Unawareness of bipolar disorder: the role of the cingulate cortex.

Reduced awareness of illness is a well-known phenomenon that has been understudied in remitted patients with bipolar disorder. In particular, the relationship between reduced awareness and executive dysfunction is an intriguing question that has yet to be resolved. The aim of the current study is to analyze the link between reduced awareness, brain dysfunction, and concomitant cognitive-behavioral disturbances from a neurocognitive perspective. In previous studies, we demonstrated the role of the anterior cingulate cortex (ACC) in the unawareness of distinct pathologies that exhibit overlapping symptoms in the context of overlapping circuit-specific dysfunction. Given the clinical importance of the results obtained, the present study considers six aware and four unaware remitted bipolar disorder patients. Cingulate functionality was assessed with functional magnetic resonance imaging while patients performed a go/no-go task. Patients were also studied on an overall cognitive task battery and with behavioral assessment of mood changes in terms of apathy and disinhibited behavior. Unaware patients showed frontoparietal hypo-perfusion, with a significant reduction of task-sensitive activity in the bilateral superior and middle frontal gyrus, putamen, insular, and ACCs.

Quantitative and qualitative characterization of plasma DNA identifies primary and recurrent colorectal cancer.

Because plasma DNA may be a useful tool for cancer detection, we screened primary tumors and related multiple plasma samples at the time of surgery and during the follow-up period for plasma DNA level as well as for K-Ras mutations and p16INK4a promoter hypermethylation in colorectal cancer patients. At the time of surgery, DNA levels were higher in tumor patients than in healthy donors, and K-Ras and p16INK4a alterations were detected in 7 and 11 cancers respectively, and in all related plasma samples. During the follow-up, plasma DNA levels decrease progressively but rapidly increased when a relapse occurred, whereas K-Ras and p16INK4a alterations were detected only in relapsed patients. Therefore, combined quantitative and qualitative analyses of plasma DNA confirm the presence of colorectal cancer, define disease-free status and indicate the presence of relapse.

Efficacy and safety of single-agent pan-human epidermal growth factor receptor (HER) inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer.

BACKGROUND: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.

Prognostic factors in Merkel cell carcinoma patients undergoing sentinel node biopsy.

INTRODUCTION: Debate remains about prognostic factors in primary Merkel cell carcinoma (MCC). We investigated clinicopathological factors as determinants of survival in patients with MCC submitted to sentinel node biopsy. METHODS: Sixty-four consecutive patients treated for a primary MCC were identified from a prospectively maintained database at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Time to events outcome were described by product limit estimators and proportional hazards model was used to investigate the association between outcome and potential predictors. RESULTS: The most common site of primary tumor was lower limbs (56.3%). The size of primary lesion was ≤2 cm in 67.2% of cases. Presence of residual disease after the diagnostic surgical excision was observed in 28% of cases. All patients received sentinel node biopsy (SNB) and a SN positivity was detected in 26.6%. The median follow up was 78 months. Disease recurrence occurred in 17 patients (26.6%). In the SN negative group 10 recurrences occurred (21.3%), whereas 7 (41.2%) were found in SN positive one. Nine patients SN negative (19.1%) died of disease and 3 (17.6%) among SN positive. SN status was not associated with survival (p = 0.78). Neither age, gender, size and site of primary tumor resulted predictors of patients' outcome. The presence of residual tumor in the specimen of the wide local excision, after the diagnostic surgical excision, was the only variable associated with survival (p = 0.03). CONCLUSIONS: Presence of residual tumor in the specimen of the wide local excision is the main prognostic factor in MCC patients.

Vaccination of melanoma patients with interleukin 4 gene-transduced allogeneic melanoma cells.

A human melanoma line genetically modified to release interleukin 4 (IL-4) was utilized to immunize advanced melanoma patients in order to elicit or increase a specific anti-melanoma immune response, which may affect distant lesions. Twelve metastatic melanoma patients were injected subcutaneously at least three times with 5 x 10(7) IL-4 gene-transduced and irradiated allogeneic melanoma cells per dose. Both systemic and local toxicities were mild, consisting of transient fever and erythema, swelling, and induration at the vaccination site. Two mixed but not complete or partial clinical responses were recorded. To assess the immune response of vaccinated patients, both serological and cell-mediated activities were evaluated. Antibodies to alloantigens could be detected in 2 of 11 patients tested. Mixed tumor-lymphocyte cultures were performed, utilizing autologous and allogeneic HLA-A2-matched melanoma lines as simulators and targets. A significant increase in IFN-gamma release was detected in 7 of 11 cases when postvaccination lymphocytes were stimulated by the untransduced allomelanoma cells. However, induction of a specific recognition of autologous melanoma cells by PBLs was obtained after vaccination in only one of six cases studied. This response involved the melanoma peptide Melan-A/MART-1(27-35) that was recognized in an HLA-A2-restricted fashion. These results indicate that vaccination with allogeneic melanoma cells releasing IL-4 locally can expand a T cell response against antigen(s) of autologous, untransduced tumor, although in a minority of patients.

