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With stress echo (SE) 2020 study, a new standard of practice in stress imaging was developed and disseminated: the ABCDE protocol for functional testing within and beyond CAD. ABCDE protocol was the fruit of SE 2020, and is the seed of SE 2030, which is articulated in 12 projects: 1-SE in coronary artery disease (SECAD), 2-SE in diastolic heart failure (SEDIA), 3-SE in hypertrophic cardiomyopathy (SEHCA), 4-SE post-chest radiotherapy and chemotherapy (SERA), 5-Artificial intelligence SE evaluation (AI-SEE), 6-Environmental stress echocardiography and air pollution (ESTER), 7-SE in repaired Tetralogy of Fallot (SETOF), 8-SE in post-COVID-19 (SECOV), 9: Recovery by stress echo of conventionally unfit donor good hearts (RESURGE), 10-SE for mitral ischemic regurgitation (SEMIR), 11-SE in valvular heart disease (SEVA), 12-SE for coronary vasospasm (SESPASM). The study aims to recruit in the next 5 years (2021–2025) ≥10,000 patients followed for ≥5 years (up to 2030) from ≥20 quality-controlled laboratories from ≥10 countries. In this COVID-19 era of sustainable health care delivery, SE2030 will provide the evidence to finally recommend SE as the optimal and versatile imaging modality for functional testing anywhere, any time, and in any patient.

Hypertrophic cardiomyopathy (HCM) is a common myocardial disease characterized by otherwise unexplained left ventricular hypertrophy. The main cause of disabling symptoms in patients with HCM is left ventricular outflow tract (LVOT) obstruction. This phenomenon is multifactorial, determined both by anatomical and functional abnormalities: myocardial hypercontractility is believed to represent one of its major determinants. The anatomical anomalies are targeted by surgical interventions, whereas attenuating hypercontractility is the objective of old and new drugs including the novel class of allosteric myosin inhibitors. This review summarizes the current treatment modalities and discusses the emerging therapeutical opportunities focusing on the recently developed cardiac myosin ATPase inhibitors Mavacamten and CK-274. Novel surgical and interventional approaches are also discussed.

Objectives To assess the association of pre-morbid functional status [Barthel Index (BI)] and frailty [modified Frailty Index (mFI)] with in-hospital mortality and a risk scoring system developed for COVID-19 in patients ≥75 years diagnosed with COVID-19. Design Retrospective bicentric observational study. Setting and Participants Data on consecutive patients aged ≥75 years admitted with COVID-19 at 2 Italian tertiary care centers were collected from February 22 to May 30, 2020. Methods Overall, 221 consecutive patients with COVID-19 aged ≥75 years were admitted to 2 hospitals in the study period and were included in the analysis. Clinical, functional (BI), frailty (mFI), laboratory, and imaging data were collected. Mortality risk on admission was assessed with the COVID-19 Mortality Risk Score (COVID-19 MRS), a dedicated score developed for hospital triage. Results Ninety-seven (43.9%) patients died. BI, frailty, age, dementia, respiratory rate, Pa o 2/Fi o 2 ratio, creatinine, and platelet count were associated with mortality. Analysis of the area under the receiver operating characteristic (AUC) indicated that the predictivity of age was modest and the combination of BI, mFI, and COVID-19 MRS yielded the highest prediction accuracy (AUCCOVID-19MRS+BI+mFI vs AUCAge: 0.87 vs 0.59; difference: +0.28, lower bound–upper bound: 0.17-0.34, P Conclusions and Implications Premorbid BI and mFI are associated with mortality and improved the accuracy of the COVID-19 MRS. Functional status may prove useful to guide clinical management of older individuals.

We evaluated 100 postacute coronavirus disease 2019 (COVID-19) patients a median (interquartile range) of 60 (48–67) days after discharge from the Careggi University Hospital, Italy. Eighty-four (84%) had at least 1 persistent symptom, irrespective of COVID-19 severity. A considerable number of hospital readmissions (10%) and/or infectious diseases (14%) during the postdischarge period were reported.

Whether diagnostic timing in transthyretin (TTR) cardiac amyloidosis (CA) predisposes patients to worse outcomes is unresolved. We aimed to describe the long-term association of diagnostic timing (time from first onset of symptoms consistent with CA leading to medical contact to definitive diagnosis) with mortality in patients with wild-type TTR-CA (ATTRwt-CA). Overall, we reviewed the medical records of 160 patients seen at a tertiary care amyloidosis unit from January 1, 2016, to January 1, 2020 (median [interquartile range] follow-up, 21 [10 to 34] months), and compared them by survival. Median diagnostic timing was 4 (2 to 12) months and was longer in nonsurvivors (9 [3 to 15] vs 3 [1 to 7] months; P.001). Patients diagnosed 6 or more months after symptom onset had higher mortality, with a median survival of 30 months (95% CI, 22 to 37 months). On Cox multivariable analysis, timing was independently associated with all-cause mortality (hazard ratio per month increase, 1.049 [95% CI, 1.017 to 1.083]) together with age at diagnosis, disease stage, New York Heart Association class, and coronary artery disease. In conclusion, diagnostic timing of ATTRwt-CA is associated with mortality. Timely diagnosis is warranted whenever "red flags" are present.

