Enhancing the diagnosis of maxillary transverse discrepancy through 3-D technology and surface-to-surface superimposition. Description of the digital workflow with a documented case report.

BACKGROUND: Maxillary transverse discrepancy is often diagnosed in childhood. The evaluation of morphological characteristics of the maxilla is crucial for appropriate treatment of this condition, however conventional diagnostic method is based on visual inspection and transversal linear parameters. In this paper, we described a user-friendly diagnostic digital workflow based on the surface-to-surface analysis. We also described a case report. CASE REPORT: A 6-year-old female patient presenting mild transversal maxillary deficiency associated with functional posterior crossbite was treated by using maxillary removable appliance. In this respect, the appliance was designed in accordance to the morphological characteristics of the maxilla obtained by using the diagnostic digital work-flow and the maxillary surface-to-surface analysis. CONCLUSION: The present user-friendly diagnostic digital workflow based on surface-to-surface analysis helps clinicians to detect specific morphological characteristics of the maxilla, such as shape and area of asymmetry, in order to reach a comprehensive diagnosis and choose the correct biomechanics for treating the condition.

Serial monitoring of isavuconazole blood levels during prolonged antifungal therapy.

BACKGROUND: Isavuconazole is the newest triazole antifungal approved for the treatment of invasive aspergillosis (IA) and invasive mucormycosis in adult patients. OBJECTIVES: To characterize the assessment of the blood levels of isavuconazole and their association with efficacy and toxicity. METHODS: From January 2017 to May 2018, blood samples obtained from patients receiving isavuconazole were analysed for therapeutic drug monitoring. Factors influencing the blood concentrations of isavuconazole, such as weight, length of treatment, route of administration and results of selected liver function tests, were analysed in univariate and multivariate models. The receiver operating characteristic (ROC) curve was analysed to detect the best cut-off for isavuconazole toxicity. RESULTS: A total of 264 isavuconazole blood concentrations in 19 patients were analysed. The median value of isavuconazole concentration in all patients during the first 30 days of therapy was 3.69 mg/L (range 0.64-8.13 mg/L). A linear increase of 0.032 mg/L (range 0.023-0.041 mg/L) for each day of treatment (P = 0.002) was observed. In multivariate analysis the association between the length of treatment and higher levels of isavuconazole (P < 0.001) and higher serum GGT and lower isavuconazole levels (P = 0.001) was confirmed. Adverse events, mainly gastrointestinal, were reported in six patients (31.6%). Based on time-dependent and fixed-time ROC curve analysis, 4.87 mg/L and 5.13 mg/L, respectively, were the identified thresholds for toxicity. CONCLUSIONS: Isavuconazole was efficacious and well tolerated. Side effects, mainly gastrointestinal, were associated with prolonged administration and high serum levels.

Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update.

This is a report of 148 patients with hematologic malignancies who received an unmanipulated haploidentical bone marrow transplant (BMT), followed by post-transplant high-dose cyclophosphamide (PT-CY). All patients received a myeloablative conditioning consisting of thiotepa, busulfan, fludarabine (n=92) or TBI, fludarabine (n=56). The median age was 47 years (17-74); 47 patients were in first remission (CR1), 37 in second remission (CR2) and 64 had an active disease; all patients were first grafts. The diagnosis was acute leukemia (n=75), myelodisplastic syndrome (n=24), myelofibrosis (n=16), high-grade lymphoma (n=15) and others (n=18). GVHD prophylaxis consisted in PT-CY on days +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median day for neutrophil engraftment was day +18 (13-32). The cumulative incidence of grades II-IV acute GVHD was 24%, and of grades III-IV GVHD 10%. The incidence of moderate-severe chronic GVHD was 12%. With a median follow-up for the surviving patients of 313 days (100-1162), the cumulative incidence of transplant-related mortality (TRM) is 13%, and the relapse-related death is 23%. The actuarial 22 months overall survival is 77% for CR1 patients, 49% for CR2 patients and 38% for patients grafted in relapse (P<0.001). Major causes of death were relapse (22%), GVHD (2%) and infections (6%). We confirm our initial results, suggesting that a myeloablative conditioning regimen followed by unmanipulated haploidentical BMT with PT-CY, results in a low risk of acute and chronic GVHD and encouraging rates of TRM and overall survival, also for patients with active disease at the time of transplant.

