Search

The role of a systematic lymphadenectomy in patients undergoing surgery for clinical stage I lung lepidic adenocarcinoma is still unclear. In the last years, some authors have advocated the possibility to avoid a complete lymph-node dissection in this setting. Results of patients who received systematic hilar-mediastinal nodal dissection for this oncologic condition are here reported. Between 2012 and March 2019, 135 consecutive patients underwent lung resection for clinical stage I lepidic adenocarcinoma, at our institution. Only patients (n = 98) undergoing lobectomy or sublobar resection associated with systematic hilar-mediastinal nodal dissection were retrospectively enrolled in the study. Patients' mean age was 67.8 ± 8.7 years (range 37-84). Three were 52 females and 46 males. Resection was lobectomy in 77.6% (n = 76) and sublobar in 22.4% (n = 22). All the resections were complete (R0). Histology was lepidic predominant adenocarcinoma in 85 cases and minimally invasive adenocarcinoma in 13 cases. At pathologic examination, N0 was confirmed in 78 patients (79.6%), while N+ was found in 20 cases (20.4%), (N1 in 12, 12.2% and N2 in 8, 8.2%). No mortality occurred. Complication rate was 8.2%. At a median follow-up of 45.5 months, recurrence rate was 26.5%. Disease-free 5-year survival was 98.6% for stage I, 75% for stage II and 45% for stage III, p0.001. A complete nodal dissection can reveal occult nodal metastases in lepidic adenocarcinoma patients and can increase the accuracy of pathologic staging. N1/N2 disease is a negative prognostic factor for this histology. A systematic lymph-node dissection should be considered even in this setting.

Background Resection of lung cancer infiltrating the aortic arch or the subclavian artery can be accomplished in selected patients with the use of cardiopulmonary bypass (CPB). Direct cross-clamping of the aortic arch and the left subclavian artery without CPB for radical resection of the tumor can be an alternative. This study presents one group’s experience with this technique. Methods Between October 2016 and May 2019, 9 patients (5 male, 4 female) underwent radical resection of lung cancer infiltrating the aortic arch (n = 5) or the left subclavian artery (n = 4) by direct cross-clamping technique at Sapienza University of Rome, Italy. Seven left upper lobectomies, 1 left pneumonectomy, and 1 left upper sleeve lobectomy were performed. Reconstruction of the aortic arch was performed by direct suturing or polyethylene terephthalate (Dacron) patch, whereas the subclavian artery was reconstructed with a Dacron conduit. Three patients received neoadjuvant chemotherapy. Results Patients’ mean age was 64.7 ± 13.3 years (range, 36 to 78 years). Aortic arch resection was partial in all cases (adventitial in 1 and full thickness in 4); left subclavian artery resection was adventitial in 2 patients and circumferential in 2. All the resections were complete. Prosthetic reconstruction was performed in 4 cases. Mean operative time was 130 ± 25.6 minutes; mean vascular clamping time was 28.2 ± 3.2 minutes. No mortality occurred. The major complication rate was 11.1 %. At a mean follow-up of 17 ± 9 months (range, 5 to 29 months), the recurrence rate was 33.3%. Median survival was 20 months. Conclusions Direct cross-clamping as an alternative to CPB for resection of lung cancer infiltrating the aortic arch or the subclavian artery is a feasible, safe, and reliable procedure in selected patients.

This is the first report to our knowledge of a successful total tracheal replacement in a post-COVID-19 patient by cryopreserved aortic allograft. The graft was anastomosed to the cricoid and carina; a silicon stent was inserted to ensure patency. The patient was extubated on the operative table and was immediately able to breathe, speak, and swallow. No immunosuppression was administered. Three weeks after surgery, the patient was discharged from hospital in excellent health, and was able to resume his normal lifestyle, work, and activity as an amateur cyclist. Two months after surgery, the patient assumes aerosol with saline solution three times per day and no other therapy; routine bronchoscopy to clear secretions is no longer needed.

BACKGROUND AND OBJECTIVE Rigid tracheobronchoscopy (RTB) has seen an increasing interest over the last decades with the development of the field of IPM but no benchmark exists for complication rates in RTB. We aimed to establish benchmarks for complication rates in RTB. METHODS A multicentric retrospective analysis of RTB performed between 2009 and 2015 in eight participating centres was performed. RESULTS A total of 1546 RTB were performed over the study period. One hundred and thirty-one non-lethal complications occurred in 103 procedures (6.7%, 95% CI: 5.5-8.0%). The periprocedural mortality rate was 1.2% (95% CI: 0.6-1.8%). The 30-day mortality rate was 5.6% (95% CI: 4.5-6.8%). Complication rate increases further when procedures were performed in an emergency setting. Procedures in patients with MAO are associated with a higher 30-day mortality (8.1% vs 2.7%, P

The surgical treatment of locally advanced mediastinal tumors invading the great vessels and other nearby structures still represent a tricky question, principally due to the technical complexity of the resective phase, the contingent need to carry out viable vascular reconstructions and, therefore, the proper management of pathophysiologic issues. Published large-number series providing oncologic outcomes of patients who have undergone extended radical surgery for invasive mediastinal masses are just a few. Furthermore, the wide variety of different histologies included in some of these studies, as well as the heterogeneity of chemo and radiation therapies employed, did not allow for the development of clear oncologic guidelines. Usually in the past, surgical resections of large masses along with the neighbouring structures were not offered to patients because of related morbidity and mortality and limited information available on the prognostic advantage for long term. However, in the last decades, advances in surgical technique and perioperative management, as well as increased oncologic experience in this field, have allowed radical exeresis in selected patients with invasive tumors requiring resections extended to the surrounding structures and complex vascular reconstructions. Such aggressive surgical treatment has been proposed in association or not with adjuvant chemo- or radiotherapy regimens, achieving encouraging oncologic results with limited morbidity and mortality in experienced institutions. Congestive heart failure or impending cardiovascular collapse due to the compression by the large mass are the most frequent immediately life-threatening problems that some of these patients can experience. In this setting, medical palliation is usually ineffective and an aggressive salvage surgical treatment may remain the only therapeutic option.