Background: Sympathetic dysfunction can be evaluated by heart rate reserve (HRR) with exercise test. Objectives: To determine the value of HRR in predicting outcome of patients with hypertrophic cardiomyopathy (HCM). Methods: We enrolled 917 HCM patients (age = 49 ± 15 years, 516 men) assessed with exercise stress echocardiography (ESE) in 11 centres. ESE modality was semi-supine bicycle in 51 patients (6%), upright bicycle in 476 (52%), and treadmill in 390 (42%). During ESE, we assessed left ventricular outflow tract obstruction (LVOTO), stress-induced new regional wall motion abnormalities (RWMA), and HRR (peak/rest heart rate, HR). By selection, all patients completed the follow-up. Mortality was the predetermined outcome measure Results: During ESE, RWMA occurred in 22 patients (2.4%) and LVOTO (≥50 mmHg) in 281 (30.4%). HRR was 1.90 ± 0.40 (lowest quartile ≤ 1.61, highest quartile &gt, 2.13). Higher resting heart rate (odds ratio 1.027, 95% CI: 1.018–1.036, p &lt, 0.001), older age (odds ratio 1.021, 95% CI: 1.009–1.033, p &lt, 0.001), lower exercise tolerance (mets, odds ratio 0.761, 95% CI: 0.708–0.817, p &lt, 0.001) and resting LVOTO (odds ratio 1.504, 95% CI: 1.043–2.170, p = 0.029) predicted a reduced HRR. During a median follow-up of 89 months (interquartile range: 36–145 months), 90 all-cause deaths occurred. At multivariable analysis, lowest quartile HRR (Hazard ratio 2.354, 95% CI 1.116–4.968 p = 0.025) and RWMA (Hazard ratio 3.279, 95% CI 1.441–7.461 p = 0.004) independently predicted death, in addition to age (Hazard ratio 1.064, 95% CI 1.043–1.085 p &lt, 0.001) and maximal wall thickness (Hazard ratio 1.081, 95% CI 1.037–1.128, p &lt, 0.001). Conclusions: A blunted HRR during ESE predicts survival independently of RWMA in HCM patients.

Constrictive pericarditis is a common cause of right heart failure, characterized by increased filling pressures and passive liver congestion. As magnetic resonance (MR) T1 and T2 mapping allow quantification of liver relaxation times, we hypothesized liver mapping may allow depiction of passive liver congestion. We studied 45 pericarditis patients, of whom 25 presented constrictive physiology (CP+) and 20 normal physiology (CP-), and 30 control subjects. Pericarditis patients were predominantly male, but CP+ patients were on average 13 years older than CP- patients (p=0.003). Native T1 and T2 values as well as extracellular volume (ECV) values of the liver were significantly higher in CP+ than in CP- patients and controls, i.e. native T1: 765±102ms vs 581±56ms and 537±30ms; T2: 63±13ms vs 50±4ms and 46±4ms; ECV: 42±7% vs 31±3% and 30±3% control (all p5 mm Hg to discriminate between normal and increased RA pressure, native T1 liver yielded the highest AUC (0.926) at ROC analysis with a sensitivity of 79.3% and specificity of 95.6%. Moreover, liver mapping showed excellent intra- and inter-reader agreement. In conclusion, liver mapping as part of a comprehensive cardiovascular MR exam is valuable to depict liver congestion in pericarditis patients.

