A Disseminated Mycobacterium Abscessus Infection in a Patient Affected by Pulmonary Graft versus Host Disease: Case Report with a Revision of Literature.

Mycobacterium abscessus complex, hereinafter Mab, is a taxonomic group of rapidly growing, nontuberculous mycobacteria (NTM). Despite major advances in understanding virulence, pathogenicity and mechanism of antibiotic resistance, Mab remains a significant cause of pulmonary and extra-pulmonary disease. Herein, we describe a disseminated, macrolide-resistant, Mab subspecies abscessus infection occurring in a severely immune-compromised 34-year-old allotransplanted female patient affected by pulmonary chronic graft versus host disease (cGVHD). The infection was characterized by hematogenous spread, and besides lungs, it involved skin, and soft tissues, resulting in a highly debilitating, painful, and finally fatal disease. Our case describes the severe impact of Mab infections in the setting of allogeneic hematopoietic stem cells transplant (alloHSCT) and related complications. It also highlights the unmet need of preventive and surveillance measures together with the urgency of developing effective vaccines and drugs against emerging NTM. The scarce literature regarding Mab infections in alloHSCT patients is also reviewed.

Neoangiogenesis in laryngeal carcinoma: angiogenin and CD105 expression is related to carcinoma recurrence rate and disease-free survival.

AIMS: Angiogenin regulates angiogenesis supporting primary and metastatic tumour growth. CD105 is a proliferation-associated protein expressed in angiogenic endothelial cells. The aim of this study was to investigate for the first time angiogenin expression in laryngeal squamous cell carcinoma (LSCC) and to evaluate the relationship between angiogenin and CD105 expression, clinicopathological and prognostic parameters. METHODS AND RESULTS: A total of 108 consecutive operable LSCCs were studied. Angiogenin expression was determined immunohistochemically in both carcinoma cells and intratumoral vessels. CD105 expression was evaluated in endothelial cells of LSCC and calculated by a computer-based image analysis system. The percentage of the fields occupied by CD105-assessed microvessels was determined. Angiogenin expression in carcinoma cells was higher in LSCC patients who experienced loco-regional recurrence of disease (P=0.032). Disease-free survival (DFS) was shorter in cases with carcinoma cells showing angiogenin expression >21.0% (P=0.035). Angiogenin expression in carcinoma cells was correlated strongly with the angiogenin score in endothelial cells of intratumoral vessels (P=0.0000). Higher loco-regional carcinoma recurrence rate and shorter DFS in patients with high CD105 expression were found (P=0.0004, P=0.0001). CONCLUSIONS: Angiogenin expression in laryngeal carcinoma cells and CD105 expression can be considered as potentially useful to detect LSCC patients with higher risk of disease recurrence who might benefit from more aggressive therapy.

CD105 is a marker of tumour vasculature and a potential target for the treatment of head and neck squamous cell carcinoma.

BACKGROUND: The importance of angiogenesis in solid tumour growth is well recognised. Tumour angiogenesis is considered the result of an imbalance between pro- and anti-angiogenic factors produced by both the malignancy and normal cells. Endoglin (CD105) is a proliferation-associated, hypoxia-inducible glycoprotein that seems to be clinically superior to other pan-endothelial markers in the selective evaluation of tumour angiogenesis. Several studies have revealed CD105 up-regulation in a wide range of tumour endothelia. Since 2002, endothelial CD105 expression has also been retrospectively investigated in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: An exhaustive literature review was performed to investigate available evidence on CD105 expression and its biological role and therapeutic potential in HNSCC. RESULTS: The available evidence supports the hypothesis that CD105 expression in HNSCC may be a valuable parameter for pinpointing patients at greater risk of recurrent malignancy and with a worse prognosis. A high CD105 expression in HNSCC was associated with metastatic lymph nodes in most of the studies. CONCLUSIONS: Prospective studies are mandatory to confirm that CD105 expression is a significant prognostic hallmark in HNSCC. The results of prospective studies could be relevant for the adoption of stricter follow-up protocols and/or alternative therapeutic regimens for patients with a high CD105 expression in HNSCC. Great interest is currently being focused on vascular targeting for therapeutic purposes. Preclinical studies on appropriate animal models resembling HNSCC to investigate the effects of inhibiting CD105 may show the efficacy of combined treatment strategies associating angiogenic-targeted with conventional therapies for HNSCC.

