Consensus clustering methodology to improve molecular stratification of non-small cell lung cancer.

Recent advances in machine learning research, combined with the reduced sequencing costs enabled by modern next-generation sequencing, paved the way to the implementation of precision medicine through routine multi-omics molecular profiling of tumours. Thus, there is an emerging need of reliable models exploiting such data to retrieve clinically useful information. Here, we introduce an original consensus clustering approach, overcoming the intrinsic instability of common clustering methods based on molecular data. This approach is applied to the case of non-small cell lung cancer (NSCLC), integrating data of an ongoing clinical study (PROMOLE) with those made available by The Cancer Genome Atlas, to define a molecular-based stratification of the patients beyond, but still preserving, histological subtyping. The resulting subgroups are biologically characterized by well-defined mutational and gene-expression profiles and are significantly related to disease-free survival (DFS). Interestingly, it was observed that (1) cluster B, characterized by a short DFS, is enriched in KEAP1 and SKP2 mutations, that makes it an ideal candidate for further studies with inhibitors, and (2) over- and under-representation of inflammation and immune systems pathways in squamous-cell carcinomas subgroups could be potentially exploited to stratify patients treated with immunotherapy.

A phase II trial of short course fludarabine, mitoxantrone, rituximab followed by 9°Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma.

BACKGROUND: A prospective, single-arm, open-label, multicenter, nonrandomised phase II trial to evaluate efficacy and safety of short fludarabine, mitoxantrone, and rituximab (FMR) induction followed by radioimmunotherapy, in untreated, intermediate/high-risk follicular non-Hodgkin's lymphoma (NHL) patients. PATIENTS AND METHODS: Fifty-five patients were treated using a sequential treatment schedule of four induction cycles of FMR chemoimmunotherapy, and a subsequent consolidating single administration of (90)Y-ibritumomab tiuxetan ((90)Y-IT), 8-14 weeks later. Patients were eligible for radioimmunotherapy if at least in partial response (PR) after induction, with normal platelet and granulocyte counts and a bone marrow infiltration ≤ 25%. Primary study end points were response rate and hematologic toxic effects; secondary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: All the 55 patients received four induction cycles with an overall response rate of 96% (38 complete responses [CR] and 15 PR). Fifty-one patients (38 in CR and 13 in PR) received (90)Y-IT. By the end of the treatment, 49/55 patients achieved a CR. With a median follow-up of 21 months, the estimated 3-year PFS was 81% and the 3-year OS 100%. CONCLUSIONS: This study has established feasibility, tolerability, and efficacy of a regimen composed by short FMR induction with (90)Y-IT consolidation in untreated intermediate/high-risk follicular NHL patients.

Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome.

BACKGROUND: Peripheral T-cell lymphoma unspecified (PTCLU) and mycosis fungoides (MF) often show resistance to conventional chemotherapy. Gemcitabine should be considered a suitable option. We report the long-term update of 39 pretreated T-cell lymphoma patients treated with gemcitabine. PATIENTS AND METHODS: From May 1997 to September 2007, 39 pretreated MF and PTCLU patients received gemcitabine. Inclusion criteria were as follows: histologic diagnosis of MF or PTCLU; relapsed/refractory disease; age > or =18 years; and World Health Organization performance status of two or less. Nineteen patients had MF and 20 PTCLU. All patients with MF had a T3-T4, N0, and M0 disease and patients with PTCLU had stage III-IV disease. Gemcitabine was given on days 1, 8, and 15 on a 28-day schedule (1200 mg/m(2)/day) for a total of three to six cycles. RESULTS: Overall response rate was 51% (20 of 39 patients); complete response (CR) and partial response (PR) rates were 23% (9 of 39 patients) and 28% (11 of 39 patients), respectively. Patients with MF had a CR rate of 16% and a PR rate of 32% compared with a CR rate of 30% and a PR rate of 25% of PTCLU patients. Among the CR patients, 7 of 9 are in continuous complete response with a variable disease-free interval (15-120 months). CONCLUSION: In our experience, gemcitabine proved to be effective in pretreated MF and PTCLU patients, even in the long term.

MACOP-B regimen in the treatment of adult Langerhans cell histiocytosis: experience on seven patients.