Background Heart rate reserve (HRR) during exercise evaluates chronotropic incompetence and is a prognostically important marker of cardiac autonomic dysfunction, additive to regional wall motion abnormalities (RWMA) in patients with coronary artery disease. Objectives To assess determinants and prognostic value of HRR in patients with hypertrophic cardiomyopathy (HCM). Methods From 1998 to 2019, we enrolled 774 HCM patients (age = 48.8±15.9 years, 410 men) with exercise stress echocardiography (ESE) in 10 certified centres of the international stress echo network. During ESE we assessed: left ventricular outflow tract obstruction (LVOTO, significant when >50 mmHg); RWMA; HRR (peak/ rest heart rate), 344 in beta-blockers therapy (44.4%). Patients were followed for a median 49 months (IQ range, 25–78 months). The study end-point was all-cause mortality. Results During ESE, we observed stress-induced RWMA in 42 (5.4%) and LVOTO in 248 (33%); HRR was 1.92.±0.41. There were no difference in patients with normal and abnormal HRR with and without beta-blockers therapy (147, 41.1% vs 211, 58.9%, p=0.079). During follow-up, 43 deaths occurred. Beta blockers therapy in univariate analysis did not have prognostic role (HR 1.105, 95% CI 0.602–2.028, p=0.768). The lowest HRR quartile (≤1.62) had a 10-fold higher 6-year death rate (10.9%) than the highest quartile (>2.16, 1.04%): see figure. At multivariable analysis, lowest HRR quartile (HR 2.074, 95% CI 1.082–6.773, p=0.034), age (HR 1.045, 95% CI 1.014–1.077, p=0.004), maximal wall thickness (HR 1.137, 95% CI 1.054–1.226, p=0.001), stress-induced RWMA s(HR 4.289, 95% CI 1.733–10.615, p=0.002) and ≥ moderate mitral regurgitation at rest (HR 3.127, 95% CI 1.507–6.488, p=0.002) predicted death. Conclusions A blunted HRR during ESE predicts adverse outcome independent of inducible RWMA in HCM patients. Autonomic dysfunction deserves consideration as a potential therapeutic target in this disease. Figure 1 Funding Acknowledgement Type of funding source: None

Light-chain amyloidosis (AL) is considered a rare disease, although few studies have assessed its epidemiology. Therefore, we felt it appropriate to examine the regional incidence of new AL diagnos...

There is growing evidence supporting a possible role for metabolic syndrome and its determinants, such as dyslipidemia, in uterine fibroid (UF) pathogenesis. The present study aims to investigate the association between UFs and visceral and subcutaneous fat thickness (SFT), lipid profile, and oxidative and antioxidative status. In this cross-sectional study, 35 patients diagnosed with UFs and 15 women without UFs were enrolled. Clinical history and anthropometric parameters were collected for every woman. Characteristics of UFs, preperitoneal fat thickness (PFT), and SFT were assessed ultrasonically. Lipid profile, glucose, thiobarbituric acid reactive substances (TBARs), and superoxide dismutase (SOD) activity were evaluated on plasma from participants. Women with UFs showed a significantly increased PFT (11.63 ± 3.39 vs 7.01 ± 3.10 mm; P

The aim of this multicenter, randomized, prospective study was to reveal a difference in terms of a guided healing period in the case of stoma orifices after reestablishing digestive continuity by comparing an alginate mesh with a polyvidone iodine mesh.Between April 2004 and September 2005, a total of 73 patients were randomized into two groups: A (alginate mesh) and M (polyvidone iodine mesh). The groups were comparable for demographic data, indications for and the type of stoma, and perioperative data. The main evaluation criterion was percentage healing at the 28th postoperative day (D28); and the secondary criteria were healing time, rate of infectious complications, and number of dressing changes applied.The mean percentage healing at D28 was 91% in group A and 87% in group M (p = 0.49). The mean healing time was 31 days in group A and 32 days in group M (p = 0.80). One parietal abscess (3%) occurred in group A (p = 0.37). The mean number of meshes used was 13 +/- 5 in group A and 18 +/- 8 in group M (p0.005).The use of an alginate mesh for guided healing of stoma orifices after reestablishing digestive continuity allows effective healing within a normal period of time with a lower number of meshes.

Surgical simulation increasingly appears to be an essential aspect of tomorrow's surgery. The development of a hepatic surgery simulator is an advanced concept calling for a new writing system which will transform the medical world: virtual reality. Virtual reality extends the perception of our five senses by representing more than the real state of things by the means of computer sciences and robotics. It consists of three concepts: immersion, navigation and interaction. Three reasons have led us to develop this simulator: the first is to provide the surgeon with a comprehensive visualisation of the organ. The second reasons is to allow for planning and surgical simulation that could be compared with the detailed flight-plan for a commercial jet pilot. The third lies in the fact that virtual reality is an integrated part of the concept of computer assisted surgical procedure. The project consists of a sophisticated simulator which must include five requirements: a) visual fidelity, b) interactivity, c) physical properties, d) physiological properties, e) sensory input and output. In this report we describe how to obtain a realistic 3D model of the liver from bi-dimensional 2D medical images for anatomical and surgical training. The introduction of a tumor and the consequent planning and virtual resection is also described, as are force feedback and real-time interaction.

