Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.

BACKGROUND: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. PATIENTS AND METHODS: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. RESULTS: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. CONCLUSIONS: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.

Clinical characteristics and outcome of patients over 60 years with Hodgkin lymphoma treated in Switzerland.

Hodgkin lymphoma (HL) in older patients appears to be a different disease compared with younger patients with historically lower survival rates. This is related to a variety of factors, including increased treatment-related toxicity, the presence of comorbidities, and biologic differences. In order to better assess the clinical characteristics, treatment strategies, and outcome of this particular population, we conducted a population-based, retrospective analysis including 269 patients with HL older than 60 years (median age 71 years, range 60-94), treated between 2000 and 2017 in 15 referral centers across Switzerland. Primary endpoints were overall survival (OS), progression-free survival (PFS), and cause-specific survival (CSS). The vast majority of patients were treated with curative intent, either with a combined modality approach (chemotherapy followed by radiation therapy) or with systemic therapy. At a median follow-up of 6.6 years (95% confidence interval [CI], 6.0-7.6), 5-year PFS was 52.2% (95% CI, 46.0-59.2), 5-year OS was 62.5% (95% CI, 56.4-69.2), and 5-year CSS was 85.1.8% (95% CI, 80.3-90.1) for the entire cohort. A significant difference in terms of CSS was observed for patients older than 71 years in comparison to patients aged 60-70 years (hazard ratio 2.6, 1.3-5.0, p = 0.005). Bleomycin-induced lung toxicity (BLT) was documented in 26 patients (17.7%) out of the 147 patients exposed to this compound and was more frequent in patients older than 71 years (15/60, 25%). Outcome of HL pts older than 71 years appeared to decrease substantially in comparison to the younger counterpart. Treatment-related toxicities appeared to be relevant, in particular, BLT. New, potentially less toxic strategies need to be investigated in prospective clinical trials in this particular frail population.

Cervical vertebrae maturation: a blinded trial study.

This blinded trial was conducted to analyze possible correlations between the cervical vertebrae maturation method (CVM) and the mineralization of mandibular teeth as described by Demirjian et al. (TMS). Panoramic and cephalometric radiographs of 500 orthodontic patients were analyzed by two blinded operators. TMS was utilized to analyze mineralization of second molar, second and first premolar and canine on the left side of the mandible; CVM stage was also evaluated. A blinded statistician performed statistical correlations and multiple regression analysis. Significant relations between CVM and TMS stages were identified for each tooth. Significant age differences resulted for CVM, second molar and second premolar (p<0.05). Significant correlations for second molar were observed between TMS D and CVM I-II, TMS G and CVM III, TMS H and CVM V-VI (p less than 0.01). Second molar stage G for both sexes indicates the ongoing of growth spurt. Stage G for boys and stage H for girls correlate significantly with the late part of PGS.

Is static friction affected by aging and amount of elastomeric ligatures in orthodontic sliding mechanics? An in-vitro investigation.

In straight-wire mechanics, friction can significantly influence the forces expressed by wires. The aim of this study is to assess whether the aging and the sum of elastomeric ligatures affect the static friction during orthodontic space closure. A 0.017x 0.025-in SS was drawn throughout a 3-bracket experimental model and engaged with elastomeric ligatures. Before performing the test, the ligatures were soaked in artificial saliva for 48 hours (Group 1), 2 weeks (Group 2) and 4 weeks (Group 3); brand-new ligatures were also tested as control group (Group 4). The resistance to sliding (RS) was recorded at 3 different numerical configurations of ligatures using a customized testing machine and tests were repeated for ten times. Data of RS were statistically analysed by using two way analysis of variance (ANOVA) and Tukey's multiple comparison tests. RS was found to increase systematically when more elastomeric ligatures were included in the wire engaging system. At two weeks of immersion in artificial saliva elastomeric ligatures showed the lowest values of RS while they became significantly more frictional after immersion for 4 weeks. The results of this study showed that in multi-bracket orthodontic therapy, the RS increases with the number of elastomeric ligatures involved for arch-wire engagement. Differently from the frictional behavior of elastomeric modules, the aging of these ligatures does not influence their incremental effect of frictional forces.

