Clinical activity and tolerability of FOLFIRI and cetuximab in elderly patients with metastatic colorectal cancer in the CAPRI-GOIM first-line trial.

BACKGROUND: In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups. METHODS: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by age-groups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (≥65; ≥70 and ≥75 years). RESULTS: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were >65 years, 86 >70 years and 35 >75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were >65 years, 46 >70 and 17 >75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were ≥65 years; 29 were ≥70; 9 were ≥75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade ≥3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients ≥75 years and grade ≥3 fatigue (31% vs 20%, p=0.01) in patients <75 years. CONCLUSIONS: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade ≥3 diarrhoea and neutropaenia in patients ≥75 years and grade ≥3 fatigue in patients <75 years. TRIAL REGISTRATION NUMBER: 2009-014041-81.

Apoptotic index: discriminant feature for the differentiation of cutaneous diffuse malignant follicular center cell lymphomas from lymphoid hyperplasia.

Diffuse subtypes of cutaneous lymphoid hyperplasia (CLH; n = 18) and primary malignant follicular center cell lymphoma of the skin (FCCL, n = 11) were diagnosed by conventional histology, immunophenotyping on paraffin sections, and gene rearrangement analysis. We then counted on semithin, Azur A-stained sections of resin-re-embedded biopsy specimens the relative numbers of apoptotic bodies among all lymphoid cells (apoptotic index [AI]). The diagnostic value of AI was compared to that of mitotic indices (MI) and percentages of various cell types in the cutaneous infiltrate. Features of cellular infiltrates distinguishing to two groups of lesions, in the order of decreasing significance, were percent large lymphoid cells, percent medium-sized lymphoid cells (both higher in FCCL); percent small lymphoid cells, percent epithelioid/giant cells, and percent histiocytes/macrophages (all three higher in CLH). However, of all parameters tested, AI had the greatest discriminant value (median in FCCL 1.11%, in CLH 0.14%; p = 8 x 10(-6)). Two cases, diagnosed as CLH with all morphologic and immunologic methods used, showed B-cell monoclonality at the DNA level. Linear discriminant analysis determined the following order of distinctive power of variables: 1) AI; 2) MI; 3) percent small lymphoid cells; 4) percent medium-sized lymphoid cells; 5) percent large lymphoid cells; 6) percent epithelioid/giant cells; and 7) percent histiocytes/macrophages. The present study thus establishes AI as an important parameter in the differentiation of diffuse CLH from diffuse cutaneous FCCL.

Bronchiolo-alveolar carcinoma: an analysis of survival predictors.

Macroscopic and microscopic features of tumours have been analysed in 37 bronchiolo-alveolar carcinomas. Lymphocytes, Langerhans cells, collagen (mature and/or myofibroblastic), were quantitatively or semiquantitatively evaluated. Histology, stage, type of fibrosis, nuclear profile features (area and shape factors), amount and type of mucin secreted, number of mitoses, Langerhans cells, myofibroblasts and LeuM1+ cells were not related to survival. Gross morphology of the tumour and, to a lesser extent, lymphoid infiltrates (in particular UCHL1+ and L26+ peritumoral lymphoid cells) were the only variables significantly related to survival. Estimated survival functions were computed according to Cox's model: well demarcated tumours behaved significantly better than poorly demarcated tumours and even more so than diffuse or multiple mass. Lymphoid infiltrates were significantly more represented in and around well demarcated tumours: however, their survival predicting value was less than that of the gross type.

Neurotransmitter, opiodergic system, steroid-hormone interaction and involvement in the replacement therapy of sexual disorders.

Dopamine (DA) and serotonin (5-HT) are the neurotransmitters most directly involved in sexual activity. DA plays a stimulatory role while 5-HT has an inhibitory effect. The two monoaminergic systems modulate the secretion of many hormones (GnRH, LH, testosterone, prolactin and endorphins) involved in sexual functional capacity. Furthermore, hormones influence synthesis and storage of brain neurotransmitters. Impotence can often be associated to clinical depression and altered neurotransmitter function. Moreover, stress represents an unbalance between various neurotransmitter systems and can induce impotence especially when disorders of the endorphinic system are present. Replacement therapy is based upon the understanding of these basic concepts. Impotence due to an underlying depressive illness must be treated with dopaminergic antidepressant drugs; while in stressful conditions a good response to the naloxone test is the preliminary criterion to subsequent naltrexone treatment. When a hormonal deficiency has been proved, the hormone replacement therapy is of course highly effective (gonadotropins in hypogonadotropic syndromes, testosterone in aging, etc.). Finally, idiopathic impotence could be treated by DA agonist and/or 5-HT antagonist drugs either alone or better yet in association with psychotherapy.

Estrogen receptor content, immunohistochemically determined by monoclonal antibodies, in endometrial stromal sarcoma.