Background. Laparoscopic appendectomy has now gained wider acceptance in clinical practice, particularly in the treatment of women with right iliac fossa pain. However, the precise role of laparoscopic appendectomy in men is unclear, and this study was therefore undertaken to examine this specific issue in a prospective randomized trial. Methods. One hundred men between the ages of 16 and 65 years who had suspected appendicitis were recruited and randomized to undergo either open or laparoscopic appendectomy. Both groups were compared in terms of their clinical parameters, duration of anesthetic and operation times, postoperative pain, duration of ileus, and length of hospital stay. Results. The histologic confirmation of appendicitis was present in 94% of the cases for both groups of patients. Laparoscopic appendectomy required significantly longer anesthetic time (72.5 minutes versus 55 minutes) and actual operating time (45 minutes versus 25 minutes) compared with open appendectomy. Postoperative pain as measured by visual analog scale on postoperative days 1 and 2 were not significantly different between the patients who underwent laparoscopic and open surgery with values of 4.7 versus 4.4 and 2.1 versus 2.2, respectively. Also no significant difference was seen between the laparoscopic and open appendectomy groups in the recovery of bowel function (24.7 hours versus 21 hours) and in the length of hospital stay (4.9 days versus 5.3 days). Conclusions. The results of this prospective randomized trial showed that there were no significant advantages of laparoscopic appendectomy over open appendectomy for the treatment of male patients with suspected appendicitis. We recommend that the use of laparoscopy be limited to men with atypical pain of uncertain diagnosis and in obese patients.

Objectives: The therapy of advanced, relapsed or refractory primary cutaneous lymphomas is often unsatisfactory. Recent data indicate a favourable pharmacokynetic, pharmacodynamic and toxicity profile of pegylated liposomal doxorubicin (Peg-Doxo) in primary cutaneous T-cell lymphomas, while in primary cutaneous B-cell lymphomas (PCBCLs), the drug efficacy has never been assessed so far. Methods: We performed a prospective phase II pilot clinical trial of Peg-Doxo monotherapy (20 mg/m2) in PCBCLs. One patient had a marginal zone B-cell lymphoma and four were affected by diffuse large B-cell lymphoma-leg type, all with widespread nodular lesions. Results: All the patients achieved a complete response (CR = 100%) in a short period of time (median 3 months), even when pretreated with radio-chemotherapy. Two experienced a relapse. At follow-up, one patient died for progressive disease; four are in CR after 5, 52, 63 and 69 months. As concerning the toxicity profile, the treatment was well-tolerated, no one decreased or delayed the dose. The haematological toxicity was mild with only one case of grade III neutropenia; a patient showed a grade I neurotoxicity. Dermatological toxicity, in particular the palmar–plantar erythrodysesthesia, did not occurred, probably because of both the low dosages of Peg-Doxo monotherapy and the oral prophylaxis with pyridoxine. Conclusions: In spite of the small number of patients, it emerges that monochemotherapy with Peg-Doxo has a significantly high clinical activity and a good safety profile in PCBCLs, even in aggressive forms, compared with other therapeutic regimens, which are completely reviewed. It suggests the need of further investigations in this field.

Rosette formation is an unusual finding in malignant lymphomas. We herein report another case of a diffuse large B-cell lymphoma (DLBCL) with ultrastructural evidence of cellular projections, sinusoidal growth pattern, and strong CD30 expression. A literature review of the DLBCL cases showing all these features was also performed.

Pegylated liposomal doxorubicin (Peg-Doxo) is a promising drug for advanced/recalcitrant primary cutaneous T-cell lymphomas (CTCLs). This prospective phase II trial enrolled 19 patients. We observed overall and complete response rates of 84.2% and 42.1% (with no significant differences between stage I-IIA and IIB-IV patients), and 11% grade III/IV toxicity. After a maximum 46 month-follow-up, median overall (OS), event-free (EFS) and progression-free (PFS) survival were 34, 18 and 19 months. OS, EFS and PFS rates at 46 months were 44%, 30% and 37% respectively. Peg-Doxo seems to be an active and safe principle that should be used in plurirelapsed, early stage-MF and in combination with other chemotherapeutic agents in advanced and aggressive CTCLs.

Objectives Combined high-dose Interferon-alpha and psoralen plus ultraviolet A irradiation (PUVA) have been reported to be effective in the treatment of early mycosis fungoides (MF); however, our study is the first controlled prospective study in the literature exploring the activity and tolerability of the combination with low dosages and evaluating further clinical outcome of early-MF patients. Methods We carried out a multicentric prospective Phase II clinical study on 89 patients with early-stage IA to IIA MF treated for 14 months with low-dose IFN-alpha2b (6-18 MU/wk) and PUVA. Treatment success was analysed in terms of freedom from treatment failure. Results and conclusions Complete remission (CR) was achieved in 84% and an overall response rate in 98% of cases: six-month CR was associated with a non-confluent skin infiltrate at histology (P = 0.044) and 14-month CR with high epidermal CD1a+ dendritic-cell density (P = 0.030). The combination protocol was successfully tolerated and the most common reason of 'failure' was related to relapse and not to toxicity. Sustained remissions were achieved in 20% of patients. High CD8+ lymphoid T-cell density was associated with a lower relapse rate (P = 0.002). We think that our combination therapy can be considered an alternative approach compared with other modalities. Good immunological host surveillance in the skin lesions seems to be an optimal basis for the therapeutic success.