Necessity of therapy for post-thyroidectomy hypocalcaemia: a multi-centre experience.

PURPOSE: Hypoparathyroidism is one of the most common and most feared complications of total thyroidectomy (TT). The aim of this study is to detect possible markers that may facilitate early tracing of hypocalcaemia-prone patients in order to reduce clinical cost by optimizing patient discharge and to avoid unnecessary treatment. METHODS: Over an 18-month period, 995 patients, 23 % male and 77 % female, aged 52.9 ± 13.4 years, underwent TT in ten Lombardy hospitals. The following parameters were analyzed: calcaemia before and 12-24 and 48 h after surgery, pre- and post-operative parathyroid hormone (PTH) at 24 h and pre-operative 25OH vitamin D. RESULTS: Mortality was nil and morbidity was 22.4 %. Mean 24-h calcaemia and PTH were 2.17 ± 0.15 mmol/l and 31.81 ± 20.35 pg/ml, respectively; mean 24-h PTH decay was 36.7 ± 34.12 %. Four hundred seventy-three (47.5 %) patients were hypocalcaemic at discharge; 142 of whom had transient hypoparathyroidism that became permanent in 27. Patients developing hypocalcaemia had significantly higher values of PTH and calcium decay. At multiple logistic regression, only 24-h calcium decay, PTH drop and the presence of symptoms and parathyroid auto-grafting were significantly related to hypoparathyroidism. The association of these factors had a 99.2 % negative predictive value (NPV) for the development of hypoparathyroidism. A 70 % PTH drop had a 93.75 NPV for transient hypoparathyroidism. A 12 % calcaemia decay had a 95.7 NPV for hypoparathyroidism. CONCLUSIONS: Hypocalcaemic asymptomatic patients with less than 70 % PTH and 12 % calcaemia decay may be safely discharged without treatment. Symptomatic patients and those with parathyroid grafting should receive calcium and vitamin D.

Acute thrombosis of abdominal aorta and hypercoagulable disorders.

Acute abdominal aortic occlusion (AAAO) is a rare, life threatening condition, which usually occurs in elderly patients, causing challenging management issues. In patients who have no cardiac or vascular disease this catastrophic event is very rare and is due to hypercoagulable disorders. This study reviews the literature on AAAO in hypercoagulable states in the light of our experience on a case of an acute thrombosis of nonaneurysmal, nonatherosclerotic abdominal aorta in a female patient with protein S deficiency and Sjögren's syndrome and her younger brother, which was found to have atherosclerotic involvement of distal aorta and elevation in homocysteine levels. Because of a misleading clinical presentation, the diagnosis was delayed and conservative treatment failed. Both were successfully treated with emergency aorto-bifemoral grafting. Other cases of arterial thrombosis and hypercoagulable disorders were found in first-degree relatives. Our experience and the review of the literature suggest that the interaction between host and environment factors can lead to acute thrombosis of the non-pathologic abdominal aorta; not only classic hypercoagulability disorders, but also immunologic, metabolic, toxicological cofactors can be involved. Delay in diagnosis is frequent and may not influence the prognosis, but does not allow conservative therapy. Prognosis depends mainly on pathologic cofactors that require detection and appropriate treatment in order to prevent complications and recurrences.

Glutathionyl-hemoglobin levels in carotid endarterectomy: a pilot study on 12 cases clinically uneventful.

Aim: Carotid endarterectomy is a widely accepted procedure for stroke prevention, and carotid clamping is a necessary surgical step. Glutathionylated haemoglobin (HbSSG) has been recently employed as a biomarker of oxidative stress, its level being increased under several conditions, including hypoxia. This study aims to evaluating whether HbSSG level in peripheral and/or jugular blood is affected during carotid surgery under normal routine operative conditions. Methods: This study enrolled 13 consecutive patients undergoing elective carotid endarterectomy under general anesthesia. At different times during surgery, blood was taken simultaneously from both a peripheral vein and the jugular vein ipsilateral to the clamped carotid. HbSSG was measured in RBC hemolysates by MALDI-ToF mass spectrometry in each sample. Results: Three patients showed a complex pattern of rise and fall of HbSSG levels in different time periods before, during and after surgery. They also showed statistically significant differences between peripheral and jugular blood, with mean HbSSG levels in jugular blood higher by approx. 30% than those of peripheral blood at the end of the period of carotid clamping. In all three patients HbSSG levels fell to pre-clamping values within 2 min from removal of carotid artery clamp. Conclusion: Although effective routine drug management allowed brain safety during carotid clamping time, a number of patients showed a fast modification over time of the HbSSG levels in jugular blood, suggesting that "resident" cerebral biochemical protection mechanisms could play some role to compensate clinically silent brain oxidative stress.