The recent spread of the Covid‐19 infection has raised important questions within the haematology community on how best to manage and treat patients with haematological malignancies, particularly acute leukaemias. Italy has witnessed a dramatic raise in infections and death rates, that has hit in particular certain areas of the most populated Northern regions of the country (Lombardia, Veneto, Piemonte, Emilia Romagna). Within the nationwide Campus ALL programme in the last week of March we sent a questionnaire addressing different issues related to the management of adult ALL patients during the Covid‐19 pandemic to 40 haematology centres located on the entire territory.

Objective Laryngotracheal resection is still considered a challenging operation and few high-volume institutions have reported large series of patients in this setting. During the 5 years, novel surgical techniques as well as new trends in the intra- and postoperative management have been proposed. We present results of our increased experience with laryngotracheal resection for benign stenosis. Methods Between 1991 and May 2019, 228 consecutive patients underwent laryngotracheal resection for subglottic stenosis. One hundred eighty-three (80.3%) were postintubation, and 45 (19.7%) were idiopathic. Most of them (58.7%) underwent surgery during the past 5 years. At the time of surgery, 139 patients (61%) had received tracheostomy, laser, or laser plus stenting. The upper limit of the stenosis ranged between actual involvement of the vocal cords to 1.5 cm from the glottis. Results There was no perioperative mortality. Two hundred twenty-two patients underwent resection and anastomosis according to the Pearson technique; 6 patients with involvement of thyroid cartilage underwent resection and reconstruction with the laryngofissure technique. Airway resection length ranged between 1.5 and 8 cm (mean, 3.8 ± 0.8 cm) and it was >4.5 cm in 19 patients. Airway complication rate was 7.8%. Overall success of airway complication treatment was 83.3%. Definitive success was achieved in 98.7% of patients. Patients presenting with idiopathic stenosis or postcoma patients showed no increased failure rate. Conclusions Laryngotracheal resection for benign subglottic stenosis is safe and effective, and provides a very high rate of success. Careful intra- and postoperative management is crucial for a successful outcome.

Background Video-Assisted Thoracic Surgery (VATS) lobectomy is now considered the preferred approach at many centers for early stage lung cancer. However, it needs an adequate learning curve, and it may be challenging in non-expert hands. The aim of this study was to evaluate the effectiveness of Transcollation Technology over Traditional Electrocautery to perform hilar and mediastinal dissection during VATS lobectomy. Methods This is a single-center retrospective study including consecutive patients undergoing VATS lobectomy for lung cancer. Patients were divided in two groups based on whether Transcollation Technology (TT Group) or Traditional Electrocautery (TE Group) was used for hilar and mediastinal lymphadenectomy. Operative time and surgical outcome, including number of transfusions, length of chest drainage, length of hospital stay, morbidity and mortality were registered, and the inter-group differences were statistically analyzed. Results 53 patients were included in the final analysis. The TT Group (n = 24) compared to the TE Group (n = 29) showed significant shorter operative time (75.2 ± 25.8 min versus 98.1 ± 33.3 min; p = 0.023), and reduction of length of chest tube stay (4.7 ± 0.8 days vs. 6.8 ± 1.1 days, p = 0.013) and length of hospital stay (5.3 ± 1.9 days vs. 6.8 ± 1.1 days, p = 0.007). No intraoperative or major postoperative complications were observed in either groups. Conclusions Transcollation Technology represents a valid alternative to standard electrocautery instruments during VATS lobectomy. It contributes to reduce the operative time and length of hospital stay. Further larger prospective studies are required to confirm our data.

Background Uniportal video‐assisted thoracoscopic surgery (VATS) lobectomy has become a common approach for the treatment of early stage lung cancer. Here, we aimed to establish whether the length of uniportal incision could affect postoperative pain and surgical outcomes in consecutive patients undergoing uniportal VATS lobectomy for early stage lung cancer. Methods This was a unicenter Randomized Control Trial (NCT 03218098). Consecutive patients undergoing uniportal VATS lobectomy for Stage I lung cancer were randomly assigned to a Small Incision group or Long Incision group in 1:1 ratio based on whether patients received a 4 cm or 8 cm incision. The endpoints were to compare the intergroup difference regarding (i) postoperative pain measured by brief pain inventory (BPI) questionnaire (first endpoint); (ii) operative time; (iii) length of chest drainage; (iv) length of hospital stay; (v) postoperative complications; and (vi) pulmonary functional status (secondary endpoints). Results A total of 48 patients were eligible for the study. Four patients were excluded; the study population included 44 patients: 23 within the Small Incision group, and 21 within the Long Incision group. The 11 BPI scores between the two groups showed no significant difference. Small Incision group presented higher operative time than Long Incision group (138.69 vs. 112.14 minutes; P = 0.0001) while no significant differences were found regarding length of hospital stay (P = 0.95); respiratory complications (P = 0.92); FEV1% (P = 0.63), and 6‐Minute Walking Test (P = 0.77). Conclusions A larger incision for uniportal VATS lobectomy significantly reduced the operative time due to better exposure of the anatomical structures without increasing postoperative pain or affecting the surgical outcome. Key points A larger incision for uniportal VATS lobectomy significantly reduced the operative time due to better exposure of the anatomical structures without increasing postoperative pain or affecting the surgical outcome. To perform a larger incision could be a valuable strategy, particularly in nonexpert hands or when the patient's anatomy or tumor size make exposure of anatomic structures through smaller incisions difficult.

The complex karyotype (CK) is an established negative prognostic marker in a number of haematological malignancies. After the introduction of effective mitogens, a growing body of evidence has suggested that the presence of 3 or more aberrations by conventional banding analysis (CBA) is associated with an unfavorable outcome in chronic lymphocytic leukemia (CLL). Thus, the importance of CBA was recognized by the 2018 guidelines of the International Workshop on CLL, which proposed the introduction of CBA in clinical trials to validate the value of karyotype aberrations. Indeed, a number of observational studies showed that cytogenetic aberrations and, particularly, the CK may have a negative independent impact on objective outcome measures (i.e. time to first treatment, progression free survival, time to chemorefractoriness and overall survival) both in patients treated with chemoimmunotherapy and, possibly, in patients receiving novel mechanism-based treatment. Here, we set out to present the scientific evidence supporting the significance of CK as a prognostic marker in CLL and to discuss the biological basis showing that the CK is a consequence of genomic instability.