Pelvic malignancies frequently require post-operative radiation therapy that may induce small bowel damage at an incidence of 5-25%. Various surgical techniques have been reported to prevent acute and chronic radiation enteritis. This article describes the technical aspects of pelvic exclusion by an intrapelvic silicone breast prosthesis.

The use of laparoscopy for assessment and treatment of malignant tumors remains controversial. The aim of this study was to evaluate the impact of tumor manipulation during laparoscopy compared with that of conventional laparotomy on growth and spread of an intraperitoneal tumor in the rat in a randomized, controlled trial.Thirty 2-month-old male Lewis rats received a single-site intrapancreatic inoculation of a ductal adenocarcinoma. Fourteen days after cancer implanting, two groups of six animals each underwent a laparotomy (30 min 6 mmHg CO2 pneumoperitoneum). The tumor was manipulated in the one group, and exclusively visualized in the other. In two other groups, a midline laparotomy with (n = 6) or without (n = 6) tumor manipulation was performed. Animals in the control group (n = 6) underwent no procedure. Tumor volume, tumor mass, local regional invasion incidence, lymph node involvement, and liver and lung metastases were evaluated on 28-day tumors.No difference in tumor growth and spread was observed between laparoscopy and laparotomy when tumor manipulation was not carried out. Tumor manipulation increased tumor growth significantly in the laparotomy group, but not in the laparoscopy one. Tumor metastases were correlated to tumor growth and increased significantly after manipulation in both groups. There was no port-site or conventional wound seeding in either the surgical procedure.This study showed that manipulation is the main factor acting on tumor dissemination in both laparoscopy and laparotomy. Laparoscopic surgery had a beneficial effect on local tumor growth compared with laparotomy in the case of tumor manipulation. This beneficial effect of laparoscopic surgery may be related to a better preservation of immune function in the early postoperative period.

BackgroundThe presence of peritonitis has previously been considered to be a contraindication for the laparoscopic approach because of the theoretical risk of malignant hypercapnia and toxic shock syndrome. The aim of this retrospective study was to demonstrate that laparoscopy is feasible, safe and efficient in cases of peritonitis.MethodsFrom January 1990 to July 1995, 231 patients had a laparoscopy for acute peritonitis in two centres (91 appendicular peritonitis, 69 gastroduodenal perforated ulcers, 35 perforations of the colon, 36 miscellaneous).ResultsThe diagnostic accuracy of laparoscopic exploration was 84·8 per cent. The clinical preoperative diagnosis was changed by laparoscopic exploration in 25·1 per cent of patients. An unnecessary laparotomy was avoided in 6·5 per cent of patients and the site of traditional incision was modified in 8·7 per cent. Conversion rates were 25 per cent for appendicular peritonitis, 16 per cent for gastroduodenal perforation and 83 per cent (29 of 35 patients) for colonic perforation. The overall mortality rate was 3·9 per cent. No malignant hypercapnia occurred. Two patients (0·9 per cent) had postoperative septic shock but survived.ConclusionLaparoscopy is feasible and safe in cases of peritonitis. Laparoscopic treatment is particularly effective in the case of appendicular and gastroduodenal perforation. In the case of colonic perforation, the conversion rate remains high but with growing experience and surgical skill, more of these cases will be treated laparoscopically in the future.

International audience; OBJECTIVE: This article describes a preliminary work on virtual reality applied to liver surgery and discusses the repercussions of assisted surgical strategy and surgical simulation on tomorrow's surgery. SUMMARY BACKGROUND DATA: Liver surgery is considered difficult because of the complexity and variability of the organ. Common generic tools for presurgical medical image visualization do not fulfill the requirements for the liver, restricting comprehension of a patient's specific liver anatomy. METHODS: Using data from the National Library of Medicine, a realistic three-dimensional image was created, including the envelope and the four internal arborescences. A computer interface was developed to manipulate the organ and to define surgical resection planes according to internal anatomy. The first step of surgical simulation was implemented, providing the organ with real-time deformation computation. RESULTS: The three-dimensional anatomy of the liver could be clearly visualized. The virtual organ could be manipulated and a resection defined depending on the anatomic relations between the arborescences, the tumor, and the external envelope. The resulting parts could also be visualized and manipulated. The simulation allowed the deformation of a liver model in real time by means of a realistic laparoscopic tool. CONCLUSIONS: Three-dimensional visualization of the organ in relation to the pathology is of great help to appreciate the complex anatomy of the liver. Using virtual reality concepts (navigation, interaction, and immersion), surgical planning, training, and teaching for this complex surgical procedure may be possible. The ability to practice a given gesture repeatedly will revolutionize surgical training, and the combination of surgical planning and simulation will improve the efficiency of intervention, leading to optimal care delivery.

