Individual participant data pooled-analysis of risk factors for recurrence after neoadjuvant radiotherapy and transanal local excision of rectal cancer: the PARTTLE study.

BACKGROUND: An organ-preserving strategy may be a valid alternative in the treatment of selected patients with rectal cancer after neoadjuvant radiotherapy. Preoperative assessment of the risk for tumor recurrence is a key component of surgical planning. The aim of the present study was to increase the current knowledge on the risk factors for tumor recurrence. METHODS: The present study included individual participant data of published studies on rectal cancer surgery. The literature was reviewed according to according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Individual Participant Data checklist (PRISMA-IPD) guidelines. Series of patients, whose data were collected prospectively, having neoadjuvant radiotherapy followed by transanal local excision for rectal cancer were reviewed. Three independent series of univariate/multivariate binary logistic regression models were estimated for the risk of local, systemic and overall recurrence, respectively. RESULTS: We identified 15 studies, and 7 centers provided individual data on 517 patients. The multivariate analysis showed higher local and overall recurrences for ypT3 stage (OR 4.79; 95% CI 2.25-10.16 and OR 6.43 95% CI 3.33-12.42), tumor size after radiotherapy > 10 mm (OR 5.86 95% CI 2.33-14.74 and OR 3.14 95% CI 1.68-5.87), and lack of combined chemotherapy (OR 3.68 95% CI 1.78-7.62 and OR 2.09 95% CI 1.10-3.97), while ypT3 was the only factor correlated with systemic recurrence (OR 5.93). The analysis of survival curves shows that the overall survival is associated with ypT and not with cT. CONCLUSIONS: Local excision should be offered with caution after neoadjuvant chemoradiotherapy to selected patients with rectal cancers, who achieved a good response to neoadjuvant chemoradiotherapy.

Single-incision laparoscopic cholecystectomy is responsible for increased adverse events: results of a meta-analysis of randomized controlled trials.

BACKGROUND: Over the last decade, single-incision laparoscopic cholecystectomy (SLC) has gained popularity, although it is not evident if benefits of this procedure overcome the potential increased risk. Aim of the study is to compare the outcome of SLC with conventional multi-incision laparoscopic cholecystectomy (MLC) in a meta-analysis of randomized controlled trials only. METHODS: A systematic Medline, Embase, and Cochrane Central Register of Controlled Trials literature search of articles on SLC and MLC for any indication was performed in June 2017. The main outcomes measured were overall adverse events, pain score (VAS), cosmetic results, quality of life, and incisional hernias. Linear regression was used to model the effect of each procedure on the different outcomes. RESULTS: Forty-six trials were included and data from 5141 participants were analysed; 2444 underwent SLC and 2697 MLC, respectively. Mortality reported was nil in both treatment groups. Overall adverse events were higher in the SLC group (RR 1.41; p < 0.001) compared to MLC group, as well severe adverse events (RR 2.06; p < 0.001) and even mild adverse events (RR 1.23; p = 0.041). This was confirmed also when only trials including 4-port techniques (RR 1.37, p = 0.004) or 3-port techniques were considered (RR 1.89, p = 0.020). The pain score showed a standardized mean difference (SMD) of - 0.36 (p < 0.001) in favour of SLC. Cosmetic outcome by time point scored a SMD of 1.49 (p < 0.001) in favour of SLC. Incisional hernias occurred more frequently (RR 2.97, p = 0.005) in the SLC group. CONCLUSIONS: Despite SLC offers a better cosmetic outcome and reduction of pain, the consistent higher rate of adverse events, both severe and mild, together with the higher rate of incisional hernias, should suggest to reconsider the application of single incision techniques when performing cholecystectomy with the existing technology.

Transanal Endoscopic Operation under spinal anaesthesia.

BACKGROUND: Transanal Endoscopic Operation (TEO(®) ) for rectal benign lesions and early rectal cancer may provide better oncological outcomes than flexible endoscopy. The major advantage of flexible endoscopy is that it does not require general anaesthesia. This prospective observational study assessed the feasibility and safety of TEO(®) performed under spinal anaesthesia. METHODS: The study population comprised eligible consecutive patients who underwent TEO(®) under spinal anaesthesia with curative or palliative intent for rectal neoplasms larger than 20 mm in diameter or for recurrent lesions of any size. The primary endpoints were feasibility and safety; secondary endpoints were postoperative pain, as measured on a visual analogue scale, heart rate, systolic and diastolic BP, opioid requested, postoperative nausea or vomiting, and urinary retention. RESULTS: The study included 50 patients (median age 70 years; 29 men and 21 women). No intraoperative complications occurred. The median duration of operation was 60 (range 20-165) min. No opioids were requested during the perioperative or postoperative period. The median postoperative pain score was 0 at 4, 8, 24 and 48 h after surgery. There were no significant fluctuations in heart rate, systolic and diastolic BP up to 48 h after the procedure (P = 0·379, P = 0·386 and P = 0·617 respectively). Postoperative nausea and vomiting occurred in one patient, and urinary retention in four. CONCLUSION: TEO(®) under spinal anaesthesia was safe and feasible with no conversions to general anaesthesia.