The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNA CCAT2 in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. We further identified that CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by down-regulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel non-APOBEC, non-ADAR, RNA editing at the SNP locus in MDS/MPN patients and CCAT2-transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies.

Introduction. The recent spread of the COVID-19 infection has represented an important challenge in the management of acute lymphoblastic leukemia (ALL) patients. Aims and methods. To investigate the incidence, features, source of contagion and outcome of patients with ALL who developed a COVID-19 infection, a survey was conducted among 34 hematology centers throughout Italy within the Campus ALL network. The period covered by the survey spanned from February 2020 to April 2021 and included 756 adult ALL patients actively followed during this time period. Results. Sixty-three of the 756 ALL patients (8.3%) developed a COVID-19 infection, with an equal distribution among the various regions. The majority of cases (90.5%) was recorded during the second wave of the pandemic, between September 2020 and April 2021. The source of the infection was nosocomial in 26 cases (41.3%), familial in 23 (36.5%), unknown in 13 (20.6%) and work-related in 1 (1.6%). The infected patients were prevalently male (n=43, 68.2%) with a similar distribution among age groups: 21 patients aged 18-35 years, 17 35-50, 15 50-65 and 10 older than 65. Seventeen patients (27%) had a diagnosis of T-ALL, 28 (44.4%) of Ph- B-ALL and 18 (28.6%) of Ph+ ALL. Thirty-six (57.1%) of the infected patients had no concomitant comorbidities, whereas 27 (42.9%) had one or more comorbidities. The infection was documented at the onset of the disease in 4 patients (6.3%), during induction in 10 (15.9%), consolidation in 13 (20.6%), chemotherapy maintenance in 11 (17.5%), after allogenic transplant in 15 (23.8%), during maintenance with tyrosine kinase inhibitors (TKI) treatment or off-treatment in 8 (12.7%) and at relapse in 2 (3.2%). Of the infected patients, 9 were asymptomatic, 10 had only isolated fever, 36 had respiratory symptoms and 8 presented other symptoms, including - but not limited to - ageusia and anosmia. As a consequence, management of the infection was variable: 29 (46%) patients did not require hospitalization, 28 (44.4%) were hospitalized in a COVID ward and 13 of them required respiratory assistance; finally, 6 (9.5%) patients were transferred to an ICU. Importantly, in 54 patients (85.7%) there were no sequelae, in 1 patient a pulmonary fibrosis was documented and in 1 patient the delay in treatment led to a relapse of the disease, while 7 (11.1%) succumbed to the infection. Finally, in 6 cases (9.5%) the infection was still ongoing at the time of the survey, and at the last update (July 2021) it had resolved in all. Since a key aspect in the management of ALL is the adherence to the timing of treatment, we also investigated if COVID-19+ patients stopped treatment during the infection. Out of the 42 evaluable patients (patients who had undergone an allogeneic transplant or were off-treatment were excluded from this analysis), ALL treatment was suspended in 28 (66.6%). Importantly, while in Ph+ ALL only very few patients stopped treatment (3/12), in Ph- B-ALL the majority did interrupt it (18/22, p Conclusions. The incidence of SARS-CoV-2 infection in adult ALL patients in Italy over a 15 month period has been similar to that observed in the general population and has been recorded mostly during the second wave of the pandemic. The contagion was mainly nosocomial, suggesting that outward care should be pursued as much as possible in ALL. The infection was manageable, with 46% of patients not requiring any medical intervention and an overall death rate of 11%. Strikingly, in line with previous reports 1, it appears that Ph+ ALL patients were more manageable, with less treatment interruptions. These findings underline the advantage of the TKI-based induction/consolidation strategy without systemic chemotherapy in Ph+ ALL used in the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) protocols and further point to a possible protective role of TKIs in COVID-19-infected patients. Foà R et al, Br J Haematol. 2020;190(1):e3-e5 Disclosures Chiaretti: Incyte: Consultancy; novartis: Consultancy; pfizer: Consultancy; amgen: Consultancy. Bonifacio: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Marco: Jazz: Consultancy; Insight,: Consultancy; Janssen: Consultancy. Curti: Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Delia: Gilead: Consultancy; Amgen: Consultancy; abbvie: Consultancy; Jazz pharmaceuticals: Consultancy. Forghieri: Jannsen: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Honoraria. Lussana: Amgen: Honoraria; Astellas Pharma: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

Objectives Resection of a long pulmonary artery (PA) segment infiltrated by tumour and reconstruction by conduit interposition or wide patch is a challenging but feasible option to avoid pneumonectomy. Our goal was to report the long-term results of our experience with this type of operation using various techniques and materials. Methods Between 1991 and 2015, 24 patients underwent sleeve resection of a long PA segment or extended resection (>2.5 cm) of 1 aspect of the circumference of the PA associated with lobectomy for centrally located lung cancer. Materials used for conduit reconstruction (20 patients) included pulmonary vein in 12 patients, autologous pericardium in 4, porcine pericardium in 3 and bovine pericardium in 1. Patches used in 4 patients consisted of porcine pericardium (2 patients) and pulmonary vein (2 patients). Results Twenty-three patients underwent left upper lobectomy without associated bronchoplasty. One patient underwent bronchovascular left upper sleeve lobectomy. The postoperative morbidity rate was 29.1%. No complications related to the reconstructive procedure occurred. There were no postoperative deaths. Complete patency of the reconstructed PA was shown in all patients by postoperative contrast computed tomography performed every 6 months. Pathological tumour stage ranged from I to IIIA. Five-year overall survival and disease-free survival rates were 69.9% and 52.7%, respectively, at a median follow-up of 41 months. Conclusions Resection of the long PA segment followed by conduit or wide patch reconstruction is a feasible, safe and effective option to avoid pneumonectomy. Different biological materials can be used to provide adequate tissue characteristics; the choice is made on a case-by-case basis. Long-term results confirm the oncological reliability of this operation.