DLI after haploidentical BMT with post-transplant CY.

Forty-two patients relapsing after an unmanipulated haploidentical BM transplant and post-transplant CY (PT-CY), were given 108 DLI, with median interval from transplant of 266 days (range, 67-1372). DLI were given at escalating doses, expressed as CD3+ cells/kg, without GVHD prophylaxis, and ranged from 1 × 10(3) to 1 × 10(7) cells/kg (median 5 × 10(5) cells/kg). The average number of DLI per patient was 2.6 (range, 1-6). The diagnosis was leukemias (n=32) grafted with a myeloablative regimen and Hodgkin's disease (n=10), grafted with a nonmyeloablative regimen. Leukemic patients with molecular relapse (n=20), received DLI alone (n=17) or in association with azacytidine (n=3); leukemic patients with hematologic relapse (n=12) received chemotherapy followed by DLI (n=11) or DLI alone (n=1); Hodgkin patients received DLI following 1-3 courses of chemotherapy. In these three groups the incidence of acute GVHD II-III was 15%, 17% and 10%; response rate was 45%, 33% and 70%; 2-year actuarial survival was 43%, 19% and 80% respectively. This study confirms that escalating doses of DLI can be given in the haploidentical setting with PT-CY, with a relatively low risk of acute GVHD. Response rates and survival are dependent on the underlying disease.

Biliodigestive fistulae and gallstone ileus: diagnostic and therapeutic considerations. Our experience.

The biliodigestive fistula is not a rare affection in the context of acute pathology of the gastrointestinal tract. It often affects patients between 63 and 85 years old , particularly the female sex, and the most common cause is acute or chronic cholecystolithiasis. Open issues are the delayed in the pre-operative diagnosis, and controversies exist regarding the best surgical approach. The choice of treatment options is influenced by the age of the patients and their clinical conditions and also by the presence of comorbidities and of a delayed right diagnosis. In the 1 to 3% of cases, the biliodigestive fistula presents a gallstone ileus as complication, whose diagnosis is particularly difficult for the lack of specific signs and symptoms. The contrast-enhanced CT is considered the gold standard for a specific pre-operative diagnosis, as it directly shows the fistula. Surgical treatments include one-stage procedure or two-stage procedure. Many studies seem to favor a deferred definitive procedure. The Authors describe 4 cases: in 3 cases, women between 70 and 80 years old presenting an history of recurrent cholecystitis, in 2 cases, and in 1 case presenting a bowel obstruction; in 1 case a 50-years-old man, with no significant past medical history, presenting a bowel obstruction. The Authors have performed in the 2 cases of gallstone ileus an enterolithotomy with cholecysto-duodenal fistula repair and cholecystectomy, in one-stage, and this has been possible because of the good clinical conditions of the patients and their low operative risk. In the case of fistula without the complication of gallstone ileus, the treatment approach has been cholecysto-gastric fistula closure with a gastroplastic using separate stitches and cholecystectomy, in one-stage. We are in agreement with data in the literature regarding the delay into the diagnosis of biliodigestive fistula and with the importance to suspect it or gallstone ileus presence, although the clinical presentation is extremely non-specific. In our experience, cholangiopancreatography-CT and CECT have made easier the pre-operative diagnosis and so reducing the delay of the treatment.

Small bowel intussussception due to metastatic melanoma of unknown primary site. Case report.

Malignant melanoma is characterized by metastases also to the gastrointestinal tract, especially in the small bowel. The diagnosis is often delayed because unspecific clinical presentation (frequently as chronic iron deficiency anemia, rectal bleeding or intestinal obstruction). We present a case of melanoma of unknown primary site, with clinical presentation of intestinal obstruction. A segmental resection of the ileum was performed including mesentery with lymph nodes. Histology revealed metastatic melanoma from unknown primary. PET and MRI confirmed disseminated disease without brain metastasis.