BACKGROUND: Adult Langerhans cell histiocytosis (LCH) is a rare disease. The combination of vinblastine and prednisone, given in a 6-month course, is the standard of care but prospective randomized trials are lacking. PATIENTS AND METHODS: We report our monocentric experience in the treatment of seven adult patients with multisystem (MS) LCH (n = 3) or single-system multifocal (SS-m) LCH (n = 4) with the short-course intensive chemotherapy regimen methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomicin (MACOP-B). RESULTS: The overall response rate was 100% [five complete response (CR), two partial response (PR)]. After a median follow-up of 6.5 years, four patients are in first continuous CR and three patients relapsed after 5, 8 and 62 months, respectively. Four patients were evaluated with positron emission tomography (PET) scan: all three PET-negative patients at the end of treatment had a long-lasting response with only one patient relapsing after 5 years. PET scan detected additional bone lesions at diagnosis in two of four patients, changing the treatment program in one of them. CONCLUSIONS: MACOP-B regimen seems to be very active in the treatment of adult MS or SS-m LCH, with long-lasting responses in five of seven patients. PET scan merits further evaluation in the initial staging and in the evaluation of the response to chemotherapy.

Biological versus Clinical Risk Factors in Acute Myeloid Leukemia: Is There a Winner?

We present a case of a patient with a three-month history of peripheral blood cytopenia without a confirmed diagnosis of myelodysplastic syndrome, who developed a favourable-risk acute myeloid leukemia (AML), according to the European Leukemia Net (ELN) criteria. The patient achieved a complete remission with incomplete platelet recovery (CRi) after induction. The patient achieved the morphological CR after the first consolidation and completed the first-line treatment with a syngeneic stem cell transplantation (SCT). A disease relapse occurred after one year of CR (blast cell count in the bone marrow 15%), and the patient was offered a haplo-SCT, which he refused due to personal reasons. In this paper, we discuss the interplay between clinical and biological risk factors in non-high-risk AML patients and speculate that some old clinical risk factors (e.g., age of the patient, achievement of CR after induction, and previous history of myelodysplastic syndrome) may still impact on the treatment decision algorithm of some of these patients.

Possible role of everolimus in improving renal function in long-term heart transplantation.

Patient survival after heart transplantation has improved dramatically since the availability of calcineurine inhibitor (CNIs); the number of long-term patients is progressively increasing. However, in these patients, nephrotoxicity of CNIs has been largely responsible for the progressive development of renal dysfunction. Since impaired renal function is an important issue that reduces long-term patient survival, it is important to develop strategies to improve renal function while maintaining immunologic safety to preserve graft function. Everolimus is an mTOR inhibitor sirolimus analogue, that has proved, to be highly efficacious to prevent acute myocardial rejection and reduce the severity of cardiac allograft vasculopathy in de novo HTx patients. There is reasonable evidence that, in long term heart transplanted patients, renal function may improve when everolimus is administered associated with a progressive reduction of CNIs. So far there is no evidence to identify which patient may benefit from this therapeutic approach. Indeed everolimus alone may be equally effective to prevent rejection and improve renal function when CNIs are completely discontinued, but data are still lacking on the risks, dosages and side effects of this type of immunosuppression. Ongoing clinical studies will provide further guidance about the possibility to halt or reduce the progression of renal impairment in long term heart transplant patients.

Short-course R-CHOP followed by (90)Y-Ibritumomab tiuxetan in previously untreated high-risk elderly diffuse large B-cell lymphoma patients: 7-year long-term results.

An update at 7 years was conceived for our multicenter phase II study in which 55 elderly high-risk untreated diffuse large B-cell lymphoma patients were treated with (90)Y-ibritumomab tiuxetan after a short course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) as long-term follow-up analyses of this combined therapeutic modality are lacking. The overall response rate to the entire regimen was 80%, including 73% (40/55) of complete response (CR) rate and 7% (4/55) of partial response rate. At the time of writing, 24/55 (43.6%) patients experienced a progression disease and 20 of 40 (50%) patients who obtained a CR are still alive in continuous CR. With a median follow-up of 7 years, the disease-free survival was 43.3% and the progression-free survival was 36.1%. The overall survival at 7.9 years was 38.9% (27 deaths mainly because of lymphoma). Two patients developed secondary hematological malignancies, an acute myeloid leukemia and a myelodysplastic syndrome, at 4 and 3 years from radioimmunotherapy, respectively. Our data confirm the feasibility, efficacy and safety of four cycles of R-CHOP followed by radioimmunotherapy consolidation even in the long term: this combination allows dispensing less chemotherapy in a frail group of patients without invalidating response quality and duration.