Laryngeal carcinoma lymph node metastasis and disease-free survival correlate with MASPIN nuclear expression but not with EGFR expression: a series of 108 cases.

Despite advances in laryngeal squamous cell carcinoma (LSCC) treatment, patient survival has not improved in the last two decades. Novel, more effective strategies should be based on receptor-mediated LSCC-targeted therapy. The epidermal growth factor receptor (EGFR) is the most widely studied molecular target. MASPIN multifaceted anti-tumor effects have been rarely evaluated in LSCC. The aims of this study were to investigate EGFR and MASPIN expression and the role of sub-cellular MASPIN localization in LSSC. MASPIN and EGFR expression and the sub-cellular localization of MASPIN were assessed using a computerized image analysis system in 108 consecutive cases of operable LSCC. The rates of occurrence of lymph node metastases and recurrent disease were lower in patients with a nuclear pattern of MASPIN expression (p = 0.004, p = 0.0028). As expected, the loco-regional recurrence rate was lower in N0 patients (p = 0.009), but the disease recurrence rate was even lower in N0 patients with a nuclear localization of MASPIN (p = 0.020). Disease-free survival was longer in cases of LSCC with a nuclear MASPIN pattern (p = 0.003). The intensity of EGFR reactivity and the EGFR area fraction were unrelated to the clinico-pathological and prognostic parameters in LSCC. A nuclear MASPIN pattern is a promising prognostic indicator in LSCC, but further evidence is needed before elective neck dissection can be considered for cN0 LSCCs with a non-nuclear MASPIN pattern. Although a better understanding of the mechanisms behind sub-cellular MASPIN localization is mandatory, re-activating nuclear MASPIN in association with specific chemotherapeutic agents may be an important goal in the treatment of LSCC.

Survivin multifaceted activity in head and neck carcinoma: current evidence and future therapeutic challenges.

CONCLUSIONS: Survivin expression should be studied as a potential hallmark of higher risk oral, oropharyngeal and laryngeal squamous cell carcinomas (SCCs) to develop loco-regional recurrences. These outcomes could have a significant impact on both the treatment modalities and the intensity of post-treatment follow-up. Further investigation is necessary before considering elective neck dissection in patients with laryngeal SCC with high survivin expression. OBJECTIVES: Functioning simultaneously at cell division and apoptosis inhibition, survivin, a member of the inhibitor of apoptosis proteins family, plays a pivotal role in determining cell survival. Significant over-expression of survivin has been demonstrated in most human malignancies and correlated with more aggressive forms. This review focuses on the attempts to translate survivin biologic properties toward both a diagnostic/prognostic tool and a novel therapeutic target in head and neck SCC (HNSCC). MATERIALS AND METHODS: An exhaustive review of literature was performed to investigate available evidence about survivin expression, biological role and therapeutic potential in HNSCC. RESULTS: Multiple evidence indicates that, in HNSCC cell lines, survivin inhibition by gene therapy and by small molecule inhibitors significantly increases the anti-tumour activity of several cytotoxic and other targeted therapies.

MASPIN's prognostic role in patients with advanced head and neck carcinoma treated with primary chemotherapy (carboplatin plus vinorelbine) and radiotherapy: preliminary evidence.

CONCLUSIONS: Our very preliminary results support the hypothesis that MASPIN expression in primary head and neck squamous cell carcinoma (HNSCC) may be a valuable parameter for predicting patients' responses to a treatment based on carboplatin plus vinorelbine combined with radiotherapy. OBJECTIVES: The roles of induction chemotherapy and combined chemoradiotherapy in the treatment of locally advanced unresectable HNSCCs have evolved rapidly. MASPIN has a unique tumour-suppressing activity. Experimental evidence has shown that MASPIN suppresses tumour growth, angiogenesis, invasion and metastasis. We investigated the potential prognostic roles of MASPIN and p53 in a series of HNSCCs treated with carboplatin plus vinorelbine combined with radiotherapy. PATIENTS AND METHODS: Nineteen consecutive stage III or IV HNSCC patients were recruited. The treatment plan consisted of the administration of carboplatin on day 1 and vinorelbine on days 1 and 8. Four weeks later, carboplatin was administered concomitantly with radiation therapy. Expression of MASPIN and p53 was determined immunohistochemically in HNSCC diagnostic biopsies. RESULTS: A significant inverse relation was found between MASPIN expression and cN staging (p = 0.003). From a prognostic viewpoint, MASPIN expression was directly correlated with chemoradiotherapy response (p = 0.041). Moreover, the log-rank test showed a significant relationship between higher MASPIN expression and longer disease-free survival (p = 0.03), overall survival (p = 0.006) and disease-specific survival (p = 0.007).