Patients with primary cutaneous lymphomas (PCLs) are treated with multiple therapeutic regimens, which may increase the risk of subsequent solid and haematological neoplasms. The aim of our study was to assess the incidence of other malignancies in our series of PCLs. From March 1994 to January 2007, 272 patients with PCLs (179 M, 93 F, median age 65 yr, range 14–88) were referred to our center for staging, treatment and follow-up. The clinical charts were reviewed to detect the incidence of malignancies occurred before or after the diagnosis of PCL or concomitantly. The series was composed by 228 patients (150 M, 78 F, median age 66 yrs) with T-cell lymphomas (202 Mycosis Fungoides/MF, 10 Sézary Syndrome/SS, 9 CD30+ PCL, 7 non MF/non CD30+ T cell PCL); 43 patients (28 M, 15 F, median age 60 yrs) with B-cell lymphomas (25 Follicular/FL, 14 marginal/MZL, 3 Leg-type, 1 Lymphoblastic) and one patient with CD4+/CD56+ hematodermic neoplasm. Chemotherapy was administered to 48 patients. During follow-up 12 patients died for the disease and 24 for other causes. A second tumor was observed in 41 patients (15%): 6 of them experienced more than one neoplasms: overall we observed 48 malignancies, 38 solid and 10 haematological. The other neoplasms appeared similarly before (20) and after (21) the diagnosis of PCL; in 7 cases they were diagnosed simultaneously. Solid tumours (17 preceding, 4 concurrent, 17 subsequent) were diagnosed in: skin (11), colon (5), lung (4), breast (3), CNS (3), bladder (2), liver (2), kidney (2), uterus (2), testis (1), prostate (1), stomach (1), thyroid (1). The haematological malignancies (3 preceding, 3 concurrent, 4 subsequent) were: B-cell lymphomas (4), acute myeloid leukemias (3), plasmocytoma (1), T-cell lymphoma (1), Hodgkin’s lymphoma (1). Among the six patients with more than one adjunctive neoplasms one patient had lung and kidney carcinoma preceding PCL; two patients a preceding carcinoma (skin and bladder, respectively) and subsequently a lung carcinoma; other two patients showed both a preceding and a concurrent neoplasm (skin and colon carcinoma, B-cell lymphoma and skin carcinoma, respectively). Finally a patient had a preceding skin carcinoma, a concurrent nodal Hodgkin’s lymphoma and a subsequent nodal B-cell lymphoma. So we have reported 48 other neoplasms in 41 patients within 272 PCLs (15%). The occurrence of the other malignancy was not related to the B/T phenotype of PCLs, as it was observed in 35/228 (15.4%) T-cell lymphomas (32 MF, 2 SS, 1 non MF/non CD30+ T cell lymphoma) and in 6/43 (14%) B-cell lymphomas (3 FL, 3 MZL; χ2 test: P=0.88). The interval of occurrence was longer for tumors preceding (median 60 mo.s, range 8–180) than for tumors following PCL (median 45, range 6–122). The administration of chemotherapy for PCL was not associated with an increased incidence of second neoplasm(χ2 test, P=0.77). Multicentric studies might help in elucidating the role of genetic and immunitary factors in the pathogenesis of multiple neoplasms in patients with PCLs.

Extranodal marginal zone B-cell lymphomas are considered at the present time as “infection-associated” tumors, because their occurrence has been observed in the background of a chronic antigenic stimulation started by some recognised pathogenic microbial agents, which do not cause the lymphoid transformation by a direct infection of the lymphocytes, but by maintaining the cells with a prolonged antigenic stimulation in a continuous proliferative status and thus increasing the probabilities of a neoplastic transformation. Among them, the Helicobacter pilori is known to be active in the stomach, the Campylobacter jejuni in the ileum, the Chlamydia psittaci in the eye, the Hepatitis C virus in the spleen, whereas in the skin Borrelia burgdorferi, the agent of Lyme’s disease, which can present as erithema migrans as well as a lymphocytoma cutis, has been indicated as a potential agent involved in the pathogenesis of B-cell lymphomas. In some instances, the eradication of the Borrelia has been associated with skin lymphoma regression in cases with documented infection. In Italy there is a great variability of incidence of the disease, which is trasmitted by arthropode-bites and few cases have been observed also in our region, the Marche; this region has approximately one and half million of inhabitants. The aim of our study was to analyse by molecular techniques the presence in tissue of Borrelia burgdorferi DNA in 72 cases of primary cutaneous B-cell lymphomas, diagnosed at the Institute of Anatomic Pathology of Polytechnic Marche Region in Ancona from 1990 and 2004. In all the cases the clinical history was retrieved from clinical charts. On the basis of the pathological findings together with a complete phenotypical and clonality analysis, each case was reclassified according to the recent WHO/EORTC scheme, as follows: 16 cases of marginal-zone lymphomas, 33 cases of follicle-center lymphomas, 23 cases of diffuse large B-cell lymphomas, subdivided in “leg-type” (7), and “other” (16). DNA was extracted by paraffin-embedded tissue and amplified as previously reported, together with DNA extracted from colonies of Borrelia burgdorferi as positive control. None of the 72 cases resulted positive. The efficacy of the PCR method was documented by the expected bands obtained with control samples. Based on our results, the role of Borrelia burgdorferi in the pathogenesis of B-cell lymphomas seems to be unlikely in our geographical area, in agreement with a very low incidence of the Lyme’s disease. Therefore, also the specific antibiotic therapy do not seem to have a rationale in lymphoma treatment. Our negative results should represent a basis for searching a different combination of immunological, infectious and genetic factors to explain the occurrence of primary B-cell lymphomas, particularly the marginal types, in our region.