Graphical abstract Image 1, Prevalence of Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) varies greatly in different populations. We hypothesized that the actual prevalence of KSHV/HHV8 infection in humans is underestimated by the currently available serological tests. We analyzed four independent patient cohorts with post-surgical or post-chemotherapy sepsis, chronic lymphocytic leukemia and post-surgical patients with abdominal surgical interventions. Levels of specific KSHV-encoded miRNAs were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and KSHV/HHV-8 IgG were measured by immunoassay. We also measured specific miRNAs from Epstein Barr Virus (EBV), a virus closely related to KSHV/HHV-8, and determined the EBV serological status by ELISA for Epstein-Barr nuclear antigen 1 (EBNA-1) IgG. Finally, we identified the viral miRNAs by in situ hybridization (ISH) in bone marrow cells. In training/validation settings using independent multi-institutional cohorts of 300 plasma samples, we identified in 78.50% of the samples detectable expression of at least one of the three tested KSHV-miRNAs by RT-qPCR, while only 27.57% of samples were found to be seropositive for KSHV/HHV-8 IgG (P, Highlights • There is no agreement on a standard assay to detect the true prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) infection. • Measurement of the viral miRNAs in plasma by RT-qPCR allows a direct and accurate assessment of viral infection. • Measurement of the viral miRNAs in plasma by RT-qPCR shows prevalence of KSHV infection in immuno-depressed patients. • Measurement of plasma viral miRNAs for viral infection assessment has the potential to become a “gold” standard method in the clinical practice. Chronic viral infections represent risk factors for diseases and development of infection-related complications. There is no agreement on a standard assay to detect the true prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) infection. The current method used in the clinical practice (ELISA-test) identifies a great geographic variation in KSHV seroprevalence and may underestimate the true-prevalence of KSHV infection. Here we showed that detection of plasma viral miRNAs levels for the identification of viral infection (e.g., KSHV, Epstein-Bar virus or EBV) is more accurate than the current method for detection of virus-derived antigen, especially in patients with low number of immune cells.

The comment from Dr. Ludwig (1) to ore recent paper on lower sleeve lobectomy, the so-called “Y” sleeve (2), is interesting and it deals on some important points related to technical aspects in this setting. It is a pleasure to reply to an author that has published important contributions on sleeve lobectomy, reporting, over time, results from patients that had undergone sleeve lobectomy and pneumonectomy.

OBJECTIVES Mechanical trauma occurring during pulmonary resection through both video-assisted thoracic surgery (VATS) or thoracotomy causes profound alterations in cytokines and the cellular network. The aim of this study was to analyse biological changes occurring in both the microenvironment (wound site) and macroenvironment (systemic circulation) following pulmonary lobectomy via the VATS or thoracotomic approach. METHODS From October 2016 to July 2017, 30 patients with clinical Stage I lung cancer were recruited. In 12 cases (the VATS group), surgery was performed through a video-assisted thoracoscopic approach and in 15 cases (the thoracotomy group) through a muscle-sparing minithoracotomy. Following the skin incision, the wound was irrigated with a saline solution (20 ml) and then collected. After the pulmonary resection, the surgical incision was re-irrigated. The number of polymorphonuclears, granulocytes and lymphocytes in the fluids was determined by the fluorescence activated cell sorting (FACS) analysis. Cytokine profiles of interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-1 and IL-8 from sera and fluids were detected by the enzyme linked immunosorbent assay (ELISA) assay. Functional results were evaluated through spirometry, and pain was assessed using the visual analogue scale. RESULTS In the postoperative fluids of the VATS group, fewer polymorphonuclears were seen compared to the thoracotomy group (P = 0.001), as well as a decreased percentage of granulocytes (P = 0.01) and a parallel increased lymphocytes fraction (P = 0.001). Only the systemic IL-1β levels were significantly lower in postoperative sera of the VATS group (P = 0.038). No differences were observed regarding other cytokines. CONCLUSIONS The local microenvironment during VATS differs from that of thoracotomy by not producing the same inflammatory phenotype. The clinical efficacy of a less invasive surgical approach is confirmed by a reduced inflammation of the systemic and local districts.

Background Advanced-stage thymic tumors infiltrating the superior vena cava (SVC), when radically resectable, can be surgically treated by SVC prosthetic replacement within a multimodality therapeutic approach. We hereby present our series of patients undergoing SVC resection and prosthetic reconstruction for stage III or IV thymic malignancies. Methods Between 1989 and 2015, 27 patients with thymic tumors (21 thymoma, 6 thymic carcinoma) infiltrating the SVC underwent radical resection with a SVC prosthetic replacement by a bovine pericardial conduit in 12 cases, a polytetrafluoroethylene conduit in 13, a porcine pericardial conduit in 1, and a saphenous vein conduit in 1. All the patients underwent vascular conduit reconstruction by the cross-clamping technique. Results Six patients were myasthenic. All resections were complete (R0). Twelve patients received induction treatment. Pulmonary resection was associated in 16 patients (11 wedge, 5 pneumonectomy). Twenty-two patients were Masaoka stage III and 5 were stage IVa. Mortality rate was 7.4%; no mortality was related to the vascular reconstruction. Major complication rate was 11.1%. At a median follow-up of 58 (range, 4 to 134) months, recurrence occurred in 9 (36%) patients. Three- and 5-year overall survival rates were 80% and 58.1%, respectively. Three-and 5-year cancer-specific survival were 90.5% and 75.4%. Cancer-specific survival rates of thymoma patients at 5 years were 93.8%. Five-year cancer-specific survival of all stage III patients was 77.1%. Thymic carcinoma histology was a negative prognostic factor. Long-term patency of the pericardial conduits was 100%. Conclusions En bloc resection and conduit reconstruction of the SVC is a good option to allow radical resection of locally advanced thymic tumors. A heterologous pericardial conduit represents the favorite option in our experience.