The effects of sulfurous-arsenical-ferruginous thermal water nasal irrigation in wound healing after functional endoscopic sinus surgery for chronic rhinosinusitis: a prospective randomized study.

PURPOSE: Although several publications reported the benefits of nasal irrigation in the management of chronic rhinosinusitis and in sinonasal postoperative care, the available data are poorly controlled. The aim of this prospective randomized study was to compare the effects of sulfurous-arsenical-ferruginous thermal water nasal irrigation vs isotonic sodium chloride solution nasal irrigation after functional endoscopic sinus surgery (FESS) for chronic sinonasal disease considering the histomorphological characteristics of mucosal repair after sinus surgery. MATERIALS AND METHODS: Eighty patients who consecutively underwent FESS were randomly assigned (1:1) to postoperative nasal irrigation with sulfurous-arsenical-ferruginous thermal water or isotonic sodium chloride solution for 6 months. Intraoperative and postoperative (1, 3, and 6 months) mean counts of lymphocytes, neutrophils, eosinophils, plasma cells, histiocytes, and mast cells in ethmoid biopsies were blindly determined by a pathologist. RESULTS: Fifty-six patients underwent at least 2 postoperative biopsies. A statistically significant reduction of eosinophil count was disclosed 6 months postoperatively only after sulfurous-arsenical-ferruginous solution nasal irrigation (P = .04). After isotonic sodium chloride solution nasal irrigation, the mean eosinophil count in 6-month postoperative biopsies did not decrease. After both irrigation modalities, the mean mast cell counts in 6-month postoperative biopsies were significantly lower than in intraoperative biopsies (P < .05). Neutrophils, lymphocytes, histiocytes, and plasma cell counts were not significantly different between intraoperative vs 6-month postoperative biopsies independently from irrigation modality. CONCLUSIONS: Considering the important role of eosinophils in allergic response, we should suggest sulfurous-arsenical-ferruginous solution nasal irrigation in particular, which significantly reduces local eosinophil count, for allergic patients after FESS for chronic rhinosinusitis.

Expression of maspin in papillary Ta/T1 bladder neoplasms.

BACKGROUND: The aim of the present study was to evaluate maspin expression in bladder urothelial papillary neoplasms and test the results for correlation with clinicopathological parameters. PATIENTS AND METHODS: A total of 111 urothelial neoplasms from 66 patients were evaluated: pathological examination of primary tumours disclosed 48 pTa and 18pT1. Fourteen additional biopsies, negative for neoplasm, were collected as control biopsies. For each of the 111 neoplastic samples and for the 14 control cases maspin and MIB1 immunoreactivity was evaluated. The immunohistochemical reactions of the 66 primary neoplasms were used for statistical analysis when the disease-free interval, presence and number of relapses, and progression of the disease were tested, whereas all of the 111 tumors were used when the association between the maspin pattern and histological grade and/or pT were evaluated. Thirty-three patients with primary pTa papillary neoplasms (68.7%) and 11 out of eighteen with pT1 (61%), had subsequent relapses of disease. For maspin immunoreactivity the presence/absence of nuclear staining and the pattern of staining were considered. Four patterns of reactivity were recognized and were used for statistical analyses. RESULTS: A statistical association was found between the maspin pattern and pT, histological grade and nuclear staining. CONCLUSION: In papillary urothelial neoplasms, maspin has a pattern of distribution that is associated with the histological grade and pathological stage, and this probably reflects its different activities in the neoplastic process.

