinoma was conducted from January 1, 1975, to December 31, 1998. We identified 2143 eligible patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx. Changes in gender, clinical stage, and therapy were evaluated separately for each site of cancer across five consecutive periods. Probability of dying and overall survival rates were estimated. Odds ratios (ORs) and hazard ratios were calculated. RESULTS: An increase in T1 versus T2 or higher stage carcinoma was more probable for the oral cavity and larynx (OR = 4.1 and 3.0, respectively) in the last versus the earliest period. An increase in radical treatments was more probable for carcinomas of the oral cavity, oropharynx, hypopharynx, and larynx (10.2, 34.8, 12.5, and 2.1-fold, respectively) in the last versus the earliest period. A decreasing trend of probability of dying from the first head and neck carcinoma during the 1970s versus the 1990s was found. The overall survival rates at 5 years was 32% in 1975-1978 versus 51% in 1989-1993. CONCLUSIONS: In contrast with survival rates in the United States and Europe, our findings show a significant increase in overall survival rates during the last 20 years. This increase is attributable to changes in diagnostic-therapeutic approaches and to early consultation with a physician for symptoms arising in the head and neck region.

Interferon-gamma secretion and perforin expression are impaired in CD8+ T lymphocytes from patients with undifferentiated carcinoma of nasopharyngeal type.

An efficent antitumor and antiviral cellular immune response requires optimal interferon-gamma (IFN-gamma) secretion and perforin expression in CD8(+) T cells. The aim of this study was to define whether CD4(+) and CD8(+) T cells from patients with undifferentiated carcinoma of nasopharyngeal type (UCNT), a tumor regularly associated with the Epstein-Barr virus (EBV), have abnormal phenotype profiles, cytokine production, perforin and CD3-zeta expressions. Our data showed that CD4 and CD8 subset distribution was not grossly altered in the peripheral blood of UCNT patients, while tumor biopsies contained an increased proportion of CD8(+) T cells. The analysis of the CD4(+) subset showed a defect in interleukin-2 (IL-2) production and a moderate increase of IL-10 production, a situation consistent with a Th1/Th2 imbalance. We have also demonstrated that CD8(+) lymphocytes from UCNT patients had a marked impairment of IFN-gamma secretion and perforin expression. This impairment was not related to the presence of detectable EBV DNA in the plasma. In UCNT patients, the blockade of the perforin pathway and of IFN-gamma production may constitute important mechanisms for immune escape by the tumor and for impaired control of EBV replication.

Radiotherapy for patients with early-stage glottic carcinoma: univariate and multivariate analyses in a group of consecutive, unselected patients.

BACKGROUND: Radiotherapy (RT) has a remarkable success rate in the treatment of patients with glottic carcinoma. The objectives of the current study were to assess the results in a group of consecutive patients with comparable characteristics who were treated with RT (6-megavolt photon linear accelerator) and to determine the prognostic factors that may influence local control in patients with early-stage glottic carcinoma. The impact on local control of tobacco smoking and second primary malignancies also was investigated. METHODS: Four hundred ten patients with T1-T2 squamous cell carcinoma of the glottis who were treated between 1986 and 2001 were analyzed retrospectively with regard to local control and overall survival. Potential prognostic factors for local control were evaluated with univariate and multivariate models. The impact of technologic advances also was evaluated. RESULTS: The 5-year and 10-year overall survival rates were 83% and 63.5%, respectively. The overall 10-year local control rate for patients with T1-T2 glottic carcinoma was 89%. The median time to recurrence was 7 months. Univariate analysis showed that tumor category, tumor size, macroscopic appearance of the lesion, RT fraction size, persistent edema, year of RT treatment, unchanged dysphonia, and surgical option all had a significant influence on local control; whereas multivariate analysis showed that only persistent dysphonia and year of RT treatment were significantly associated with increased local control. A 22.2% rate of second primary malignancies was reported: second primary tumors were the major cause of death in the patients studied. Only 2 patients died of laryngeal carcinoma; 304 patients were alive with their disease in complete remission, 1 patient was alive with recurrent laryngeal carcinoma after undergoing salvage surgery, and 103 patients died of either intercurrent disease or a second primary tumor. CONCLUSIONS: The use of a 6-megavolt photon linear accelerator achieved a high rate of local control in patients with T1-T2 glottic carcinoma. Dysphonia and the year of RT treatment were the most important prognostically significant factors for patient outcome. The occurrence of a second primary tumor was the most frequent cause of death, especially among patients who did not stop smoking after a diagnosis of glottic carcinoma.