Perineal stapled prolapse resection for full-thickness external rectal prolapse: a multicentre prospective study.

AIM: Many different surgical techniques have been reported for the surgical treatment of full-thickness external rectal prolapse. Perianal stapled prolapse resection (PSP) is a relatively newly reported technique for full thickness external rectal prolapse. The aim of this prospective multicentre study was to evaluate the results of this procedure. METHOD: Consecutive patients who underwent a PSP resection for full-thickness external rectal prolapse at five centres were recruited to the study. Median operating time, hospital stay, complications, recurrence and functional results according to the Wexner Incontinence Scale and obstructive defaecation syndrome score were recorded. RESULTS: There were 27 patients treated by PSP. The median Wexner incontinence score improved from 10 presurgery to 5 after surgery (P < 0.001); the median obstructed defaecation syndrome score improved from 12 presurgery to 5 (range 4-10) after surgery (P < 0.001). A laparoscopically assisted procedure was performed in three patients (11.1%). The median number of cartridges used was six (range four to nine). The median operating time was 48 min. Early complications occurred in six patients (22.2%) and late complications in two (7.4%). The median length of hospital stay was 5 days. The recurrence rate at a median follow-up of 30.3 months was 14.8%. CONCLUSION: PSP appears to be an easy, fast and safe procedure. Early functional results are good. The recurrence rate compares favourably with other perineal procedures like the Delorme or the Altemeier operations. Long-term functional results need to be investigated further.

[-2]proPSA versus ultrasensitive PSA fluctuations over time in the first year from radical prostatectomy, in an high-risk prostate cancer population: A first report.

BACKGROUND: [-2]proPSA and its derivatives have an higher diagnostic accuracy than PSA in predicting prostate cancer (PCa). In alternative to PSA, ultrasensitive PSA (uPSA) and [-2]proPSA could be potentially useful in recurrent disease detection. This research focused on [-2]proPSA and uPSA fluctuations over time and their possible clinical and pathological determinants, in the first year after RP. METHODS: A cohort of 106 consecutive patients, undergoing RP for high-risk prostate cancer (pT3/pT4 and/or positive margins), was enrolled. No patient received either preoperative/postoperative androgen deprivation therapy or immediate adjuvant RT, this latter for patient choice. [-2]proPSA and uPSA were measured at 1, 3, 6, 9, 12 months after RP; their trends over time were estimated by the mixed-effects linear model. The uPSA relapse was defined either as 3 rising uPSA values after nadir or 2 consecutive uPSA >0.2 ng/ml after RP. RESULTS: The biochemical recurrence (BCR) rate at 1 year after RP was either 38.6 % (in case of 3 rising uPSA values) or 34.9 % (in case of PSA >0.2 ng/ml after nadir), respectively. The main risk factors for uPSA fluctuations over time were PSA at diagnosis >8 ng/ml (p = 0.014), pT (p = 0.038) and pN staging (p = 0.001). In turn, PSA at diagnosis >8 ng/ml (p = 0.012) and pN (p < 0.001) were the main determinants for [-2]proPSA trend over time. In a 39 patients subgroup, uPSA decreased from month 1 to 3, while [-2]proPSA increased in 90 % of them; subsequently, both uPSA and [-2]proPSA increased in almost all cases. The [-2]proPSA trend over time was independent from BCR status either in the whole cohort as well in the 39 men subgroup. CONCLUSIONS: Both uPSA and [-2]proPSA had independent significant fluctuations over time. PSA at diagnosis >8 ng/ml and pathological staging significantly modified both these trends over time. Since BCR was not confirmed as determinant of [-2]proPSA fluctuations, its use as marker of early biochemical relapse may not be actually recommended, in an high-risk prostate cancer patients population.

An Advanced Surgical Dressing for High-risk Patients Undergoing Breast Cancer Surgery: a Case-control Study.