Unusual association between cutaneous melanoma and axillary metastasis from occult breast cancer detected by sentinel node biopsy.

We report a case of cutaneous Stage I melanoma associated with occult breast cancer detected incidentally during a sentinel node biopsy. A brief review of the literature is presented with particular emphasis on this association and on an examination of the theoretical link which may exist between melanoma and breast cancer.

Gene therapy in melanoma.

The identification of genes involved in different biologic functions and in the pathogenesis of diseases has paved the way to the possibility of either interfering with the role of such genes or replacing them in somatic cells in case of loss, which may occur in some genetic diseases or cancer. Such progress has been accomplished thanks to advances in molecular biology and applied technology that allow the transport and insertion of genes into recipient cells by viral or physical vectors as well as the inhibition of gene transcription by antisense oligonucleotides. Methods have also been devised to transfer genes not only in vitro but also in vivo, although this latter approach is still limited owing to poor selectivity and targeting of most vectors when given systemically. Viral and physical vectors have been employed; each of these vectors has distinct advantages and disadvantages, and, therefore, the appropriate vector should be selected according to the therapeutic system involved (1). Retro viral vectors have been used largely for their ability to selectively transfect proliferating cells, a feature that can be advantageous in case one wishes to target only proliferating tumor cells. Owing to the heterogeneous proliferation rate in different parts of a tumor, however, it could be desirable, under some circumstances, to be able to target even the fraction of nonproliferating tumor cells. This can now be obtained by the use of lentivirus (2) or by switching to the use of adenoviruses that can target both dividing and quiescent cells but also induce unwanted inflammmatory reactions from the host.

Sentinel node biopsy and selective lymph node dissection in cutaneous melanoma patients.

Sentinel node biopsy allows an accurate selection of melanoma patients to be submitted to therapeutic dissection. From February 1994 to August 1998, at the National Cancer Institute, S. Pio X Hospital in Milan and Bufalini Hospital in Cesena, 580 sentinel node biopsies were performed in 540 stage I melanoma patients (242 males; 298 females; median age 47). Primary melanoma was located in the trunk in 201 patients, in lower limbs in 242 cases, in upper limbs in 80 cases and in head and neck in 17 patients. Injection of blue dye for sentinel node identification was performed in all cases; 372 patients were submitted to preoperative lymphoscintigraphy and in 272 cases an intraoperatory probe for a radioguided biopsy was utilized. Sentinel node identification rate was 91%. Sentinel node positivity rate was 15%. Frozen sections were examined in 199 cases. Distribution of positive cases according to primary thickness is the following: <1 mm: 1%; 1-1.99 mm: 5%; 2-2.99 mm: 18% and > or =3 mm: 27%. Sentinel node appeared to be the only metastatic node in 77% of patients submitted to dissection. The adoption of preoperative lymphoscintigraphy and the intraoperative use of the gamma probe contributed substantially in S.N. identification. No complications caused by the procedure were reported. Eight patients had a regional node relapse after a negative sentinel node biopsy and were submitted to therapeutic distant dissection. Currently 513 patients are alive with no evidence of disease. Present data confirm the feasibility and safety of sentinel node technique for selection of patients to be submitted to radical node dissection and to eventual adjuvant treatments.

A rare complication of surgical management for esophageal tumor: a non neoplastic belated fistula between stomach and main right bronchus.

The fistula between stomach and bronchus after surgery for cancer of the esophagus is a rare occurrence. We describe a gastric non neoplastic ulceration that arose late after six years from an esophagectomy, with an end-side cervical esophagogastrostomy, for a spino-cellular carcinoma. After the partial failure of surgical technique, of the endoscopic treatment and for the bad general conditions of patient we decided to treat the fistula by transluminal drainage. This technique involved a progressive resolution of the fistula, becoming, nowadays, in our division, the preferred treatment for these kinds of postoperative complications.

Sentinel node biopsy and selective dissection for melanoma nodal metastases.