Laryngeal carcinoma recurrence rate and disease-free interval are related to CD105 expression but not to vascular endothelial growth factor 2 (Flk-1/Kdr) expression.

BACKGROUND: Tumour angiogenesis is the result of an inbalance between anti- and pro-angiogenic factors. CD105 (endoglin) is a component of the receptor complex of transforming growth factor (TGF-beta1). Vascular endothelial growth factor receptor 2 (VEGFR2 or Flk-1/KDR) belongs to the high-affinity VEGF receptors. The aim of the study was to investigate the expression, cellular localization and role of CD105 and VEGFR2 in laryngeal carcinoma. PATIENTS AND METHODS: Sections of 62 laryngeal carcinomas were stained with CD105 and VEGFR2/Flk-1/KDR antibodies. RESULTS: A significant association between CD105 expression and locoregional recurrence was found (p = 0.009). Interestingly, in N0 patients CD105 expression was significantly associated with locoregional recurrence of the carcinoma (p = 0.03). The log-rank test showed a significant difference in the disease-free interval in patients stratified according to CD105 expression (p = 0.02). Statistical analysis showed no significant associations between vessel endothelial cell or laryngeal carcinoma cell VEGFR2 expressions and recurrence of disease or disease-free intervals. CONCLUSION: CD105 expression but not VEGFR2 expression correlated with carcinoma recurrence after treatment and shorter disease free interval. The CD105 expression may be useful to detect cervical node-negative patients with a higher risk of early laryngeal carcinoma recurrence.

Nuclear localization of mammary serine protease inhibitor (MASPIN): is its impact on the prognosis in laryngeal carcinoma due to a proapoptotic effect?

PURPOSE: Cell death by apoptosis is considered a regulator of cell number; cancer cells are defective in their response to apoptosis. Many potential markers of apoptosis are under study: M30 immunoreactivity is confined to the cytoplasm of apoptotic epithelial cells and is expressed during early apoptosis. Mammary serine protease inhibitor (MASPIN), a suppressor of tumor growth, seems to be involved in the induction of tumour cell apoptosis. The aim of our preliminary study was to investigate, for the first time, the relations between MASPIN subcellular pattern of expression, nuclear MASPIN expression, M30 expression, and prognosis in laryngeal carcinoma. MATERIALS AND METHODS: Subcellular pattern of distribution of MASPIN and nuclear MASPIN expression were immunohistochemically determined in 66 consecutive cases of laryngeal carcinoma. M30 expression in correspondent carcinoma fields was also calculated. RESULTS: M30 expression was significantly higher in the group of laryngeal carcinomas with MASPIN nuclear localization (P = .024). Our investigation found a reduced carcinoma recurrence rate in the group of patients with MASPIN nuclear localization (P value = .0086). The log-rank test showed a significantly longer disease-free interval in patients with nuclear MASPIN localization (P = .029). CONCLUSIONS: These preliminary results support the hypothesis of an apoptosis-sensitizing effect of nuclear MASPIN in laryngeal carcinoma with the potential perspective of a clinical use of the tumour suppressive proapoptotic function of MASPIN.

MASPIN subcellular localization and expression in oral cavity squamous cell carcinoma.

MASPIN, a member of serpin superfamily, has multifaceted biological functions and an unique tumour suppressing activity. Experimental evidences showed that MASPIN suppresses tumour growth, angiogenesis, invasion and metastasis. Only a very limited number of studies considered MASPIN expression in the upper aero-digestive tract carcinomas. It was recently found that nuclear localization of MASPIN was significantly associated with lower recurrence rate and longer disease-free interval in laryngeal carcinoma. The present study investigated the biological and prognostic role of MASPIN in relation to its subcellular localization in oral carcinoma. Sub-cellular pattern of distribution of MASPIN, nuclear and cytoplasmic MASPIN expressions were immunohistochemically determined in 56 consecutive cases of oral carcinoma. Statistical analysis found a significant association between pN-stage and recurrence of disease (P=0.032) and a significantly longer disease-free interval in pN0 patients than in pN+ ones (P=0.038). None of the subcellular expressions of MASPIN was significantly correlated with recurrence of disease and disease-free interval in our series of oral carcinomas. Sixty-one percent of pN0 cases was strongly MASPIN-positive in the cytoplasm of primary carcinoma cells, 33% of the pN+ cases was MASPIN-positive in the cytoplasm. Statistical analysis found a significant association between MASPIN cytoplasmic expression and pN-stage (P=0.032). Negative MASPIN immunoreactivity in carcinoma cells cytoplasm may be useful to identify patients at risk of disease disseminating to neck lymph nodes. Further investigations are necessary to understand the biological role of cytoplasmic MASPIN localization in oral carcinoma.