Background The majority of patients with chronic lymphocytic leukemia (CLL) are older and have multiple comorbidities, including other cancer diagnoses. These patients are routinely excluded from participation in clinical trials. Objective In this phase II study, we determined the activity and toxicity of ofatumumab, a fully human anti-CD20 monoclonal antibody, in older patients with CLL, poor performance status and comorbidities. Methods Treatment-naive patients with CLL aged ≥65 years with an ECOG performance status of 2–3 or Charlson comorbidity index ≥2 were eligible. Ofatumumab was administered intravenously weekly for the first month, then monthly for a total of 12 months. Results Thirty-four patients were enrolled. Median age was 73 years, and 29% had another cancer diagnosis. Among 32 patients evaluable for response, the overall response rate was 72%. We observed complete responses in 19% of patients and partial responses in 53%. The median progression-free survival duration was 21 months, and the estimated proportion of patients alive at 36 months was 87%. All 34 patients were evaluable for toxicity. Treatment was well tolerated, with infusion-related reactions being the most common treatment-related adverse event. Only one patient had a grade 3 infection. Additional grade 3 adverse events that may have been related to ofatumumab were diarrhea, nausea/vomiting, hyperglycemia, pulmonary embolism, and hypersensitivity reaction, each in one patient. No grade 4 adverse events were observed. Conclusion Single-agent ofatumumab is a well-tolerated and effective therapeutic approach for treatment-naive older patients with CLL; it can be safely administered to patients with significant comorbidities and other cancer diagnoses.

Background The purpose of this study was to compare functional and oncologic outcome of sleeve lobectomy (SL) with that of standard lobectomy (STL) in patients with non-small cell lung cancer. Methods Between January 2009 and April 2013, 44 consecutive patients undergoing upper SL (29 right side, 15 left side) were prospectively enrolled to be compared with 44 patients with the same side distribution who were randomly selected from patients undergoing upper STL during the study period. Functional and oncologic results of the two groups were compared. Results Pathologic tumor stage ranged between I and IIIa with similar patient distribution between the two groups. Postoperative complication rates were 20.5% in the SL group and 16% in the STL group. There was no postoperative mortality in either group. Mean postoperative decrease in forced expiratory volume in 1 second at 3 months postoperatively was 17.5% ± 6.2% in the SL group and 19% ± 14.8% in the STL group ( p = 0.52). There also was no significant difference ( p = 0.15) in mean postoperative decrease in 6-minute walk test (64.3 ± 2.5 m versus 69.1 ± 21.4 m) between the two groups. Evaluation of postoperative changes in quality of life at 3 and 6 months based on a standardized questionnaire (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire—Core Questionnaire) did not show significant differences between the SL group and the STL group ( p > 0.05) in terms of global health status, physical functioning, and fatigue. Actuarial survival rates at 3 and 5 years, respectively, were 85.3% and 60.1% in the SL group and 88.7% and 58.2% in the STL group, without significant difference ( p = 0.68). Conclusions Functional and oncologic results of SL are comparable to those of STL in patients with non-small cell lung cancer.

Objectives Long-term results of patients undergoing laryngotracheal resection for benign stenosis are reported. This is the largest series ever published. Methods Between 1991 and March 2015, 109 consecutive patients (64 males, 45 females; mean age 39 ± 10.9 years) underwent laryngotracheal resection for subglottic postintubation (93) or idiopathic (16) stenosis. Preoperative procedures included tracheostomy in 35 patients, laser in 17 and laser plus stenting in 18. The upper limit of the stenosis ranged between actual involvement of the vocal cords and 1.5 cm from the glottis. Airway resection length ranged between 1.5 and 6 cm (mean 3.4 ± 0.8 cm) and it was over 4.5 cm in 14 patients. Laryngotracheal release was performed in 9 patients (suprahyoid in 7, pericardial in 1 and suprahyoid + pericardial in 1). Results There was no perioperative mortality. Ninety-nine patients (90.8%) had excellent or good early results. Ten patients (9.2%) experienced complications including restenosis in 8, dehiscence in 1 and glottic oedema requiring tracheostomy in 1. Restenosis was treated in all 8 patients with endoscopic procedures (5 laser, 2 laser + stent, 1 mechanical dilatation). The patient with anastomotic dehiscence required temporary tracheostomy closed after 1 year with no sequelae. One patient presenting postoperative glottic oedema underwent permanent tracheostomy. Minor complications occurred in 4 patients (3 wound infections, 1 atrial fibrillation). Definitive excellent or good results were achieved in 94.5% of patients. Twenty-eight post-coma patients with neuropsychiatric disorders showed no increased complication and failure rate. Conclusions Laryngotracheal resection is the definitive curative treatment for subglottic stenosis allowing very high success rate at long term. Early complications can be managed by endoscopic procedures achieving excellent and stable results over time.

Hemophagocytic Lymphohistiocytosis (HLH) is a rare syndrome characterized by ineffective T-cell and NK response. We report the clinical course of a patient with relapsed CLL who developed acute symptoms soon after starting ibrutinib. Hyperpyrexia, splenomegaly, hyperferritinemia, hypertriglyceridemia, cytopenias, and a typical cytokine pattern, i.e. high interleukin (IL)−6, IL10 and IL18, were consistent with a diagnosis of HLH. Coexistent Epstein Barr virus reactivation was documented. Ibrutinib-induced impairment of NK degranulation, associated with EBV reactivation and CLL-related immunodeficiency may have contributed to the development of HLH in our patient., Highlights • This is the first report describing a case of well-documented HLH in relapsed CLL under ibrutinib. • There was a strict temporal association between ibrutinib start and HLH. • The patient had concomitant EBV reactivation, a known possible trigger of HLH. • The effect of ibrutinib on NK and T-cell was a possible contributing factor to the onset of HLH.