BACKGROUND: Early detection of nodal metastases still represents an important goal in the management of melanoma patients. A sentinel node is defined as the first colored node in the regional lymphatic basin following injection of blue dye in the site of the primary melanoma. Sentinel node biopsy may represent a feasible technique for early identification of occult disease. A therapeutic dissection is then performed only in patients with proven nodal disease, thus introducing the concept of selective dissection. METHODS: At the National Cancer Institute of Milan from February 1994 to October 1996, 74 patients with a melanoma of the trunk or limbs and without clinically detectable node metastases were submitted to sentinel node biopsy and eventual selective dissection. RESULTS: The sentinel node was identified in 67 patients (90%). Nodal metastases were detected in 11 patients (16%); 5 of these were identified by an intraoperative frozen section examination. In all but one case, only the sentinel node was affected at radical dissection. Incidence of positive sentinel nodes was correlated with depth of infiltration of the primary lesion. Mapped nodal basin failures were observed in 3 patients with negative sentinel node biopsy. All patients but one, presenting distant metastases, are alive at this writing and free of disease with a follow-up ranging from 2 to 34 months. CONCLUSIONS: Our study adds to accumulating evidence supporting the efficacy of sentinel node biopsy in detecting occult localizations and the potential of the technique to better select the group of patients that may benefit from nodal dissection.

Double-contrast barium enema and computerised tomography in the pre-operative evaluation of rectal carcinoma: are they still useful diagnostic procedures?

PURPOSE: In modern management of rectal carcinoma, the preoperative evaluation of disease parameters is important for selection of therapeutic options. Such parameters are currently defined through endorectal ultrasonography or endoscopic ultrasonography. A retrospective analysis of the parameters obtained with double-contrast barium enema (DCBE) and endorectal balloon computed tomography (CT) was conducted to verify the diagnostic reliability of the radiological techniques and to establish whether there is still an indication for their use. METHODS: 53 consecutive patients with adenocarcinoma of the distal half of the rectal ampulla underwent double contrast barium enema examination and CT of the pelvis with endorectal balloon. On the basis of the DCBE and CT assessment we evaluated: 1) the distance between the cranial extremity of the anal canal and the distal margin of the neoplasm; 2) the radial diffusion of the tumor; 3) the metastatic involvement of the perirectal and inferior mesenteric lymph nodes. RESULTS: 1) CT and DBCE measurements of the distal margin tended to coincide, but both tended to overestimate the measurement when compared to the pathologic examination; 2) in the identification of neoplastic infiltration of perirectal fat (T3) CT had 100% sensitivity, 78.7% specificity and 86.8% accuracy; 3) the CT sensitivity for detecting lymph node metastasis was 52.6%, specificity 85.3% and accuracy 73.6%. CONCLUSIONS: The diagnostic information provided by the radiological examinations is comparable to that of clinical and instrumental methods currently employed for staging of rectal carcinoma, although the latter are preferred because they are more readily accessible and less costly. DCBE and CT can therefore be usefully employed for staging of cancer of the rectum in those cases in which there are limitations of the current standard methods.

Association between cutaneous melanoma and neurofibromatosis type 1: analysis of three clinical cases and review of the literature.

The authors report a rare association between cutaneous melanoma and Von Recklinghausen's disease (NF-1) and analyze the possible meaning of this occurrence. Various types of tumors have been associated with NF-1, in particular those of neuroectodermal origin, such as malignant peripheral nerve sheath tumors (MPNST) and phaeochromocytoma. The development of malignant melanoma in NF-1 patients is rare. Data from the literature is enable to demonstrate an increased incidence of cutaneous melanoma in patients with neurofibromatosis but the association of these two disorders seems reasonable in theory, as both are abnormalities of a neural crest origin. The cases described may represent not only a clinical report of two rarely associated disorders, but may also confirm the biological mechanisms responsible for these infrequent diseases.

Surgical treatment of gastric metastases from cutaneous melanoma: experience of the National Cancer Institute of Milan.

AIM: To evaluate the role of a surgical approach in patients affected with gastric metastases from cutaneous melanoma. METHODS: A retrospective review of our local melanoma database of 2100 patients identified 31 cases with gastric metastatic deposits. Nine of them were considered candidates for surgical resection. RESULTS: Median overall survival of the 9 patients who underwent surgery was 14.2 months. Six (67%) underwent a local radical resection of disease, and 3 (33%) had a simple exploratory laparotomy. The median survival was 21.6 months (range, 4-32 months) for the subset receiving radical surgery and 3.6 months (range, 2-6 months) for the patients who had no resection. Median follow-up was 14.2 months. No specific correlation of serologic LDH levels and final outcome, as documented elsewhere, was observed. A marked decreased or substantial remission of symptoms with an improvement in quality of life was observed in all radically resected patients. CONCLUSIONS: Patients with gastric metastases from melanoma may benefit from surgery if all macroscopic disease can be removed. In addition, gastric resection in patients with symptomatic melanoma spread to the stomach provides important symptomatic palliation.