The estrogen receptor content, determined immunohistochemically by staining with monoclonal antibodies, was studied in seven consecutive cases of endometrial stromal sarcoma. In addition, the mitotic rate and immunohistochemical patterns (vimentin, desmin, actin, cytokeratins) were determined. Five of seven cases contained estrogen receptors, three low-grade (fewer than 10 mitoses/10 high-power fields [hpf]) and two high-grade (10 or more mitoses/10 hpf), the latter having a relatively low mitotic rate. The two negative cases were high-grade with a very high number of mitoses. Tumor cells were positive only to vimentin. Based on these results, we postulate that estrogen receptors are undetectable only in highly proliferating neoplasms. Thus, immunohistochemically determined estrogen receptor levels may indicate the aggressiveness of endometrial stromal sarcoma, and might be a guideline in selecting patients for hormonal therapy. The presence of positive immunostaining to vimentin confirms the mesenchymal origin of endometrial stromal sarcoma.

Pedunculated pulmonary leiomyoma with large cyst formation.

A case of single pulmonary leiomyoma with giant cyst formation is presented. Metastasizing uterine fibroleiomyoma and fibroleiomyomatous hamartoma both give rise to multiple pulmonary nodules on chest films. Leiomyoma of the lung presenting as a single pedunculated lesion with cyst formation is exceptional. This report documents the existence of other rare cystic lesions that may mimic the more common cystic air space and bullous disease.

Uncommon intrathoracic extrapulmonary tumor: primary hemangiopericytoma.

We report an unusual case of primary intrathoracic extrapulmonary hemangiopericytoma. Despite the large size and rapid growth of the tumor, no histological sign of malignancy was present. Tumor cells immunostained positively only to vimentin.

Primary branchiogenic carcinoma - immunohistochemical and ultrastructural features - a case-report and review of the literature.

A case with histological evidence of malignancy developed in a branchial cleft cyst (BCC), which conforms with the criteria for primary branchiogenic carcinoma (PBC) was analyzed by electron microscopy and immunchistochemistry; our findings reveal peculiar analogies between PBC and BBC, further supporting the primitive nature of the lesion.

Validation of a functional method for the estimation of hip joint centre location.

The present study assesses the accuracy with which the subject specific coordinates of the hip joint centre (HJC) in a pelvic anatomical frame can be estimated using different methods. The functional method was applied by calculating the centre of the best sphere described by the trajectory of markers placed on the thigh during several trials of hip rotations. Different prediction methods, proposed in the literature and in the present investigation, which estimate the HJC of adult subjects using regression equations and anthropometric measurements, were also assessed. The accuracy of each of the above-mentioned methods was investigated by comparing their predictions with measurements obtained on a sample of 11 male adult able-bodied volunteers using roentgen stereophotogrammetric analysis (RSA), assumed to provide the true HJC locations. Prediction methods estimated the HJC location at an average rms distance of 25-30 mm. The functional method performed significantly better and estimated HJCs within a rms distance of 13 mm on average. This result may be confidently generalised if the photogrammetric experiment is carefully conducted and an optimal analytical approach used. The method is therefore suggested for use in motion analysis when the subject's hip range of motion is not limited. In addition, the facts that it is not an invasive technique and that it has relatively small and un-biased errors, make it suitable for regression equations identification with no limit to sample size and population typology.

Plasma prolactin response to domperidone in acute schizophrenia and schizophreniform illness.

The prolactin (PRL) response to 20 mg of domperidone, a peripheral dopamine (DA) blocking agent, was evaluated in a group of 16 drug-free, acute, young schizophreniform and schizophrenic males and in a group of age-matched normal males. Although basal plasma PRL levels were normal, the PRL responses following domperidone were blunted in both patient groups. The PRL response was more blunted in the schizophreniform patients than in the schizophrenic patients. Possible explanations for these results include pharmacokinetic factors or abnormalities of the pituitary D2 DA receptors.

Morphometrical assessment of mean nuclear area in breast cancer in comparison with that of lymph node metastases.

Morphometrical measurements of nuclear area and form factors are carried out by means of a semiautomated image analyzer on 90 cases of ductal breast cancers and on lymph node tumor deposits. The value of the mean nuclear area in lymph node metastases is significantly higher than in primary tumors regardless of the size of the tumor. Since the value of mean nuclear area is also significantly higher in primary tumors with lymph node involvement than in those without lymph node involvement it is possible to assume that primary tumors with large-nucleus areas are more liable to invade lymph nodes. No significant differences are noted as far as the form factors are concerned.

The nuclei in cutaneous malignant melanoma, stage I, are smaller in survivors than in non-survivors.

Cutaneous melanoma, stage I, from 35 survivors at 5 year follow-up and 16 non-survivors were studied. Mean nuclear area in the superficial layer was significantly larger than in the deep layer both in survivors and non-survivors, but the ratio between nuclear area in superficial and deep layers (so-called maturation index) did not differ between survivors and non-survivors. In comparison with the survivors, the mean nuclear area of non-survivors was significantly larger both in the superficial (51.1 microns2 vs 43.7 microns2, p less than 0.01) and deep (42.9 microns2 vs 36.4 microns2, p less than 0.05) layer. This points to a general increase in nuclear areas in metastasizing tumors. Furthermore, the coefficient of variation of nuclear area [(standard deviation/mean) x 100] was not different between survivors and non-survivors, either in the superficial or in the deep layer. Inspection of histograms of areas of 1000-2000 nuclei per case in 20 random cases (10 survivors and 10 non-survivors) showed a homogeneous increase in nuclear area in non-survivors. None of the histograms revealed a cell clone with especially large nuclei. These data show that the increased mean nuclear area in non-survivors is due to a homogeneous increase of all nuclei throughout the tumor and not to a special cell clone with large nuclei within nuclei of otherwise normal size. The difference in mean nuclear area in superficial and deep layers indicates that careful selection of nuclei in either of these layers is essential to obtain reproducible and comparable results with interactive morphometry.

