[New melanoma immunotherapies: mechanisms of action, efficiency and management of toxicities]. / Nouvelles immunotherapies du mélanome: mécanismes d'action, efficacité et prise en charge des toxicities.

In recent years the therapy of metastatic melanoma has been revolutionized from a disease with very few efficient treatment options to one with access to multiple therapies which can impact on patient survival. Two main classes of therapies have been developed: 1. Immunotherapy by immune checkpoint inhibitors and 2. Small molecule inhibitors of the MAPK pathway. Immunotherapies achieved by either inhibition of CTLA-4 or the PD1/PD-Ll axes are impacting the overall survival in an important fraction of patients. In addition, the side effects of these immune therapy approaches require early detection by all the specialists involved as well as early management according to precise guidelines for optimal outcome.

[Melanoma: a new therapeutic era]. / Mélanome: une nouvette ère thérapeutique.

Melanoma is the cancer with the fastest incidence increase in Switzerland. 30% of the cases arise before the age of 50 years. Once metastatic, the median survival under current systemic therapies is about 8 months, with less than 5% of patients alive at 5 years. Many efforts in the understanding of cellular biology, intracellular signaling pathways, as well as the role of cellular immunity have been made in the recent years. This has resulted in the development of novel and very promising therapies. In this review, we will cover the results obtained with targeted therapies such as "tyrosin kinase inhibitors" (TKI), as well as those obtained with a monoclonal antibody directed against the CTLA-4 receptor of lymphocytes.

[New developments in cancer immunotherapy]. / Nouveautés dans l'immunothérapie du cancer.

Recent progress unveiling the cellular and molecular basis of the immune response allows nowadays the design of novel therapies for tumor immunotherapy. These recent approaches translate into response rates that often surpass what can be obtained by conventional chemotherapies or targeted therapies. Here we present the main current developments with an accent on the Lausanne experience in the treatment of melanoma. First, the new developments of peptide-based vaccination are presented. Second, approaches related to adoptive transfer are illustrated with a particular attention for the patient conditioning using lymphodepletion. Finally, the Lausanne project of rational lymphocyte TCR optimization is described.

Sentinel lymph node involvement and a high Breslow index are independent factors of risk for early relapse of melanoma.

AIM: The clinical relevance of sentinel lymph node (SLN) analysis was evaluated prospectively and compared with other known risk factors of relapse in early stage melanoma. METHODS: Surgery was guided by lymphoscintigraphy, blue dye and gamma probe detection. SLN were analysed by haematoxylin eosin (HE) histochemistry and multimarker immunohistochemistry (IHC). Disease free survival (DFS) was evaluated with Kaplan-Meier plots according to different parameters and Cox analyses of variance. RESULTS: From 210 patients a total of 381 SLN were excised. Lymphoscintigraphy identified all excised SLN with only 2 false positive lymphatic lakes. Fifty patients (24%) had tumour positive SLN. With a mean follow-up of 31.3 months, 29 tumour recurrences were observed, 19 (38%) in 50 SLN positive and 10 (6%) in 160 SLN negative patients. Strong predictive factors for early relapse (p < 0.0005) were SLN positivity and a high Breslow index. CONCLUSION: SLN tumour positivity is an independent factor of high risk for early relapse with a higher power of discrimination than the Breslow index.

p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer.

Mutations of the TP53 and Ki-ras genes have been reported to be of prognostic importance in colorectal carcinomas. An increased intracellular concentration of the p53 protein, although not identical to, is sometimes seen in tumours with TP53 mutation and has been correlated with poor prognosis in some tumour types. Previous colorectal cancer studies, addressing the prognostic importance of Ki-ras mutation and TP53 aberrations, yielded contradictory results. The aim of this study was to determine in a clinically and therapeutically homogeneous group of 122 sporadic Dukes' B colorectal carcinomas with a median follow-up of 67 months (3-144 months) whether or not p53 protein expression, TP53 mutation and K-ras mutation correlated with prognosis. p53 staining was performed by immunohistochemistry, using the monoclonal antibody DO7 on paraffin-embedded tissue. Mutations in exons 5-8 of the TP53 gene and in codons 12 and 13 of the K-ras gene were assayed in paraffin-embedded tissue by the single-strand conformation polymorphism (SSCP) assay. Nuclear p53 staining was found in 57 (47%) tumours. Aberrant migration patterns indicating mutation of the TP53 gene were found in 39 (32%) tumours. Forty-six carcinomas (38%) showed a mutation of the Ki-ras codons 12 or 13. In a univariate analysis, patients with wild-type TP53 status showed a trend towards better survival, compared with those with mutated TP53 (log-rank test, P = 0.051). Likewise, tumours immunohistochemically positive for p53 showed a worse prognosis than p53-negative tumours (P = 0.010). The presence or absence of mutations in Ki-ras did not correlate with prognosis (P = 0.703). In multivariate analysis, only p53 immunoreactivity emerged as an independent marker for prognosis hazard ratio (HR) = 2.16, 95% confidence interval (CI) 1.12-4.11, P = 0.02). Assessment of p53 protein expression is more discriminative than TP53 mutation to predict the outcome of Dukes' stage B tumours and could be a useful tool to identify patients who might benefit from adjuvant therapy.