Sentinel node biopsy in patients with cutaneous melanoma of the head and neck.

Biopsy of head and neck sentinel nodes (SNs) can be technically problematic due to the unpredictable and variable drainage patterns of this anatomic region. The aim of the present study was to evaluate the feasibility of SN biopsy for cutaneous melanoma of the head and neck. We performed SN biopsy in 17 patients affected by stage I cutaneous melanoma of the head and neck on the basis of lymphoscintigraphy, blue dye and gamma probe. A total of 24 procedures were performed. Drainage to more than one lymphatic basin was observed in five patients (two basins in three cases and three basins in two cases) and in all cases SN biopsy was performed in all basins. The biopsy distribution by site was: six cervical nodes, five parotid nodes, four supraclavicular and submandibular nodes, three auricular and axillary nodes. The SN identification rate was 87.5% (21/24); metastases were discovered in four cases, with a positivity rate of 23.6%. At the time of writing, 1 patient is alive with local disease, 3 patients are dead and 13 are alive and free of disease with a follow-up ranging from 1 to 40 months (median, 21 months) following SN biopsy. In our opinion preoperative lymphoscintigraphy and the intraoperative use of a gamma probe are useful for the identification of lymphatic drainage of cutaneous melanoma of the head and neck.

[Naltrexone in the therapeutic relation in cases of opioid abuse and dependence]. / Il naltrexone nella relazione terapeutica in caso di abuso e dipendenza da oppiacei.

The paper describes the use of naltrexone, an opium-receptor antagonist, in the multimodal treatment of drug addiction and in particular in preventing the recidivation of heroin abuse. Naltrexone appears to lack the ambiguous characteristics of methadone which, in spite of not provoking all the effects of heroin, may be seen by the drug addict as a reasonable substitute, in particular if it is difficult to find. Since naltrexone is clearly a member of the drug category, and does not overlap into the pleasure category, it is possible to break the perverse triangle which is often created between the drug addict, doctor and methadone, thus making it possible to install a more authentic relationship between operators and the users of Ser.T.

[Inappropriate drug use in elderly patients. Considerations on various psychologic aspects]. / L'assunzione incongrua di farmaci negli anziani. Considerazioni su alcuni aspetti psicologici.

The paper examines the hypothesis that inappropriate drug taking by elderly patients may be related to particular psychological motivations. On the one hand, this may aim to confirm their own "status" as patients for the secondary advantages brought about by illness (attention from other members of the family), even through the use of drugs, and, on the other, the excessive use of drug treatment might represent an attempt to obtain revenge on a society which has isolated them or be the consequence of insufficient attention by the prescribing doctor to their relational problems. It is hoped that greater attention paid by the doctor to these problems may improve the method with which drugs are taken.

[Pulmonary metastasis of basal cell carcinoma of the skin. 3 case reports]. / Le metastasi polmonari da carcinoma basocellulare della cute. Presentazione di tre casi.

The Authors describe three cases of lung metastasis from a basal cell carcinoma of the skin observed in the Department of Thoracic Surgery of the National Cancer Institute in Milan. The incidence of this rare occurrence reported in the literature is approximately 0.1%, The aim of the study was to evaluate the therapeutic treatment adopted in these unusual situations. In all cases the primary basal cell carcinoma of the skin was located in the head. All three patients had several local and regional recurrences and underwent multiple surgical excisions and subsequent plastic procedures. In each case complementary radiotherapy was implemented. The metastases appeared in the lung 9, 17 and 21 years, respectively, after onset of the primary tumour as bilateral nodules in two cases and as a single nodule in one. Curative surgery was possible only in one subject, consisting in a bilateral metastasectomy via a midline sternotomy, with 5-year survival. Surgery was withheld in the other two subjects owing to advanced age and the presence of bilateral nodules with concomitant bone metastasis, respectively. Both were treated by chemotherapy and the patient with synchronous bone metastasis also received radiotherapy. The elderly subject died after six months, and the other patient after 19 months despite partial remission of disease. In our experience, curative therapy proves difficult due to multiple metastases. In the literature there are few reports regarding this rare type of metastatic lung disease, but surgical intervention would appear to be the therapy offering the best chance of long-term survival while chemotherapy constitutes the second-choice treatment.