Aluminum alters intracellular calcium homeostasis in vitro.

The present paper reports data regarding the influence of aluminum, at micromolar concentrations, on intracellular calcium homeostasis. Al3+ modifies Ca2+ uptake in the endoplasmic reticulum (ER), accelerates Ca2+ release from mitochondria and strongly inhibits Ca2+-ATPase activity with a consequent high-level calcium accumulation inside the cell. These results suggest that Al3+ neurotoxicity may be related to an alteration of the intracellular calcium regulatory system.

Synthesis of beta-D-Galf-(1-3)-D-GlcNAc by the trichloroacetamidate method and of beta-D-Galf-(1-6)-D-GlcNAc by SnCl4-promoted glycosylation.

In a continuation of our studies on the characterization of the glycoproteins of T. cruzi new galactofuranosyl disaccharides were synthesized. Beta-D-Galf-(1-3)-D-GlcNAc was prepared by employing the trichloroacetamidate procedure for the glycosylation step. The mild conditions of this reaction are appropriate for condensation of 2,3,5,6-tetra-O-benzoyl-beta-D-galactofuranosyl trichloroacetamidate with acid-labile benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-alpha-D-glucopyranoside. On the other hand, tin(IV) chloride promoted condensation of benzyl 2-acetamido-3-O-benzoyl-2-deoxy-alpha-D-glucopyranoside with penta-O-benzoyl-alpha-beta-D-galactofuranose gave the derivative of beta-D-Galf-(1-6)-D-GlcNAc in 78% yield.

The role of ultrasound in the differential diagnosis of serous and mucinous cystic tumours of the pancreas.

OBJECTIVE: To evaluate the usefulness of a series of ultrasound parameters in the differential diagnosis between serous and mucinous forms of cystic tumours of the pancreas. SETTING: Retrospective comparative study between the histological analysis of surgical specimens from cystic tumours of the pancreas (4 serous cystadenomas, 6 mucinous cystadenomas and 11 mucinous cystadenocarcinomas) and ultrasound evaluation. METHODS: The ultrasound images of the 21 tumours were analysed by an operator who did not know the result of the histological diagnosis and were divided according to Johnson's criteria (number of cysts > 6 and diameter < 2 cm for serous tumours; number of cysts <6 and diameter >2cm for mucinous tumours) and according to other anatomicopathological parameters such as the presence of septae, endocystic projections, central scar, central calcification and/or in the tumour wall. RESULTS: The ultrasound study gave a correct diagnosis in two out of the four (50%) serous cystic tumours. A central scar and internal calcification was present in one of them. Fifteen (88.2%) of the 17 mucinous tumours were correctly diagnosed; one presented peripheral calcifications and three endocystic projections. CONCLUSION: Ultrasound has a high degree of sensitivity in the differential diagnosis of serous and mucinous cystic tumours of the pancreas if the ultrasound aspects corresponding to the anatomicopathological structure of the neoplasms are correctly evaluated.

The source of Campylobacter pylori.

Sera from 98 abattoir workers were tested for IgG as well as for IgA to Campylobacter pylori, C. jejuni and Klebsiella. Clerical workers had significantly lower C. pylori and C. jejuni antibody levels than any of the groups in direct contact with freshly cut animal parts. No difference was found for antibodies to Klebsiella. Twenty-nine non-clerical workers with high IgG antibody levels against C. pylori consented to upper gastrointestinal endoscopy. C. pylori associated gastritis was found in all 29, and 4 weeks of colloidal bismuth subcitrate (240 mg/twice daily) was prescribed. On repeat testing at 3 months, all showed a decrease in IgG antibody levels to C. pylori but not to C. jejuni, whereas 18 untreated non-endoscoped workers showed no change. These findings raise the possibility that C. pylori infection is a zoonosis.

Bilateral acute suppurative parotitis due to Staphylococcus aureus: an hospital acquired case with fatal outcome.

During recent decades, acute bacterial parotitis has progressively changed its etiological and clinical spectrum. New risk factors and causative agents are emerging, while the associated rates of complications and mortality may remain still significant. A rare case of concurrent bilateral suppurative parotitis caused by Staphylococcus aureus has been observed in a patient hospitalized for prior abdominal surgery and multiple underlying illnesses. The disease had a complicated and ultimately fatal outcome, despite a timely diagnosis being made and a specific treatment started. A literature review dealing with risk factors, microbiology, clinical picture, complications, differential diagnosis, treatment and outcome of suppurative parotitis is presented.