In the skin of 50–75% patients with early mycosis fungoides (MF) a dominant T-cell receptor (TCR) γ gene rearrangement can be detected. An identical T-cell clone is also detectable in the peripheral blood (PB) in 15–40% of these patients, as well as in 39–61% of skin biopsies showing histological remission after therapy. At the present time, it is still unclear if molecular analyses might be helpful to recognize an unfavourable subset of patients less responsive to skin-directed therapy or with a higher risk of disease recurrence. 89 patients (56 men, 33 women) with a median age of 60 years (range, 17–80), with a histologically confirmed diagnosis of early MF, were treated with a combination protocol of PUVA and low dose IFN-α for 14 months and then closely followed up. Only patients with a dominant clone in the affected skin at diagnosis, and in whom peripheral blood samples at diagnosis and a second tissue biopsy at the end of treatment were available, were selected for the present study. Twenty-four patients (10 men, 14 women; median age 62.5 yrs, range 17–77; 6 in stage IA, 15 IB, 3 IIA) met the inclusion criteria. PCR amplification for TCR γ gene was performed on DNA extracted from formalin-fixed and paraffin-embedded skin tissue samples and from frozen PB lymphocytes, as previously reported. Amplification products were visualised by 10% polyacrylamide gel electrophoresis at the same time, on the same gel, thereby allowing precise comparison of the dominant clonal populations. In one patient the identity of T-cell clones in the skin at diagnosis and at the end of therapy was assessed by sequencing analysis. After a mean time of 4 months (range 1–11), all 24 patients responded to the combination therapy, obtaining a clinical complete remission (CCR), even if three of them showed histological persistence of disease. During the follow-up, 11 patients had a disease recurrence (median time 70 months range 27–108). PCR analysis of TCR γ gene in the PB showed a circulating T-cell clone identical to the one detected in the skin in 9 cases (37.5%) at diagnosis. An identical T-cell clone was observed in the skin at the end of therapy in 17 cases (71%). Disease-free survival curves plotted by Kaplan-Meier method showed that patients with or without a peripheral T cell clone did not behave differently, that is, half of them would have experienced a relapse after a similar period of time in any case. The same behaviour was observed in patients showing different molecular responses after therapy. Only in one third of patients a molecular cure for the disease could be obtained by combination IFN-α and PUVA therapy, since a high rate of persistence of monoclonal PCR signals following CR was observed (71% of CR cases with a dominant clone at diagnosis); surprisingly, such a molecular outcome seems not to protect patients from subsequent disease relapses. On the other hand, our data seems to indicate that the combination of a skin-directed therapy like PUVA in addition to the systemic immunoregulatory effects of IFN-α may abolish the negative influence of a circulating clone.