Morphological aspects of the human intimal surface at scanning electron microscope. A preliminary approach in surgical material (iliac arteries).

Human iliac arteries, obtained at surgery, were examined at SEM. The ultrastructural aspects has evidenced pathological pictures, quite unexpected. The material observed resulted very adapt for scanning electron microscope.

Critical evaluation of limb salvage concept and indication for infrapopliteal reconstructive surgery.

A large number of surgical procedures aimed at revascularizing the popliteal and infrapopliteal arteries has been reported in patients affected by rest pain or gangrene of the extremities as well as intermittent claudication. In consideration of the high incidence of early and late unsuccessful results following this type of surgery as reported in the literature, we believe that peripheral reconstructions should be restricted to those patients presenting a clinical picture of such severity that major amputation is unavoidable in the short run. In these patients our choice of the appropriate surgical procedure is strictly related to the patency or not of the popliteal artery. The role of the above knee femoropopliteal bypass is discussed. A series of patients that we have operated upon according to these criteria is analyzed. The low number of cases in our group of patients and the high rate of postoperative failures reflect our policy on this matter.

Ultrastructural (SEM and TEM) observations on arterial lesions of the human aorto-iliac area obtained at surgery from donors.

Ultrastructural observations on arterial lesions of the human aorto-iliac area obtained at surgery from donors after bilateral nephrectomy for kidney transplantation have revealed the presence of intimal fibro-muscular lesions, very similar to the "early lesions" of experimental animal models in the younger people of this group.

Ultramicroscopic observations on the pseudointimal coating in implanted dacron vascular grafts.

The common use of Dacron arterial prostheses produced enormous improvement in vascular surgery, yet some serious complications such as thrombosis or infection persist, which are connected to the utilization of this material. Light and electron microscopic studies may allow a better understanding of such complications. Scanning electron microscopy and semithick sections were used to examine dacron arterial prostheses removed for failure after long-term implantation. Semithick sections showed periprosthetic inflammatory reaction and the neointimal surface never exhibited a regular endothelial layer (at S.E.M.).

Lomustine (CCNU)-induced pulmonary fibrosis.

A case of progressive pulmonary interstitial fibrosis following adjuvant lomustine (CCNU)-5-fluorouracil therapy for a colon carcinoma is reported. A close relationship between lomustine assumption and lung damage seems to emerge from the clinical, radiologic and histologic findings presented. On the basis of this experience and previous available data from literature, pulmonary toxicity must be regarded as a possible adverse effect of lomustine therapy.

Non-Hodgkin's lymphoma primarily involving the bronchial tree.

Among extranodal localizations, the bronchial one is very unusual, especially as primary involvement. The authors present 2 cases of non-Hodgkin's lymphoma (NHL) admitted to the hospital because of thoracic abnormalities. Chest x-ray revealed lobar atelectasis. Fiberoptic bronchoscopic findings agreed with the diagnosis of unresectable bronchogenic tumor in both cases. Histologic examination of biopsy specimens was nonrevealing in the first patient, and suggested small cell lung cancer in the second one. Further histologic and immunohistochemical examinations excluded bronchial tumors (particularly small cell bronchogenic carcinoma) and led to the diagnosis of lymphocytic lymphoma in one case and centroblastic lymphoma in the other. In the differential diagnosis of bronchogenic tumors, it is necessary to keep in mind the hypothesis of lymphomatous involvement of the bronchial wall, although it rarely occurs.

Quality data: what are they?

Nowadays, quality has become a very important factor in almost all areas of endeavour. The data generated from tests for the assessment of potentially toxic chemicals is obviously no exception. It is necessary, therefore, that quality systems be developed to ensure that the data generated to support these tests are of good quality. An acceptable quality system should require that, where applicable, the tests be performed according to defined guidelines. Once defined guidelines have been identified for the type of test to be performed, it is then necessary to design a plan which describes how, when, where and by whom the data will be generated. If at all possible, the data should be generated according to written standard procedures which provide for the production of data to the same quality standard. The data should be generated and collected by properly trained staff using data collection systems (paper or electronic media) which ensure the accuracy, reliability and integrity of the data recorded. The data must then be recorded in such a way as to ensure that they are reported completely clearly and accurately. The report, whether it be in the form of scientific article, monograph or formal study report, should present the data in a consistent manner and allow for adequate reconstruction of the events which took place during the test. Finally, the report and the data supporting it should be verified to ensure that the test was carried out according to the relevant guidelines (if used), that the study plan was correctly followed and finally that all data were properly generated and accurately reported in the report.(ABSTRACT TRUNCATED AT 250 WORDS)