Hepatitis B reactivation in HBsAg-negative/HBcAb-positive allogeneic haematopoietic stem cell transplant recipients: risk factors and outcome.

HBsAg-negative/HBcAb-positive haematopoietic stem cell transplant (HSCT) recipients are at high risk of hepatitis B virus (HBV) reactivation. Allogeneic HSCT recipients from years 2000 to 2010 were evaluated in order to study the impact of being HBsAg-negative/HBcAb-positive in this population. Overall, 137 of 764 patients (18%) were HBsAg-negative/HBcAb-positive before HSCT. Overall survival, non-relapse mortality (NRM), acute and chronic graft-vs.-host disease were similar in HBcAb-positive and HBcAb-negative patients. Reactivation occurred in 14 patients (10%) within a median of 19 months after HSCT (range 9-77). Cause-specific hazard for reactivation was decreased in the case of an HBV-immune/exposed donor (HRadjusted = 0.12; 95% CI, 0.02-0.96; p 0.045) and increased in patients who received rituximab treatment (HRadjusted = 2.91; 95%CI, 0.77-10.97; p 0.11). Competing risk analyses documented a protective role of an HBV-immune/exposed donor (p 0.041) and an increased probability associated with the length of treatment with cyclosporine (p <0.001) and treatment with rituximab (but not with low-dose rituximab prophylaxis, p <0.001 at each landmark point). No differences in overall survival and NRM were found between patients with and without HBV reactivation. The donor's immunity was independently and consistently associated with a decreased risk of HBV reactivation, while rituximab and cyclosporine treatments increased the probability.

Risk management in surgery.

Malpractice is the responsible for the greatest number of legal claims. At the present time, legal actions against physicians in Italy are 15,000 per year, and a stunning increase about costs to refund patients injured by therapeutic and diagnostic errors is expected. The method for the medical prevention is "Risk Management", that is the setting-up of organizational instruments, methods and actions that enable the measurement or estimation of medical risk; it allows to develop strategies to govern and reduce medical error. In the present work, the reconstruction about the history of risk management in Italy was carried out. After then the latest initiatives undertaken by Italy about the issue of risk management were examined.

Single-incision laparoscopic appendectomy is comparable to conventional laparoscopic and laparotomic appendectomy: our single center single surgeon experience.

Several studies have demonstrated the clinical and technical benefits of the laparoscopic surgery for complicated and uncomplicated appendicitis. Our retrospective study included 12 patient who underwent SILS appendectomy (SILS-A), 14 who received conventional laparoscopic surgery (VL-A), and 12 who received laparotomic appendectomy (OA); performed in all cases by the same surgeon (C.F.). The aim of this study was the comparison between this three different surgical techniques on same features: post operative leukocytosis, post operative pain, need abdominal drainage, esthetic viewpoint, incidence of complication, hospital stay. The results showed no significant differences between SILS-A and VLS-A, while an evident improvement shows versus O-A, even though not statistically significative. SILS was more effective in decreasing the risk of postoperative wound infection.

Technique and outcomes about a new laparoscopic procedure: the Pelvic Organ Prolapse Suspension (POPS).

Pelvic organ prolapse suspension (POPS) is a recent surgical procedure for one-stage treatment of multiorgan female pelvic prolapse. This study evaluates the preliminary results of laparoscopic POPS in 54 women with a mean age of 55.2 and a BMI of 28.3. Patients underwent at the same time stapled transanal rectal resection (STARR) to correct the residual rectal prolapse. We had no relapses and the preliminary results were excellent. We evaluated the patients after 1 year follow-up and we confirmed the validity of our treatment. The technique is simpler than traditional treatments with an important reduction or completely disappearance of the pre-operative symptomatology.

Cholecystectomy by single incision laparoscopic surgery (SILS): early experience and technique standardization.