Background The unfavorable prognosis of Ph+ ALL has improved following the introduction of tyrosine kinase inhibitors (TKIs). While the GIMEMA trials are based on a chemo-free induction strategy, information is lacking on long-term follow-up of enrolled patients, and of patients treated outside of clinical trials. Aims and methods To evaluate the real-life experience on newly diagnosed adult Ph+ ALL patients treated with TKIs in Italy, we retrospectively collected data from 7 centers from 1/2000 to 12/2017 within the Campus ALL program. Results 158 patients (mean age: 51.8 years) were included; 69 were treated within GIMEMA trials. Induction therapy was: TKI+steroids (n=91), TKI+chemotherapy (n=39), and chemotherapy alone (n=28). A complete hematologic remission (CHR) was achieved in 99%, 100%, and 87% of patients, respectively. Minimal residual disease (MRD) at 3 months was available in 92 patients (52 outside of a clinical trial): 75% had MRD levels > 0.01 and 25% ≤0.01. Fifty-five patients received TKIs as consolidation and 77 chemotherapy. Seventy patients underwent an allogeneic and 5 an autologous transplant, 41 in first CHR. Of the allografted patients, 19/75 (25%) relapsed; 32 received TKIs post-transplant. Among the 77 non-transplanted cases, 35 (45%) relapsed; the majority (71%) continued TKI treatment: among those still alive, 3 stopped it. With a median follow-up of 61.8 months, overall survival (OS) and disease-free survival (DFS) at 5 years are 50% and 59% (median not reached). Prognostic factors for OS were transplantation (HR 0.44, p 65 yo; HR 2.14, p 40% of cases; nevertheless, the lack of its impact suggests that in MRD+ cases, salvage with novel treatments (i.e., newer generation TKIs and immunotherapy) can improve the outcome of Ph+ ALL. Conclusions We provide an overview of the long-term outcome of an unselected cohort of patients treated between 2000 and 2017, which documents the improved prognosis of Ph+ ALL also in the real-life setting. Further cases are being collected.

Haematological malignancies include a broad spectrum of diseases ranging from indolent disorders up to very aggressive leukemias. Recently, numerous studies have contributed to deepen the knowledge of the mechanisms underlying leukemogenesis. Interestingly, different types of leukemias may share the same molecular abnormality (for example, the loss of the TP53 gene). Conversely, only few haematological malignancies harbour a single and specific aberration (for example the BCR/ABL gene fusion in chronic myeloid leukemia). Rather, they represent the final step of a complex transformation process starting from a normal cell that acquires multiple genetic abnormalities because of an intrinsic genetic “frailty” along with stimuli from the cellular microenvironment triggering clonal evolution. Furthermore, either the damage of the genes that are critical in cell growth and death pathways or the disruption of the check-machinery that tunes and supervise the expression of the genome inside the cell (epigenetics), may occur during the clonal evolution. The knowledge of the mechanisms underlying leukemogenesis has addressed the scientific community to test molecules that are able to target specific proteins or genes to verify whether they could replace or integrate the conventional chemotherapy in order to either spare in terms of unneeded toxicity or improve in terms of disease remission and survival. In many cases, the survival improvement and a more acceptable therapy-related toxicity were achieved following the spread of the “target” therapy. This chapter aims to discuss the new insights in the mechanisms of leukemogenesis and their consequences on therapeutic goals.

Background Lung metastases occur in 10% to 20% of patients with colorectal cancer (CRC). Lung metastatic pathways of CRC are poorly known, and the optimal management for recurrent lung metastases remains uncertain. Methods Long-term oncologic outcomes of 203 patients with CRC lung metastases who underwent metastasectomy were investigated in this multicenter retrospective study. Ninety-two patients (45.3%) with tumor relapse underwent repeated metastasectomy and 11 (5.4%) received a third metastasectomy for a second relapse. Demographic and clinical data, including histologic grade of primary tumor, presence of CRC liver metastases, type of primary tumor resection, number, size, location, and resection type of pulmonary metastases, were evaluated. Overall survival (OS) and disease-free survival were analyzed. Cox regression model was performed to identify variables that influenced OS. Results One hundred seventy-three patients (85.2%) received a wedge resection, 21 (10.3%) underwent pulmonary lobectomy, and 9 (4.4%) underwent other procedures (pneumonectomy, bilobectomy). The mean follow-up was 39 months (range: 7 to 154 months). One-, 3-, and 5-year global OS from CRC diagnosis was 99%, 80%, and 60%, respectively, and 97%, 60%, and 34% from the first metastasectomy, respectively. Log-rank test between OS (one versus repeated metastasectomy) did not show significant differences (p = 0.659). Cox regression model showed that nodal status (hazard ratio [HR] 17.7, p = 0.008) and administration of adjuvant chemotherapy (HR 0.33, p = 0.026) are risk and protective factors, respectively, for OS. Conclusions Repeated pulmonary metastasectomy should be offered to patients with metastatic CRC because there are no differences in terms of OS between patients undergoing single and repeated metastasectomy. Adjuvant chemotherapy should be suggested in case of metastatic CRC.

Surgical treatment of benign subglottic stenosis encases a current therapeutic trouble. The need to achieve a complete resection with respect to recurrent nerves and proximity of the anastomosis to the vocal cords are the main technical issues. Interventional endoscopic treatments play a limited role in this setting due to the high rate of recurrences requiring repeated procedures. Surgical resection and reconstruction with primary anastomosis represent the curative treatment of choice for most subglottic strictures, allowing definitive and stable high success rate on long-term. Technical aspects and surgical results are discussed in the present review.

OBJECTIVES The advantages of a bronchial sleeve resection are well established. A clear majority of reported cases are of upper lobe sleeve resection. Reimplantation of the upper lobe bronchus after a lower sleeve lobectomy or bilobectomy (the so-called Y-sleeve resection) is infrequent. Related technical peculiarities are the main issues. We present our experience and results in this setting. METHODS Between 1989 and 2015, we performed 28 Y-sleeve resections of the left lower lobe (n = 18) or right middle and lower lobes (n = 10). The lung-sparing reconstructive operation was performed for non-small-cell lung cancer in 23 cases, for bronchial carcinoid tumour in 4 cases and for a cystic adenoid carcinoma in 1 case. Anastomotic reconstruction was performed by interrupted 4-0 absorbable sutures (monofilament material). RESULTS All the resections were complete (R0). Postoperative mortality was 3.6%. The rate of major complications was 10.7% (1 myocardial infarction, 1 anastomotic stenosis requiring dilatation and 1 anastomotic fistula). Among the 23 patients with non-small-cell lung cancer (18 men and 5 women; mean age 58 ± 12 years), 8 were Stage I, 9 were Stage II and 6 were Stage IIIa. At a mean follow-up of 46 months, the recurrence rate was 32%. There were 2 loco-regional recurrences. No endobronchial or perianastomotic recurrence occurred. The 3- and 5-year overall and disease-free survival rates of patients with non-small-cell lung cancer were 76.3% and 55.1% and 68.7% and 62.9%, respectively. CONCLUSIONS A Y-sleeve resection with reimplantation of the upper load bronchus is a technically feasible and oncologically adequate operation.