Sézary syndrome (SS) is a cutaneous T cell lymphoma in which the demonstration of a T-cell clone in the skin and in the peripheral blood (PB) together with cytomorpho-immunophenotypical criteria are needed for a correct diagnosis besides the typical erytrhoderma and lymphadenopathies. In March 2004 a 63-year-old white man developed a rapidly growing and slightly itching squamous macular eruption on the interscapular region: skin biopsy revealed superficial dermal band-like infiltrates, consisting of small CD3+ CD4+ CD8- lymphocytes with epidermotropism and a few Pautrier’s microabscesses, suggesting a diagnosis of mycosis fungoides (MF). A simultaneous blood involvement was detected with lymphocytosis (14000/μl), increased CD4, CD3, CD2, CD5, CD7 positive T cells and T cell receptor (TCR) Vβ5.1 chain monoclonality. As for initial staging, bone marrow (BM) trephine biopsy demonstrated an interstitial infiltrate of small CD3+ and CD5+ lymphocytes and CT scan did not show any visceral involvement or lymphoadenopathies. TCRγ and TCRδ gene rearrangement patterns in PB and BM analyzed by PCR showed, respectively, a monoclonal Jpγ and a oligoclonal Vδ3Jδ1 rearrangement. Circulating Lutzner cells were seen by electronic microscopy. Cytogenetic analysis in PB using fluorescence in situ hybridization (FISH) techniques revealed multiple abnormalities (add7q, i8q, 10p+, 12p-). In September 2004 the patient started chemotherapy with fludarabine 25 mg/m2 (days 1 to 5 every 4 weeks) for 5 courses. In April 2005 he was still in good condition, not showing skin lesions; CT scan was negative, but lymphocytosis had increased (45000/μl). A BM trephine biopsy and the cytogenetic analysis of PB confirmed the above mentioned alterations. Cytofluorimetric analysis of the CD4+ CD5+ CD7+ population showed two different pattern as regarding CD3 positivity; half of the T cells was expressing CD3 antigens on the membrane surface, the other half in the citosol; however both isoforms of the molecule expressed the same Vβ5.1 chain; another cytofluorimetric characteristic was the strong expression of CD5 and CD7 in terms of elevated fluorescence intensity, a characteristic feature of T-cell prolymphocytic leukemia (T-PLL). The study of TCRγ and TCRδ gene rearrangement in PB showed, respectively, a monoclonal Jpγ and a monoclonal Vδ3Jδ1 rearrangement. In May 2005 the patient started a second line therapy with 30 mg alemtuzumab administered subcutaneously 3 times a week. At the end of the 5th week a complete haematological, immunophenotypical and cytogenetic response was obtained, even if the molecular analysis showed a persistent clonal expansion of T cells. This case demonstrates that the currently proposed haematological, flowcytometric and molecular criteria for SS are not forceful enough to differentiate between SS, MF with blood involvement and some T-PLL cases. A more detailed characterization of Sezary cells is therefore needed. Some investigators suggest that a loss of T-cell lineage markers together with the amount of CD4+ CD26- cells in PB in an appropriate clinical and histological contest, could be a more sensitive criterion of SS.

In patients with early Mycosis Fungoides (MF), a dominant T-cell receptor (TCR) gene rearrangement can be detected in the skin in 50–75% of cases, while in 15–40%, an identical T-cell clone is detectable also in the peripheral blood This may indicate an unfavourable subset of patients. We observed on omogeneus group of early MF patients all receiving the some protocol. The purpuose of this study were: - T-cell receptor gene rearrangement analisys of peropheral blood samples; - evaluation of the prognostic impact of T-cell monoclonality on CR and relapse rate. 44 patients diagnosed as having MF at early stage (25 M, 19 F; mean age 58.7 yrs, range 34–77; 11 in stage IA, 28 in stage IB, 5 in stage IIB) and showing a dominant T cell clone in the skin lesions at diagnosis, were included in the present study. Peripheral blood samples were collected for DNA extraction at diagnosis. PCR amplification for TCRγ gene was performed as previously reported by Ashton-Key et al. (1997) in all 44 cases both in peripheral blood and skin and reduplicated: amplification products were visualised by 10% polyacrylamide gel electrophoresis. Peripheral blood samples were considered positive for a circulating T cell clone only if the monoclonal signals in peripheral blood and skin were reproducible and overlapping. All patients received the same treatment, consisting of a combination protocol with low-dose IFNα + PUVA for 14 months, and then followed up. Clinical response to the therapy and further disease recurrences were registered. After a mean time of 6.02 months (range, 1–21), 7 patients failed to respond to combination therapy, while 37 obtained a clinical complete remission (CCR). Among them, 15 experienced a disease recurrence during the follow-up (mean time, 29.8 months, range, 1–77 months). PCR analysis of TCRγ gene showed in the peripheral blood the same T-cell clone detected in the skin in 16 cases (36.4%). Failure to obtain a CCR was found in 3 out of 28 cases without a T cell clone in peripheral blood (10.7%) and in 4 out 16 cases with a circulating T cell clone (25%; c2 test: P=0.41, NS). Disease recurrence was observed in 9 out of 25 cases without a T cell clone in peripheral blood (36%) and in 6 out of 12 cases with a circulating T cell clone (50%; c2 test: P=0.65, NS). Disease-free survival curves plotted by Kaplan-Meier method showed that patients with and without a circulating T cell clone did not behave differently and that half of the patients would have experienced a relapse after a similar period of time (34 and 36 months, respectively, for patients with TCRg+ and − peripheral blood; log rank test, P=0.79). PCR analysis of TCRγ gene rearrangement analysis has allowed us to detect monoclonality in the peripheral blood in 36% of early MF cases with a documented monoclonality in the skin. At this stage of the disease a circulating T cell clone could indicate a subset of patients in which skin-directed therapies are more likely to fail to completely eradicate the malignant cells. Interestingly, our data seems to show that the negative influence of a circulating clone can be bypassed by the combination of a skin-directed therapy like PUVA and the systemic immunoregulatory effects of IFNα.