Prognostic factors in colorectal cancer.

Prognosis of patients after colorectal cancer resection is predominantly influenced by the extent of local tumour growth and the presence or absence of nodal or distant metastasis. However, many factors have been used to generate numerous classification systems, leading to some debate and confusion. The effects on survival of 7 clinical and pathological parameters were reviewed in 801 consecutive patients operated upon with locally curative intent for colorectal cancer over a ten-year period. Age less than 50 or more than 70 years, poor cellular differentiation, high mucous secretion by tumour cells and Dukes' staging were the parameters significantly correlated to poor overall survival (p<0.001 for each). The Cox's regression analysis identified the same parameters as independent prognostic factors. The value of age as a prognostic factor remains debatable, but the other three parameters must be considered when evaluating prognosis after curative surgery for colorectal cancer and when considering adjuvant therapy.

The type of K-ras mutation determines prognosis in colorectal cancer.

BACKGROUND: Mutations involving the oncogene K-ras in colorectal cancer may be related to tumor aggressiveness. However, the value of K-ras gene determination as a prognostic marker has not been clearly established. PATIENTS AND METHODS: The results from 98 patients recruited in a prospective study analyzing the effect of a K-ras mutation as a prognostic factor in colorectal cancer are reported. RESULTS: Disease-free (P = 0.02) and overall survival (P = 0.03) were significantly reduced for patients harboring a K-ras mutation. Two specific mutations demonstrated a significantly increased risk of disease recurrence, namely, 12-TGT (P = 0.04) and 13-GAC substitutions (P = 0.002). Patients with either of these substitutions had a 2-year disease-free survival rate of 37% compared with that of 67% for the group of patients harboring any other mutation type or a wild-type status (P = 0.01). CONCLUSIONS: The results herein presented suggest that K-ras acts as a prognostic factor in colorectal cancer and that this effect is probably related to a limited number of defined mutations.

Pemphigus vulgaris occurring simultaneously on a recent and an old surgical scar due to a Koebner's phenomenon.

Pemphigus vulgaris is an autoimmune bullous disorder involving the skin and sometimes the mucosa. Koebner's phenomenon is encountered when the typical features of a dermatosis are observed on a part of the skin previously subject to friction or trauma. A few cases of pemphigus vulgaris developing after damage to the skin and especially scars have been described. To the best of our knowledge, we report the first case where typical lesions of pemphigus vulgaris appeared simultaneously on a recent and an old scar as the sign of the reactivation of the disease.

[Muckle-Wells syndrome: 4 cases in three generations]. / Syndrome de Muckle-Wells: description de 4 cas sur trois générations.

BACKGROUND: Muckle-Wells syndrome is a hereditary condition with variable penetrance. The main manifestations are urticarial rash, malaise in the evening, joint pain, perception deafness and renal amylosis. CASE REPORT: We describe a family with 4 affected members in 3 successive generations. Clinical expression was variable. DISCUSSION: Despite the absence of renal amylosis in our patients, this family presented the syndrome described by Muckle and Wells in 1962. As for other cases reported in the literature, the clinical course was favorable with low-dose corticosteroid therapy.

[Prognostic value of K-ras gene mutation in colorectal cancer]. / Valeur pronostique des mutations du gène K-RAS dans le cancer colorectal.

Numerous acquired genetical mutations are now well described by molecular biology and seem to be related to tumour progression. K-RAS mutation is of interest in colorectal cancer where it could be correlated to an aggressive tumoral behaviour leading to a high risk of recurrence or metastasis.

Cutaneous plasmacytosis: an unusual presentation sharing features with POEMS syndrome?

