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.

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.

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.

Distinction between diffuse cutaneous malignant follicular center cell lymphoma and lymphoid hyperplasia by computerized nuclear image analysis.

The difficult differential diagnosis between the diffuse variants of cutaneous lymphoid hyperplasia (CLH; synonym; pseudolymphoma) and malignant follicular center cell lymphomas (FCCL) often requires a multidisciplinary approach. Eighteen CLH and 11 FCCL, diagnosed by conventional histology and immunophenotyping and subsequently examined with a polymerase chain reaction to show clonal immunoglobulin heavy-chain gene rearrangements, were subjected to a novel type of automated nuclear image analysis. Of all nuclear parameters tested in azure A-stained semithin sections, the mean nuclear profile area (TN) of lymphoid cells was the best criterion to distinguish between CLH and FCCL (p = 9 x 10(-6)). Additional distinctive features, in the order of decreasing significance, were the SD of TN; all chromatin textural parameters combined; and the light and the dark fractions of the central nuclear profile areas. Parameters related to the chromatin pattern were independent of nuclear profile size in FCCL, but not in CLH. Two lesions registered as CLH displayed the nuclear characteristics favoring this diagnosis, but showed B-cell monoclonality at the DNA level. In conclusion, computerized nuclear image analysis is a helpful additional diagnostic tool in the evaluation of diffuse CLH and cutaneous FCCL.

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.

Gastric intestinal metaplasia type III cases are classified as low-grade dysplasia on the basis of morphometry.

The aim of this study was to try to place gastric intestinal metaplasia, type III (type III IM) in the stepwise chain of events from atrophic gastritis to cancer. A number of dysplastic, periulcer regenerative, and type III IM lesions were qualitatively diagnosed (and graded) blindly and independently by several pathologists. These lesions were further analysed by means of quantitative parameters, with the aim of differentiating dysplastic from regenerative changes. Inconsistencies between the qualitative and quantitative classification (about 7 per cent of cases) were eliminated and homogeneous groups (low-grade dysplasia, high-grade dysplasia, regenerative changes) were obtained. These cases were taken as the gold standard against which type III IM was compared. The results indicate that the great majority (91.4 per cent) of cases of type III IM fulfil the nuclear and architectural criteria for low-grade dysplasia.

Pleural malignant mesothelioma in Tuscany, Italy (1970-1988): I. Anatomo-pathologic aspects.

Our investigation did not confirm the general experience that significant numbers of cases initially considered malignant mesothelioma or metastatic carcinoma are actually found to be metastatic carcinoma or malignant mesothelioma, respectively, upon deeper investigation using ancillary techniques (e.g., histochemistry, immunohistochemistry, electron microscopy). Well-trained pathologists, expert in thoraco-pulmonary pathology, have a high inter- and intra-rater agreement and significantly better results than standard hospital pathologists in correctly differentiating malignant mesothelioma from metastatic carcinoma. Therefore, epidemiologic investigations which exclude an accurate and rigorous reevaluation of the histologic slides have to be considered unreliable, unless the data come from a specialized medical center experienced in this type of pathology.

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.

Morphometry and the differential diagnosis between peripheral neuroepithelioma and neuroblastoma.

The differential diagnosis based on morphology between neuroblastoma (NB) and peripheral neuroepithelioma (PN) is difficult, since these tumors share many architectural and cytological features. In this study, a morphometrical approach to this diagnosis is made by using nuclear (shape factors) and tissue (volume density of nuclei and stroma) parameters. Quantitative morphological analysis adds important information, which when used with clinical and biochemical data facilitates the distinction. In the majority of cases, nuclei of PN are significantly less round than those of NB and their profile is much more irregular. The density of neoplastic nuclei is significantly higher in PN. However, in a certain number of cases, even the morphometrical study confirms how difficult it may be to differentiate these two neoplastic entities, since the values of parameters are largely overlapping. This suggests the existence of a "continuum" of changing features between NB and PN, which may substantiate the hypothesis of a common histogenesis.

Morphometric definition and grading of gastric intestinal metaplasia.

Type I and type III intestinal metaplasia in gastric mucosa have been examined using morphometric methods. Tissue (volume per cent gland, lumen, epithelium, goblet cell vacuoles) and nuclear parameters (area, with related standard deviation, and form factors) were used as indicators of gland crowding, nuclear-cytoplasmic ratio, nuclear atypia, and pleomorphism. In type III intestinal metaplasia, there is significantly (i) greater nuclear pleomorphism, (ii) a higher nuclear-cytoplasmic ratio, and (iii) smaller and less numerous goblet cell vacuoles in both the upper and the lower parts of the crypts. These two parameters have significantly higher values in the lower than in the upper part of individual crypts. No cell population with large pleomorphic nuclei characterized type III metaplasia, though there was more variation in nuclear size.

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.

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.

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.

Flow-cytometric assessment of DNA index and percent S phase cells in bronchogenic epidermoid carcinoma.

The DNA index and percent S phase cells were assessed in 45 bronchogenic epidermoid carcinomas from paraffin-embedded retrieved material by flow cytometry. Previously, a comparison between flow cytometric findings from fresh and from paraffin-embedded material was made. The DNA index and the percent S phase cells from fresh and paraffin-embedded material were strongly correlated. Only 3 of the 45 cases were diploid. The DNA index was significantly lower in grade 1 than in grade 2-3 tumors. No correlations were found between DNA index and presence of lymph node metastases, but the percent S phase cells was significantly higher in lymph-node-positive tumors.

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.

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.).

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.

Correlation between immunohistochemically determined oestrogen receptor content, using monoclonal antibodies, and qualitative and quantitative tissue features in ductal breast cancer.

Previous studies have shown that oestrogen receptor content in breast cancer was correlated with qualitative and also, more strongly, with quantitative nuclear features in tissue sections. However, even with the better reproducible quantitative microscopical assessments, the variance in the correlation with oestrogen receptor was considerable. This might be due to the implicit problems of oestrogen receptor determination with the biochemical assay. Therefore, receptor content was studied using monoclonal antibodies in 50 consecutive invasive ductal breast cancers. Oestrogen receptor status was compared with qualitative features and with the mean and standard deviation of the nuclear area, morphometrically evaluated on immunostained and adjacent haematoxylin and eosin stained sections. In agreement with earlier observations, nearly all tumours with prominent elastosis were oestrogen receptor positive; but a minority of negative cases also showed elastosis. The correlation between the other qualitative features and receptor status was weak. A significant inverse correlation (P less than 0.001) existed between the receptor status and the mean and standard deviation of the nuclear area. Even with the highly reproducible morphometrical analysis, correlation between nuclear oestrogen receptor content and quantitative nuclear features was relatively weak. This might indicate that receptor status and nuclear morphometric features reflect different biological characteristics of breast cancers.