The value of ultrasonography in the diagnosis of hepatic haemangiomas.

The following ultrasonographic (U.S.) patterns were observed in 21 cases of proven hepatic haemangiomas: 1) Hyper-echoic (6 cases); 2) Hypo-echoic (4 cases); 3) Complex (11 cases). Several characteristic aspects of the echo structure (uneven appearance and fine internal parallel echoes) and the location of the lesion (para-caval or sub-diaphragmatic) may be useful for differential diagnosis with malignant neoplasia. The U.S. findings of a further 17 cases of hyperechoic focal lesion of the liver are reported. Although a definitive diagnosis was not possible in these subjects, the U.S. characteristics which remained unchanged for over 6 months, made the diagnosis of haemangioma highly likely.

Echo-guided percutaneous ethanol injection in small hepatocellular carcinoma: personal experience.

We performed echo-guided percutaneous ethanol injection of the lesion in 26 cirrhotic patients with 33 hepatocellular carcinomas measuring 3 cm in diameter or less. Post-treatment lesions had disappeared in 4 patients, while in the remaining 22 patients the echo pattern of the lesion had changed and biopsies were negative. Fifteen patients (follow-up 11-30 months) remain disease-free, while recurrence occurred between 3 and 36 months in 7 cases. Percutaneous ethanol injection was successfully repeated in 4 cases; 5 patients died, 1 of HCC, 2 of esophageal variceal bleeding, and 2 of liver failure; 3 of the last four patients had Child's C disease. Percutaneous ethanol injection is a valuable treatment for hepatocellular carcinomas measuring not more than 3 cm. It has yet to be established how far this treatment influences the survival rates of patients and the natural course of hepatocellular carcinoma.

Small hepatocellular carcinoma: an Italian experience.

Recent reports have demonstrated the possibility of using ultrasound to detect hepatocellular carcinomas under 3 cm (small HCC). Our aim was to assess the incidence of small HCC in an Italian ultrasonographic series. Among 17,133 scans of unselected patients, we detected 85 HCC, 9 of which were under 3 cm. All patients had cirrhosis and 6 were HBsAg positive. An echo-guided biopsy was performed in all cases, and the diagnosis was always correct. We conclude that echographic follow-up is warranted in Italy for cases at risk for HCC such as HBsAg+ cirrhotics and patients with chronic aggressive HBsAg+ hepatitis older than 35, in agreement with the reports of Far Eastern authors.

Intratumoral echo-guided injection of interleukin-2 and lymphokine-activated killer cells in hepatocellular carcinoma.

Interleukin-2 has proved to be effective for the intralesional treatment of tumors of the bladder. There are examples in literature of hepatocellular carcinoma (HCC) treatment with lymphokine-activated killer (LAK) cells infused in the hepatic artery. We decided to check the effects of echo-guided intralesional injection of these cells in this disease. We treated 5 patients with inoperable hepatocellular carcinoma, following cirrhosis; in 4 cases the mass had a diameter less than 3 cm (small HCC) while in the remaining case it measured 7 cm. Tumor size remained unchanged in 3 of the 4 small HCC, and increased only slightly in the other (over a period of 10 months). This would appear to indicate that treatment halted neoplasm growth or at least slowed it down. The echo pattern of the lesions changed, with a constant reduction in echogenicity. Finally, in multiple control biopsies, fibrosis, present in only one case before treatment, was found fairly constantly after treatment. There were no significant side effects, apart from slight water retention in one patient. On the basis of our preliminary results, we consider it worthwhile continuing this study to establish the most suitable IL-2 doses and analyze in more detail the modifications induced in the neoplasm.

[The analgesic treatment of the surgical patient]. / Il trattamento antalgico del paziente operato.

An effective treatment of postoperative pain can achieve a better postop course especially in high risk patients. Pain is unacceptable when it can be relieved and, beside all it causes vasoconstriction, hypertension, tachycardia, fluid retention and pulmonary hypoventilation. A correct use of both narcotic drugs and NSAIDs are sufficient in most cases. In high risk patients, mainly after thoracic and upper abdominal procedures, insertion of a peridural catheter for drug administration can be very useful. The authors discuss the therapeutic possibilities according mainly to their experience.