How to assess appearance distress and motivation in plastic surgery candidates: Italian validation of Derriford Appearance Scale 59 (DAS 59).

OBJECTIVE: The Derriford Appearance Scale (DAS) 59 was specifically designed to measure psychosocial adjustment in patients with appearance problems. Previous studies using the DAS59 have proven it to be a reliable method of assessing the appearance-related quality of life after plastic surgery procedures. The aim of this study was to develop a valid and reliable Italian version of the DAS59. PATIENTS AND METHODS: The first Italian translation of this questionnaire was conducted according to the DAS59 protocol that was designed by the original authors of the questionnaire. Eight hundred patients participated in this study and filled out three questionnaires (DAS59, General Health Questionnaire (GHQ)12 and Beck's Depression Inventory (BDI)-II). There were 400 adult patients with a history of previous plastic surgeries and 400 adult patients without any personal history of previous plastic surgery procedures. A total of 50 patients were selected randomly for test-retest analysis. RESULTS: The overall internal consistency was excellent (α = 0.95) and equal to that of the original article that first described the scale. There was a good correlation between all the items. Domains demonstrated good internal consistency (Cronbach's alpha) and correlation within themselves. The construct validity of the Italian DAS59 was assessed under convergent validity that confirmed the correlation with scales related to other psychological conditions. GHQ12 showed relevant correlation with DAS59, while BDI-II did not. CONCLUSIONS: A valid and reliable Italian DAS59 version was developed that can be used for research and clinical assessment of patients with appearance problems and concerns, especially before and after plastic surgery procedures.

Matrix metalloproteinase-1 promoter polymorphism 1G/2G is correlated with colorectal cancer invasiveness.

PURPOSE: Matrix metalloproteinase-1 (MMP-1) is likely to be involved in invasion and metastasis of several tumors by degrading the extracellular matrix. A single guanine insertion polymorphism (2G) in the MMP-1 promoter region creates an Ets binding site causing the elevation of transcriptional level and local expression of MMP-1. The aim of this study was to evaluate the impact of this 2G insertion type polymorphism on invasion and metastasis of colorectal cancer (CRC). EXPERIMENTAL DESIGN: We genotyped for this 1G/2G polymorphism 60 patients, who were operated on for CRC and followed for 6-30 months (median: 21). A control population of 164 age- and sex-matched tumor-free subjects was also genotyped for the same polymorphism. RESULTS: The proportion of 2G homozygotes was higher in the CRC group than in the controls (P = 0.014; odds ratio, 2.21; 95% confidence interval, 1.17-4.16). The CRC group was divided in a group without metastasis (M-) and a group that had developed metastasis (M+). At the time of diagnosis, 2G homozygotes were more represented in the M+ group than in M- (P = 0.0082; odds ratio, 4.73; 95% confidence interval, 1.46-15.26). The difference between M- patients and controls did not achieve statistical significance (P = 0.52). CONCLUSIONS: Our results suggest that the presence of 2G polymorphism at the MMP-1 promoter region may favor the growth and the metastatic process in CRC patients and could be looked at as a risk factor for a worse prognosis.

Loss of heterozygosity of the NOS3 dinucleotide repeat marker in atherosclerotic plaques of human carotid arteries.