Dysregulation of microRNAs has been studied thoroughly, and has been observed in a variety of tumors including vulvar carcinomas, a rare type of gynecological tumor with increasing incidence. However, very few therapeutic alternatives have reached the clinical setting, and there is an urgent unmet need to develop novel strategies for patients with this tumor type. Thus, a microRNA (miRNA) sponge for the miR-17 miRNA family was designed, synthesized and validated in vitro in order to explore a new therapeutic strategy based on inhibiting this oncogenic miRNA family in vulvar cancer. Members of the miR-17 family were evaluated for expression in a vulvar tumor cell line (SW954) and 20 HPV negative formalin-fixed paraffin-embedded (FFPE) samples by quantitative real-time PCR (qRT-PCR). Six in tandem, bulged sequences that were complementary to these miRNAs were designed, synthesized, cloned, and transfected into SW954 cells. A luciferase reporter assay with a psiCheck2 vector was used to test the specificity of the sponge sequences for miR-17 family miRNA binding. Taqman qRT-PCR was used to test how the sponges affected miRNA expression. In FFPE samples, higher expression of miR-20a and miR-106a correlated with deeper tumor invasion (P = 0.0187 and P = 0.0404, respectively). The luciferase reporter assay validated the specificity of the sponge for miR-17 family members. Using qRT-PCR, we confirmed this specificity with decreased expression in 5 (out of six) miRNAs of the miR-17 family in SW954 cells. Although our results are preliminary, these results demonstrate that these miRNA sponges are potent inhibitors of the miR-17 family of miRNAs in SW954. Therefore, this miRNA-specific sponge may be developed into a novel therapeutic treatment for patients with vulvar cancer.

Idiopathic subglottic stenosis is the most challenging condition in the field of upper airway reconstruction. We describe a successful novel technique for enlarging the airway space at the site of the laryngotracheal anastomosis in very high-level reconstructions.

Background: Tracheobronchial stents are a treatment option for inoperable benign or malignant tracheobronchial stenosis (TBS) or postoperative bronchopleural fistulas (POBPF). The present study evaluated the outcomes of patients with TBS and POBPF who were treated by placement of recent generation, fully covered, self-expanding metallic stents (SEMS) and determined stent efficacy relative to airway pathology. Methods: From January 2009 to January 2016, 68 patients with TBS or POBPF underwent rigid bronchoscopy, laser/mechanical debridement and placement of fully covered SEMS. Eighteen patients had benign stenosis, 38 had malignant stenosis, and 12 patients had POBPF. Results: Seventy-four SEMS were successfully placed in 68 patients. There were no perioperative deaths. Stent-related complications occurred in 20 (29.4%) patients: granulation tissue formation [TBS group, 10.7% (n=6); POBPF group, 8.3% (n=1)]; stent fracture [TBS group, 5.4% (n=3); POBF group, 8.3% (n=1)], stent migration [TBS group, 7.1% (n=4); POBF group, 0% (n=0)], severe secretions not removable by flexible bronchoscopy [TBS group, 7.1% (n=4); POBF group, 8.3% (n=1)]. No stent migration was observed in the POBPF group. Four patients (7.1%) in the TBS group had stent migration requiring stent replacement. After stenting, all TBS patients had a Hugh-Jones classification score improvement ≥1 grade and 42 patients (75%) had an improvement ≥2 grades. Logistic regression analysis showed that the disease (stenosis vs. fistula) did not influence the occurrence of stent complications [OR 0.96, 95% confidence interval (CI) 0.71–1.13, P=0.13]. Conclusions: Fully covered SEMS are effective and provide a versatile treatment option for patients with inoperable TBS and POBPF.

Background: Complete resection for stage II thymic tumors can be easily accomplished even if the capsula and adjacent mediastinal tissue are macroscopically involved; however, also at this stage, recurrence may occur, particularly for B2, B3 and thymic carcinoma. The criteria for the administration of adjuvant therapy remain controversial and it is unclear whether patients at this stage may benefit from it. We reviewed a series of patients at this stage receiving adjuvant chemo-radiotherapy (chemo-RT) based on histology. Methods: Eighty-eight consecutive patients with stage II thymic tumors were reviewed; 59 patients (67%) with B thymoma or thymic carcinoma received adjuvant treatment with mediastinal irradiation (40–55 Gy), chemotherapy (CH) (PAC regimen) or a combination of both. Results: Complete resection was achieved in all patients. Fifty-four patients (61%) received post-operative chemo-RT, 2 (2%) patients received adjuvant CH only and 3 (3%) post-operative RT only; they all had B2, B3 histology or thymic carcinoma. The median follow up was 107±83 months. 5-year and 10-year survival were 96%±2% and 83.4%±5%. Recurrence was observed in 5 patients (5.7%). Disease-free 5 and 10-year survival was 94%±2% and 92%±3% respectively. Five patients (5.7%) had recurrence. Conclusions: The administration of adjuvant chemo-RT to patients with stage II type B thymoma and thymic carcinoma contributes to reduce the recurrence rate and to increase long-term survival.

The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNA CCAT2 in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. We further identified that CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by down-regulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel non-APOBEC, non-ADAR, RNA editing at the SNP locus in MDS/MPN patients and CCAT2-transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies.