Oncological breast surgeries, classified as breast conserving surgery, oncoplastic surgery, and mastectomies (standard or with tissue sparing and reconstruction), are burdened with an overall complication rate up to 33%. Aquacel Ag Surgical is a combined hydrofiber-hydrocolloids dressing. The aim of this study is to evaluate the incidence of surgical site complications in patients presenting with three or more risk factors (or two, of which at least one classified as "high risk"), undergoing breast cancer surgery with/without reconstruction, comparing advanced (Aquacel Ag Surgical) with traditional dressing. METHODS: This is a retrospective, monocentric, case-control study based at the breast unit of the Città della Salute e della Scienza Hospital of Turin, Italy. Forty-two patients who underwent breast surgeries and met the inclusion criteria were enrolled, from February 1 to July 31, 2018. The primary endpoint was comparing the incidence of surgical site complications (skin alterations, infection, and wound dehiscence) in the two groups. The secondary endpoints were evaluating patient's quality of life, aesthetic outcomes, and compliance to the dressings. RESULTS: The distribution of risk factors at the baseline between the two groups was balanced, without statistically significant differences. Wound complications' incidence at 1 week was lower in the advanced dressing group (P = 0.015). On the bivariate descriptive analysis, advanced dressing proved to be easier to remove for the operator (P = 0.026). The aesthetic outcomes vouched for better scores in the advanced dressing group. CONCLUSION: In the presented study Aquacel Ag Surgical dressing reduces surgical site complications in the first week after surgery in patients affected by three or more risk factors (or two with at least one classified as "high risk").

Pharmacokinetic evaluation of gemcitabine and 2',2'-difluorodeoxycytidine-5'-triphosphate after prolonged infusion in patients affected by different solid tumors.

BACKGROUND: The study determined pharmacokinetic parameters, toxicity profile and preliminary clinical activity of gemcitabine administered i.v. at different infusion rates in patients with a range of solid tumors. PATIENTS AND METHODS: Twenty patients were enrolled for both pharmacokinetic and clinical studies. Gemcitabine 300 mg/m(2) was administered during 1 h, 2 h or 3 h, and as a conventional dose of 1000 mg/m(2) during 30 min infusion. Administration was on days 1, 8 and 15 every 4 weeks. RESULTS: Patients were randomly assigned to one of the four arms. After 30 min infusion of 1000 mg/m(2) gemcitabine the plasma concentration remained above the saturation level of 10-20 microM, whereas after 1, 2 or 3 h infusion 300 mg/m(2) gemcitabine it remained below the saturation level for most of the time (being in the range 2.5-10 microM). Gemcitabine triphosphate was determined in the four arms in white blood cells; for infusion times from 0.5 to 3 h there was a progressive enhancement of gemcitabine triphosphate levels. In all evaluable patients the toxicity was mild, myelosuppression being the main toxicity. No grade 3 or 4 toxicities occurred. Clinical response was similar in patients receiving 300 mg/m(2) gemcitabine in 2 and 3 h and in the 1000 mg/m(2) arm. CONCLUSIONS: 300 mg/m(2) gemcitabine during 3 h infusion produced the highest accumulation of gemcitabine triphosphate. Thus, to achieve the highest possible gemcitabine triphosphate level, prolonged infusion time would appear to be more important than a high dose administered as a short infusion. However, there was no substantial difference in toxicity or antitumoral activity in the all different patient groups.

A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma.

This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ⩾75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ⩾3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ⩾3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients.

Deep-vein thrombosis rates after major orthopedic surgery in Asia. An epidemiological study based on postoperative screening with centrally adjudicated bilateral venography.

BACKGROUND: The incidence of postsurgical venous thromboembolism is thought to be low in Asian ethnic populations. OBJECTIVE: We studied the incidence of deep-vein thrombosis (DVT) in Asian patients undergoing major orthopedic surgery of the lower limbs. PATIENTS/METHODS: We performed a prospective epidemiological study in 19 centers across Asia (China, Indonesia, South Korea, Malaysia, Philippines, Taiwan, and Thailand) in patients undergoing elective total hip replacement (THR), total knee replacement (TKR) or hip fracture surgery (HFS) without pharmacological thromboprophylaxis. The primary endpoint was the rate of DVT of the lower limbs documented objectively with bilateral ascending venography performed 6-10 days after surgery using a standardized technique and evaluated by a central adjudication committee unaware of local interpretation. RESULTS: Overall, of 837 Asian patients screened for this survey, 407 (48.6%, aged 20-99 years) undergoing THR (n = 175), TKR (n = 136) or HFS (n = 96) were recruited in 19 centers. DVT was diagnosed in 121 of 295 evaluable patients [41.0%, (95% confidence interval (CI): 35.4-46.7)]. Proximal DVT was found in 30 patients [10.2% (7.0-14.2)]. Total DVT and proximal DVT rates were highest in TKR patients (58.1% and 17.1%, respectively), followed by HFS patients (42.0% and 7.2%, respectively), then THR patients (25.6% and 5.8%, respectively). DVT was more frequent in female patients aged at least 65 years. Pulmonary embolism was clinically suspected in 10 of 407 patients (2.5%) and objectively confirmed in two (0.5%). CONCLUSIONS: The rate of venographic thrombosis in the absence of thromboprophylaxis after major joint surgery in Asian patients is similar to that previously reported in patients in Western countries.