We have investigated 28 atherosclerotic plaques of human carotid arteries with a panel of 39 microsatellite markers for the presence of LOH. The objective of this research was to verify if LOH, described in association with tumorigenic process, could be involved also in benign fibroproliferative disease. Seventy percent of samples demonstrated allelic imbalance: 50% of cases showed LOH at a minimum of one locus, 3.5% at a minimum of two loci and 14.3% at three or more loci. The percentages of LOH ranged between 3.8 and 14.3% and the highest involved polymorphic marker is the NOS3 internal dinucleotide repeat. Our results indicate that, like tumorigenesis, the atherogenic process could also involve LOH mechanism. Furthermore, the finding regarding the NOS3 internal polymorphism suggests a possible role of the gene as cofactor in formation of the atheromas.

Pulmonary embolism secondary to puerperal ovarian vein thrombophlebitis.

Four cases of pulmonary embolism (PE) secondary to puerperal ovarian vein thrombophlebitis (POVT) were treated surgically during the first semester 1990. Clinical features are described in detail. The diagnosis was made by echotomography in three cases, but the crucial examination was contrast phlebocavography in all the subjects. Ovarian vein ligation, caval thrombectomy and inferior vena cava interruption by DeWeese clip positioning was the operation performed in any cases. Postoperative courses were always uneventful and three to six months follow-up was available. The extensive practice of echotomography during the first week of puerperium could demonstrate that POVT is more frequent than previously thought.

Surgical approach to combined abdominal aortic aneurysm and renal artery stenosis.

Thirty-four cases of combined abdominal aortic aneurysm (AAA) and renal artery stenosis (RAS) are reported. Hypertension was found at admission in 32 subjects, the other two being well responsive to drug therapy. Angiography and selective renal vein renin assay were always performed: renal artery stenosis was unilateral in 21 (61.7%) subjects and bilateral in 13 (38.3%). In 9 cases renal artery stenosis was not correlated to the hypertensive state. Mild chronic renal insufficiency was demonstrated preoperatively in 20 patients (58.8%). Simultaneous surgical treatment was carried out in 25 cases (73.5%). Mortality was 4% (one subject), severe renal insufficiency 8% (two subjects) and permanent renal failure 4% (one subject) All complications occurred among the group with bilateral RAS. While surgical repair of AAA is always mandatory, simultaneous surgical treatment of AAA and RAS should be carried out in carefully selected cases, due to elevated mortality rates reported in the literature, in order to cure renovascular hypertension, when it is demonstrated as related to RAS, or to preserve renal functionality, when RAS is contralateral to a functionally excluded or hypotrophic kidney or it exceeds 80% of the diameter of the artery.

The femorofemoral bypass graft. Report of a 11-year experience.

A series of 62 femorofemoral bypass grafts (FFBG) is reported. The indication for this operation was unilateral iliofemoral occlusion with severe ischemia of the lower limb in poor-risk patients. Severe ischemia presented as rest pain and/or minor necrotic lesions to the foot fingers, while patients were defined poor-risk for aging and concomitant diseases advising major surgical procedures and general anaesthesia. Claudication was not considered as an indication for this operation, and this statement is discussed in detail reviewing the literature. Operative death rate was approximately 6.4% (4 subjects), due to acute renal failure, revascularization syndrome, cardiac arrest and pulmonary oedema. Twenty subjects had had a total of 33 previous vascular reconstructive procedures; this occurrence did not reveal any statistically significant consequences on long-term patency rate, although a difference was seen in favour of the patients who had not undergone previous vascular reconstructive procedures. In the group of patients who underwent FFBG as the first vascular procedure, five early occlusions occurred: three Fogarty catheter thrombectomies were successful. Cumulative patency rate was then 77% at 36 months in the series of 58 survivors. Rest pain was relieved in any instances and a satisfactory improvement of claudication was obtained.

The concomitance of renal artery stenosis and Conn's adenoma in a hypertensive woman.

A case of adrenal aldosterone-secreting adenoma concomitant with active renal artery stenosis in a hypertensive middle-aged woman is reported. The concomitance of the two lesions was previously reported in the literature only in five more reports, that are mentioned and commented here. This association is thought to be almost anecdotal, but some remarks must be done in order to rule out the risk of leaving an ignored lesion at the time of the definitive treatment. The widespread use of noninvasive imaging techniques is effective to find unsuspected adrenal adenoma in the presence of renovascular hypertensive disease, whereas unknown renal artery stenosis can be revealed by more aggressive diagnostic attitude, that is justified only in well selected cases of Conn's disease.