OBJECTIVES This prospective randomized study was designed to assess the safety and efficacy of a haemostatic matrix in intraoperative bleeding control and prevention of postoperative bleeding after major lung surgery. METHODS One hundred and twenty patients undergoing major lung resection and presenting with intraoperative persistent active bleeding have been prospectively enrolled and randomly assigned to receive [Floseal® group (FG)] or not (control group) the application of Floseal® to the bleeding site and to the site of the hilar dissection. To evaluate the efficacy of the product, several intraoperative and postoperative data were compared between the two groups. RESULTS No adverse event related to the haemostatic matrix application occurred. The intraoperative haemostasis rate at 3 (primary end-point), 6 and 10 min was significantly higher and the mean time to haemostasis was significantly shorter in the FG. The quantity of chest drain fluids did not show significant differences at 24, 48 and 72 h between the two groups. Postoperative haemoglobin-level variation was significantly lower in patients of the FG (-0.7 ± 0.66 vs -2.3 ± 5.87 g/dl; P = 0.04). Similarly, haematocrit variation was lower in the haemostatic group (-2.6 ± 2.19 vs -4.2 ± 3.71; P = 0.006). The chest drain duration resulted significantly shorter in the FG (10.3 ± 5.05 vs 13.3 ± 6.28 days; P = 0.005). In-hospital stay was shorter in the FG (6.4 ± 2.9 vs 8.1 ± 5.42 days; P = 0.044). CONCLUSIONS In conclusion, the application of Floseal® in major lung resections proved safe and effective in increasing the intraoperative successful haemostasis rate and in reducing postoperative variation in haemoglobin and haematocrit levels. The sealant use was also related with a significantly shorter chest drain duration and hospitalization.

SUMMARY Chronic lymphocytic leukemia (CLL) is most commonly diagnosed in patients older than 65 years. Although CLL is commonly believed to be indolent in elderly patients, several studies have shown that CLL reduces life expectancy. In elderly patients who need treatment for CLL, evaluation of disease-specific risk factors should be accompanied by measurement of fitness status and co-morbidities so that a treatment option can be selected that best fits the individual patient's goals of therapy. To help define such treatments, a number of recently conducted clinical trials have included elderly or unfit patients. Although purine analog-containing regimens are still recommended for elderly patients who are fit, new approaches are rapidly expanding the treatment options for elderly and unfit individuals.

Over the years reducing the number of ports during Video-assisted thoracic surgery (VATS) has allowed to accomplish pulmonary lobectomy with a single incision. Endoscopic view and instruments maneuvers issues could be improved by using flexible endoscope. We report our experience of fifteen uniportal VATS (UVATS) using a flexible thoracoscope. A single incision of about 4–5 cm long was performed at the 5th intercostal space along the anterior axillary line. No additional skin incisions were made. A flexible videoscope and multiple VATS instruments were simultaneously inserted into the uniport. Pulmonary lobectomy with systematic mediastinal lymph node dissection was performed. Verbal pain scores were registered using the visual analog scale from 0 to 10 at the first post-operative day. No post-operative complications or hospital mortality were recorded. Mean operative time was 112.6 min (range 70–200) and mean postoperative hospital stay 3.2 days (range 2–6). Mean pain score was 0.5 (range 0–2). Single-incision VATS lobectomy using a flexible thoracoscope is a feasible and safe approach.

Background The use of an autologous pulmonary vein (PV) conduit for reconstruction of the pulmonary artery (PA) in lung-sparing resections was first described in 2009, but to date only two case reports appeared and no medium-term and long-term results have been reported, to our knowledge. We present the first case series with medium-term follow-up. Methods Between December 2009 and December 2012, 9 patients undergoing PA sleeve resection for centrally located lung cancer received reconstruction by this technique. Three of these patients underwent induction chemotherapy. The venous graft was obtained from the proximal extraparenchymal portion of the superior PV and was sutured to the proximal and distal PA stumps with the standard anastomotic technique. Results All 9 patients underwent left upper lobectomy with sleeve resection of the PA without associated bronchoplasty. The postoperative morbidity rate was 33% (1 chylothorax, 1 atrial fibrillation, and 1 parenchymal atelectasis). No adverse events related to the reconstructive procedure occurred. There was no postoperative mortality. Complete patency of the reconstructed PA was shown in all patients by postoperative contrast computed tomography every 6 months. All patients are alive at a mean follow-up time of 32 ± 12.4 months (range, 6 to 42 months). Tumor recurrence has been observed in 2 patients (1 local, 1 systemic). The median survival time is 38 months. The median disease-free survival time is 33 months. Conclusions Reconstruction of the PA by a PV graft is a feasible and effective option for parenchymal-sparing resections. The PV conduit shows tissue characteristics similar to those of the arterial wall. This technique is safe and is supported by good medium-term results.

Treatment of chronic lymphocytic leukemia (CLL) has dramatically changed over the last years, with significant improvement in overall survival (OS) and increased efficacy in genetically defined "high-risk" disease. Besides prospective clinical trials usually enrolling young and fit patients, retrospective studies were performed comparing the outcome of patients belonging to different age groups and showing longer survival in patients diagnosed in the most recent periods. In patients younger than 70 years the 10-year relative survival was 43-53% in the 1980s as compared with 59-63% in the 2000s. Likewise, the 10-year relative survival in patients >70 years was 22-42% in the 1980s and 46-55% in the 2000s. Improved outcome derived in part by the introduction of effective regimens in genetically defined "high-risk" disease (i.e., 17p-, 11q-, TP53, NOTCH1, SF3B1 mutations), especially in the younger and/or fit patients. The unfavorable prognostic significance of 11q- was overcome by chemoimmunotherapy. High-dose steroids with anti-CD52 appeared to improve the response rate in 17p-/TP53 mutated cases and allogeneic transplantation achieved prolonged disease control irrespective of high-risk disease. Further improvement is being generated by the new anti-CD20 obinutuzumab in the elderly and by mechanism-based treatment using kinase-targeting agents or anti-BCL2 molecules yielding high-response rate and impressive progression-free survival in the chemorefractory setting as well as in previously untreated patients.