Cutaneous plasmacytosis is a recently described skin disorder consisting of brown to red papules and nodules containing polyclonal plasmacytes. In this particular case, leg ulcers developed but also a diffuse patchy hyperpigmentation coexisting with a primary hypothyroidisim. The last two signs have only been described to date in POEMS syndrome, which is linked to monoclonal plasmacytic proliferation, and might suggest an overlap between these two entities.

For patients with Dukes' B (TNM Stage II) colorectal carcinoma, examination of six or fewer lymph nodes is related to poor prognosis.

BACKGROUND: Lymph node status is pivotal to the staging of colorectal carcinoma. The diagnosis of a lymph node negative tumor should imply a good prognosis; however, the outcomes for Dukes' B (TNM Stage II) patients remain variable, possibly in part due to understaging. The aim of this study was to determine whether examining a specified minimum number of lymph nodes using conventional techniques would eliminate the risk of understaging and thus have an effect on prognosis. METHODS: Data on patients who underwent surgery for colorectal carcinoma at a single institution between 1985 and 1990 were reviewed. Patients with Dukes' B (TNM Stage II) or C (TNM Stage III) tumors and histologically confirmed disease-free resection margins who were treated with curative intent were included. Correlations among variables were assessed using the chi-square test, and survival comparisons were made using Kaplan-Meier curves and the log rank test. Multivariate analysis was performed using a Cox regression model. RESULTS: Dukes' B (TNM Stage II) patients with < or =6 lymph nodes examined had significantly poorer overall survival than those with > or =7 lymph nodes examined (P = 0.0014). Such a significant difference was not observed among Dukes' C (TNM Stage III) patients (P = 0.7). Survival of Dukes' C patients was significantly worse compared with that of Dukes' B patients overall and Dukes' B patients with > or =7 lymph nodes examined (P < 0.0001). There was no significant difference in survival between Dukes' C and Dukes' B patients with < or =6 lymph nodes examined (P = 0.02). The number of examined lymph nodes was the only significant parameter correlated with survival in the multivariate analysis (P = 0.002). CONCLUSIONS: Because Dukes' B patients with < or =6 examined lymph nodes have poorer outcomes than those with a higher number examined (probably due to understaging), the total number of examined lymph nodes should always be reported.

p53 mutations as a possible predictor of response to chemotherapy in metastatic colorectal carcinomas.

Although intrahepatic infusion therapy with 5-fluorouracil for unresectable colorectal liver metastases may lead to improved overall survival for some patients, it is not clear why a response is not observed in others. Gene alterations in oncogenes or tumor-suppressor genes are critical events in tumor formation, and some of them could play a role in the process of drug resistance. The tumor-suppressor gene p53, which is known to trigger cell arrest or apoptosis in response to DNA damage, is found to be mutated in a wide range of human tumors. The aim of this work is to establish whether a relationship is found between p53 mutations and survival in patients undergoing adjuvant chemotherapy for advanced Dukes' D colorectal cancers. Seventeen tumors from patients treated with 5-fluorouracil regimen via intrahepatic infusion for unresectable colorectal hepatic metastasis were considered. p53 mutations from tumor DNA were detected, after amplification by PCR of exons 5 to 8, by non-radioactive single-strand conformation polymorphism and direct DNA sequencing. Patients with mutated p53 colorectal tumors had short survival, whereas prolonged survival was associated with the presence of wild-type p53 (p = 0.019). Our data suggest that mutated p53 colorectal tumors had a weak response, or even no response, to chemotherapeutic treatment. Routine assessment of p53 status would be helpful in selecting patients with only wild-type p53 gene who have a predictably better response to chemotherapy.

Wegener's granulomatosis: description of a case where cutaneous involvement was correlated with elevation of the c-ANCA titer.

Wegener's granulomatosis is a systemic disease characterized by necrotizing granulomas and vasculitis involving the upper and lower respiratory tract as well as the kidneys. Cutaneous manifestations consist mainly of papules or papulonecrotic lesions. c-ANCA are known to be a valuable adjunct for the diagnosis and follow-up of Wegener's granulomatosis with systemic involvement. We report the case of a 49-year-old man with Wegener's granulomatosis who developed two relapses of the disease with cutaneous manifestation and who presented with concomitant elevation of the c-ANCA and more precisely the subset PR3-ANCA during the acute phase of the disease.

Drug-induced linear IgA bullous dermatosis probably induced by furosemide.

Linear IgA bullous dermatosis (LABD) is an autoimmune disease, characterized by linear deposition of IgA along the basement membrane zone. Drug-induced LABD is rare but increasing in frequency. A new case of drug-induced LABD associated with the administration of furosemide is described.