Posttraumatic aneurysm of splanchnic arteries. Report of two cases.

Two cases of posttraumatic aneurysms of splanchnic arteries were referred to Istituto di Chirurgia Generale e Cardiovascolare del-l'Università di Milano (Italy) during 1989, and are the subject of this report. In both the instances a history of blunt abdominal trauma was collected, and histology confirmed the characters of false aneurysms of the lesions. The arteries involved were the middle colic and the splenic, respectively, with a long lasting history of recurrent abdominal pain related with particular physiologic events (e.g. meals or effort) only in the first case. The physiopathology, clinical feature, and problems related to surgical treatment in each cases are discussed in detail.

Endoscopy and surgery. A combined strategy for diagnosis and therapy of polyposis-cancer sequence in the colon.

BACKGROUND: The aim of the paper is to evaluate retrospectively the series of patients affected by colon polyps and colon cancer to purpose a planned follow-up for patients who underwent colon polypectomy. METHODS: Out of 198 patients affected by colon carcinoma, the authors describe 95 cases of previous, synchronous or metachronous polyps, with a global prevalence of 47.9%, and respectively of 13.6%, 16.6%, and 17.6%. RESULTS: The evolutive sequence between colon polyp and carcinoma is shown through both clinical experience and experimental tests. The epidemiologic curve of adenoma rate precedes by five years the curve of carcinoma, and such is the average period of time for the transformation of an adenoma into invasive carcinoma. In clinical practice, it is frequent to note synchronous or metachronous polyps with respect to colon carcinoma. It is also possible to note carcinoma in patients with previous polypectomies. CONCLUSIONS: On the basis of the retrospective evaluation of the clinical cases, and reviewing international literature, the authors suggest their diagnostic-therapeutic and endoscopic follow-up protocol for patients affected by colon neoformations (Fig. 1).

Indications and role of isolated profundaplasty in patients affected by limb ischemia.

The deep femoral artery is the primary source of blood supply to the lower extremity in presence of superficial and/or popliteal occlusion. The atherosclerotic involvement of the profunda femoris artery is relatively less frequent and generally is localized in the initial segment of the artery. The profundaplasty employed to relieve limb threatening ischemia is infrequently used as an isolated procedure. However many authors demonstrated that restoration of flow through this vessel alone, in patients without significative lesions of the aorto-femoral district, will effectively relieve ischemia when the superficial femoral artery is also occluded. Our experience gained in the last eight years concerns 24 patients (21 male, 3 female). All the patients had severe ischemia of the lower limb with invalidating claudication (13), rest pain (9) and gangrene (2). On the basis of our results, we think that the operation is recommended, whenever possible, in patients with critical ischemia when the possibilities of more extensive revascularizing procedures are absent.

Surgical treatment of abdominal aortic aneurysm. A ten-year experience (1980-1989) referred to 1725 patients operated on.

The authors' experience of surgical management of abdominal aortic aneurysms (AAA), in 1725 consecutive patients, operated on in a ten years period (1980-1989) is presented. Surgical indications, operative technique, and outcome of elective and emergency procedures are analyzed. A ten years follow-up period is also presented. This shows a significantly better survival rate in surgically treated patients than in nonoperated cases.

Abdominal aortic aneurysms surgery in over 75 years old patients. Experience in 142 cases treated between 1980-1989.

The paper describes the Authors' experience of abdominal aortic aneurysm surgery in over 75-year-old patients. One hundred and forty-two cases were operated over a 10-year period (1980-89). Seventy-two patients were treated electively and 70 underwent emergency surgery following rupture of the aneurysm. Operative mortality during elective surgery was comparable to that in younger patients, whereas the mortality rate during emergency surgery was notably higher than that in under 75-year-old patients. Follow-up confirmed that the life expectancy of operated patients is significantly better than that of patients with untreated abdominal aortic aneurysms.