Bisphosphonate-associated osteonecrosis can hide jaw metastases.

BACKGROUND: Osteonecrosis of the jaw is a well known potential complication of bisphosphonate treatment but its pathogenesis is poorly understood. The current management of patients with bisphosphonate-associated osteonecrosis (BON) is based on "expert recommendations" and there is a recognized need of better evidence. We report two cases where BON hid jaw metastases and use them to discuss some limitations of the current recommendations. PATIENTS: Two patients undergoing long-term I.V. amino-bisphosphonate treatment for metastatic cancer presented with areas of intraorally exposed jawbone. Bisphosphonate-associated osteonecrosis was diagnosed on the basis of medical history, clinical and radiological features. They underwent surgical resection of the affected jaw due to unrelenting pain and lack of response to conservative treatments. RESULTS: Histological examination of the surgical specimen revealed cancer cells at the margins of the site of osteonecrosis. Our patients did not undergo bone biopsy according to current recommendations, due to lack of clinical and radiological signs suggestive of jaw metastases. CONCLUSIONS: Our findings show that: i) patients with BON may also have jaw metastases; ii) there may not be clinical or imaging hints to this fact and; iii) that a biopsy based on careful selection of the site (with inclusion of necrotic margins) may be needed to reach the correct diagnosis. Further studies should be performed on this topic because of its very important prognostic implications.

Maspin expression in adenocarcinoma of the ampulla of Vater: relation with clinicopathological parameters and apoptosis.

AIM: Maspin is a unique serine proteinase inhibitor which has tumor suppressor activity. The aim of the present study was to investigate the role of maspin in ampullary adenocarcinomas, its correlation with apoptosis and its value as a prognostic marker. PATIENTS AND METHODS: Twenty-three cases of ampulla of Vater adenocarcinoma were collected from archival material. For each sample, maspin, M30, p53 and Mib1 immunohistochemical reactivity were evaluated and results compared with clinicopathological parameters. RESULTS: A statistical relation was found between nuclear maspin and M30 (Spearman's Q = 0.46, p = 0.02), and p53 (Kruskal-Wallis = 0.03); a trend was found between nuclear maspin and pT (Kruskal-Wallis = 0.09), and pM (Mann-Whitney = 0.08) and pN status (Fisher's mid-point test: p = 0.070). CONCLUSION: The present study evaluated the role of maspin in ampullary adenocarcinomas and for the first time demonstrated its association with apoptosis, tumor growth and metastasis.

Maspin nuclear localization is related to reduced density of tumour-associated micro-vessels in laryngeal carcinoma.

BACKGROUND: MASPIN, a tumour suppressing serpin, is a potent inhibitor of angiogenesis. CD105 is a proliferation-associated protein acting in endothelial cells of angiogenic tissues. For the first time the relation between nuclear MASPIN expression and CD105-assessed micro-vessel density (MVD) in laryngeal carcinoma was investigated. PATIENTS AND METHODS: The sub-cellular distribution of MASPIN and nuclear MASPIN expression were immunohistochemically determined in 35 cases of laryngeal carcinoma. The percentage of the fields occupied by CDl05-assessed micro-vessels was also calculated. RESULTS: MVD was significantly lower in laryngeal carcinomas with MASPIN nuclear staining than in carcinomas with cytoplasmic staining (p=0.02). The mean nuclear MASPIN expression was higher in patients without carcinoma recurrence than in those with recurrence (p=0.06). The mean MVD was significantly higher in patients with recurrence of carcinoma (p=0.024). CONCLUSION: The crucial role of MASPIN nuclear localization in reducing the MVD has been demonstrated. Nuclear MASPIN re-expression should be investigated as a potential therapeutic option in the treatment of laryngeal carcinoma.