Selective suppression of cytokine secretion in whole blood cell cultures of patients with colorectal cancer.

We have investigated the secretion of interferon alpha (IFN-alpha), IFN-gamma, interleukin-1alpha (IL-1alpha), IL-1beta, IL-2 and tumour necrosis factor alpha (TNF-alpha) in whole blood cell cultures (WBCCs) of colorectal cancer patients upon mitogen stimulation. Whereas the values for IL-1beta and TNF-alpha remained virtually unchanged in comparison with healthy control subjects, WBCCs of colorectal cancer patients secreted significantly lower amounts of IFN-alpha (P < 0.005), IFN-gamma (P < 0.0001), IL-1alpha (P < 0.0001) and IL-2 (P < 0.05). This reduction correlated with the progression of the disease. The total leucocyte and monocyte population were almost identical in both groups. In contrast, a dramatic depletion of lymphocytes was observed in colorectal cancer patients, which affected both lymphocyte counts (P < 0.0005) and their distribution (P < 0.0001). Our results suggest a selective suppression of cytokines in colorectal cancer patients that is related to tumour burden. Several mechanisms might account for this phenomenon, one of which might be lymphocyte depletion.

Expression of Melan-A/MART-1 antigen as a prognostic factor in primary cutaneous melanoma.

In this study we assessed the expression of the Melan-A/MART-1 antigen by immunohistochemistry using monoclonal antibody A103 in 73 primary cutaneous melanomas and its correlation with tumor staging and patient survival. Melan-A/MART-1 was expressed in 90% of primary tumors, with loss of expression increasing with Breslow thickness. Kaplan-Meier analysis demonstrated a significantly reduced disease-free interval and overall survival rate for patients not expressing this antigen. The poor prognosis of such patients was even worse for those presenting with a primary melanoma and a Breslow thickness of > or = 1 mm. Thus, Melan-A/MART-1 is not only a useful and specific additional marker for the diagnosis of primary cutaneous melanoma, but it may also help refine the prognosis of patients with malignant melanoma.

Thromboangiitis obliterans: a rare cause of a reversible Raynaud's phenomenon.

A 25-year-old woman with progressive Raynaud's phenomenon and digital necrosis is presented. Systemic sclerosis and other connective tissue disorders as well as atherosclerosis and arterial emboli were excluded with appropriate laboratory examinations. Arteriography revealed multiple palmar and digital occlusions with corkscrew-shaped vessels. Based on these characteristic arteriographic and clinical findings, the diagnosis of thromboangiitis obliterans was finally retained. With intravenous perfusion of the prostacyclin analogue iloprost (2 ng/kg/min, 6 h daily during 21 days), a complete healing of Raynaud's phenomenon and of the digital necrosis was observed. There was no recurrence during the 1-year follow-up. This observation demonstrates that thromboangiitis obliterans is a potential reversible cause of severe Raynaud's phenomenon in young women even in the absence of lower limb involvement. Early recognition is important to avoid irreversible complications such as loss of digits.

Prognosis in Duke's B colorectal carcinoma: the Jass classification revisited.

OBJECTIVE: To assess whether Jass staging enhances prognostic prediction in Dukes' B colorectal carcinoma. DESIGN: A historical cohort observational study. SETTING: A university tertiary care centre, Switzerland. SUBJECTS: 108 consecutive patients. INTERVENTIONS: Curative resection of Dukes' B colorectal carcinoma between January 1985 and December 1988, Patients with familial adenomatous polyposis; hereditary non-polyposis colorectal cancer; Crohns' disease; ulcerative colitis and synchronous and recurrent tumours were excluded. A comparable group of 155 consecutive patients with Dukes' C carcinoma were included for reference purposes. MAIN OUTCOME MEASURES: Disease free and overall survival for Dukes' B and overall survival for Dukes' C tumours. RESULTS: Dukes' B tumours in Jass group III or with an infiltrated margin had a significantly worse disease-free survival (p = 0.001 and 0.0001, respectively) and those with infiltrated margins had a significantly worse overall survival (p = 0.002). Overall survival among those with Dukes' B Jass III and Dukes' B with infiltrated margins was no better than overall survival among all patients with Dukes' C tumours. CONCLUSION: Jass staging and the nature of the margin of invasion allow patients undergoing curative surgery for Dukes' B colorectal carcinoma to be separated into prognostic groups. A group of patients with Dukes' B tumours whose prognosis is inseparable from those with Dukes' C tumours can be identified, the nature of the margin of invasion being used to classify a larger number of patients.