Clinical impact of immunophenotypic remission after allogeneic hematopoietic cell transplantation in multiple myeloma.

Immunophenotypic remission (IR) is a strong prognostic factor in myeloma patients. The combination of IR and conventional CR was retrospectively evaluated in 66 patients after allografting. IR was defined as the absence of monoclonal plasma cells in BM aspirates by multiparameter flow cytometry. Conditioning was non-myeloablative in 55 patients; reduced-intensity in 10 and myeloablative in 1 patient. The allograft was given upfront in 35/66 (53%) patients. After a median follow-up of 7.1 years, 24 patients achieved both CR and IR (CR/IR group), 21 achieved IR but not CR with persistence of a urine/serum M-component (no CR/IR group) and 21 did not achieve either CR or IR (no CR/no IR group). Median OS and EFS were 'not reached' and 59 months in the CR/IR group; 64 and 16 months in the no CR/IR; and 36 and 6 months in the no CR/no IR, respectively (P<0.001). Cumulative incidence of extramedullary disease was 4.4% in the CR/IR, 38.1% in the no CR/IR and 14.3% in the no CR/no IR groups, respectively, at 4 years (P<0.001). IR was a valid tool to monitor residual disease after allografting, and allowed definition of a cohort of patients at higher incidence of extramedullary relapse.

Using PET-CT in the restaging of primitive mediastinal B-cell lymphoma (PMBCL) after chemotherapy: which criteria should we use?

AIM: Primitive mediastinal B-cell lymphoma (PMBCL) is a relatively rare form of non-Hodgkin lymphoma (NHL), typically concerning the youngster, with an aggressive course and poor prognosis. The therapy generally consists of high dose chemotherapy followed by radiotherapy. PET-CT is used at staging, restaging after chemotherapy and after radiotherapy, or when relapse is suspected. Aim of the study was to compare different criteria in the evaluation of response to chemotherapy in this setting. METHODS: Thirty-eight patients with PMBCL (15 M, 23 F, median age 33 yrs [range 18-79]), all treated with chemo-immunotherapy and radiotherapy, who had undergone baseline (b-PET) and end of chemotherapy (f-CHT-PET) 18F-FDG-PET-CT scans at our institution between July 2004 and September 2014 were retrospectively re-evaluated; the median follow-up was 42 months (range 4-109), at which 4/38 (11%) had died, 5/38 (13%) were in partial response (PR) and 29/38 (76%) were in complete response (CR). The primary endpoint was progression-free survival (PFS), while the secondary one was overall survival (OS), according to the Cheson criteria. SUV max of the mediastinal disease mass at staging, of the residual mass at CT after chemo-immunotherapy, SUV max of the liver and of the mediastinal blood pool (MBP) were calculated for all patients. RESULTS: In our population, we observed that: 1) visual criteria performs better when positivity-negativity threshold is set at point 3 of the 5-point scale (5-PS); 2) semiquantitative approach by use of Δ SUV max performs better when the threshold is set at 66% decrease: in fact, at Δ SUV max analysis with 66% decrease, 9 patients resulted positive at the test (Δ SUV max ≤66%), 29 negative (Δ SUV max >66%). CONCLUSION: In our population Δ SUV max could be working well in these patients because the baseline values are very high and very homogeneous. Our data, though limited in numerosity of patients and events, suggests that in this particular setting the use of the 5-PS reporting system could not be the best tool available; on the other hand, Δ SUV max could prove to be reliable in the evaluation of response to chemotherapy.

Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival.

Polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis is a useful prognostic tool in multiple myeloma (MM), although its long-term impact still needs to be addressed. This report presents the updated results of the GIMEMA-VEL-03-096 trial. Thirty-nine MM patients receiving bortezomib-thalidomide-dexamethasone after autologous transplantation were monitored for MRD by both nested and real-time quantitative-PCR until relapse. Our data confirm the strong impact of MRD on survival: overall survival was 72% at 8 years median follow-up for patients in major MRD response versus 48% for those experiencing MRD persistence (P=0.041). In addition, MRD kinetics resulted predictive for relapse: indeed median remission duration was not reached for patients in major MRD response, 38 months for those experiencing MRD reappearance and 9 months for patients with MRD persistence (P<0.001). Moreover: (1) 26 patients achieving major MRD response (67%) benefit of excellent disease control (median TNT: 42 months); (2) MRD reappearance heralds relapse, with a TNT comparable to that of MRD persistence (9 versus 10 months, P=0.706); (3) the median lag between MRD reappearance and need for salvage treatment is 9 months. These results suggest the usefulness of a long-term MRD monitoring in MM patients and the need for maintenance or pre-emptive treatments ensuring durable responses.

[Tuberculosis in dialysis patients]. / La tubercolosi nei pazienti in dialisi.

Seven cases of T.B. were observed in 300 patients subjected to dialysis in period 30.4.1977-30.1.1980. This frequency is much higher than that in the ordinary population. An account is given of the statistical and clinical aspects of this morbid associations. The way in which it can be treated is also discussed.

Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders.

In this study, we compared immunoglobulin heavy-chain-gene-based minimal residual disease (MRD) detection by real-time quantitative PCR (RQ-PCR) and next-generation sequencing (NGS) to assess whether NGS could overcome some limitations of RQ-PCR and further increase sensitivity, specificity, accuracy and reproducibility. In total, 378 samples from 55 patients with acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) or multiple myeloma (MM) were investigated for clonotype identification, clonotype identity and comparability of MRD results. Forty-five clonotypes were identified by RQ-PCR and 49 by NGS. Clonotypes identified by both tools were identical or >97% homologous in 96% of cases. Both tools were able to routinely reach a sensitivity level of 1 × E-05. A good correlation of MRD results was observed (R=0.791, P<0.001), with excellent concordance in 79.6% of cases. Few discordant cases were observed across all disease subtypes. NGS showed at least the same level of sensitivity as allele-specific oligonucleotides-PCR, without the need for patient-specific reagents. We conclude that NGS is an effective tool for MRD monitoring in ALL, MCL and MM. Prospective comparative analysis of unselected cases is required to validate the clinical impact of NGS-based MRD assessment.

Bone marrow disease detection with FDG-PET/CT and bone marrow biopsy during the staging of malignant lymphoma: results from a large multicentre study.

AIM: To compare the accuracy of bone marrow biopsy (BMb) and positron emission tomography (PET) in bone marrow disease (BMD) detection, in a large multicentre population of patients with new diagnosis of malignant lymphoma. METHODS: PET and BMb were performed to complete disease staging in 337 consecutive patients: 130 Hodgkin's disease (HD), 207 aggressive non Hodgkin's lymphoma (NHL). Sensitivity, specificity and accuracy of both techniques in BMD detection were evaluated and compared. RESULTS: 87 patients with BMD (25 positives at both exams, 27 only at the BMb and 35 only at the PET study). PET vs. BMb were reordered: sensitivity: 69% vs. 59.8%; specificity: 99.2% vs. 100%; accuracy: 91.4% vs. 89.6%; positive predictive value: 96.8% vs. 100%; negative predictive value: 90.2% vs. 87.7%. CONCLUSION: The sensitivity of PET and BMb is similar (69% and 60%, respectively), PET and BMb are complementary: in fact out of 87 patients with confirmed BMD only 25 are positive at both exams, while 27 only at the BMb and 35 only at the PET exam; the integration of PET findings with BMb ones increases the diagnostic accuracy. Consequentially PET is essential during the staging of malignant lymphomas.

Stem cell mobilization in patients with newly diagnosed multiple myeloma after lenalidomide induction therapy.

Lenalidomide has raised concerns regarding its potential impact on the ability to collect stem cells for autologous stem cell transplantation, especially after prolonged exposure. The use of cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells may overcome this concern. In newly diagnosed multiple myeloma (MM) patients, we investigated the influence of lenalidomide on stem cell collection. In a prospective study, 346 patients received four cycles of lenalidomide-dexamethasone (Rd). Stem cells were mobilized with cyclophosphamide and G-CSF. Patients failing to collect a minimum of 4 × 10(6) CD34(+)/kg cells received a second mobilization course. After mobilization, a median yield of 8.7 × 10(6) CD34(+)/kg was obtained from patients receiving Rd induction. After first mobilization, inadequate yield was observed in 21% of patients, whereas only 9% of patients failed to collect the target yield after the second mobilization attempt. In conclusion, we confirm that a short induction with lenalidomide allowed sufficient stem cells collection to perform autologous transplantation in 91% of newly diagnosed patients.