Single Incision Laparoscopic Surgery (SILS) is a recent surgical technique, first described in the 1990s. Its aim is to optimize the esthetic result offered by laparoscopy by minimizing the number of abdominal incisions. Various preliminary studies have been carried out on the application of SILS, especially in cholecystectomy and appendectomy. This study evaluates the preliminary results of cholecystectomy by SILS (SILS™ Port) conducted between October 2009 and February 2011 on 21 patients (4 men and 17 women) with a mean age of 49.9 years and a mean Body Mass Index (BMI) of 22.8. All patients were treated by the same team, which had previously undergone six months' simulator training. There were two main selection criteria, both evaluated intraoperatively: absence of adhesions and of significant inflammatory sequelae from previous cholecystitis; and suitable distance between gallbladder and SILS access port. Conversion to traditional laparoscopy was necessary in just two cases, while an accessory trocar was introduced in another two cases. Conversion to open surgery was not necessary in any case. One case of SILS cholecystectomy was complicated by postoperative bile leakage, which was treated conservatively, as the fistula had a low output. The mean duration of hospitalization was 3.6 days. This preliminary experience led us to conclude that SILS is safe and highly satisfactory in the postoperative phase, thanks to the reduced need for painkillers and the improved esthetic result.

Liver resection for hemoperitoneum caused by spontaneous rupture of unrecognized hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an increasingly common form of cancer. Although its spontaneous rupture is rare in Western countries, it constitutes a surgical emergency and is associated with high mortality. There is a lack of consensus as to the best approach and what parameters to use in choosing it. The three main approaches are conservative, endovascular and resection - the treatment of choice for acute abdominal bleeding. We report a case of hemoperitoneum following the spontaneous rupture of an unrecognized HCV-related HCC in a patient with no history of liver disease. The patient was successfully treated by emergency surgery, with resection of two segments of the left liver.

Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD.

Extracorporeal photopheresis (ECP) was given to 23 patients with steroid-refractory acute GVHD (aGVHD, grade II (n=10), III (n=7) or IV (n=6)). The median duration of ECP was 7 months (1-33) and the median number of ECP cycles in each patient was 10. Twelve patients (52%) had complete responses. Eleven patients (48%) survived and 12 died, 10 of GVHD with or without infections and two of leukaemia relapse. The average grade of GVHD was reduced from 2.8 (on the first day of ECP) to 1.4 (on day +90 from ECP) (P=0.08), and the average dose of i.v. methylprednisolone from 2.17 to 0.2 mg/kg/d (P=0.004). Complete responses were obtained in 70, 42 and 0% of patients, respectively, with grades II, III and IV aGVHD; complete responses in the skin, liver and gut were 66, 27 and 40%. Patients treated within 35 days from onset of aGVHD had higher responses (83 vs 47%; P=0.1). A trend for improved survival was seen in grade III-IV aGVHD treated with ECP as compared to matched controls (38 vs 16%; P 0.08). ECP is a treatment option for patients with steroid refractory aGVHD and should be considered early in the course of the disease.

Allogeneic hemopoietic stem cell transplants for patients with relapsed acute leukemia: long-term outcome.

We assessed the long-term outcome of patients with relapsed acute myeloid (n=86) or acute lymphoid leukemia (n=66), undergoing an allogeneic hemopoietic stem cell transplantation in our unit. The median blast count in the marrow was 30%. Conditioning regimen included total body irradiation (TBI) (10-12 Gy) in 115 patients. The donor was a matched donor (n=132) or a family mismatched donor (n=20). Twenty-two patients (15%) survive disease free, with a median follow-up of 14 years: 18 are off medications. The cumulative incidence of transplant related mortality is 40% and the cumulative incidence of relapse related death (RRD) is 45%. In multivariate analysis of survival, favorable predictors were chronic graft-versus-host disease (GvHD) (P=0.0003), donor other than family mismatched (P=0.02), donor age less than 34 years (P=0.02) and blast count less than 30% (P=0.07). Patients with all four favorable predictors had a 54% survival. In multivariate analysis of relapse, protective variables were the use of TBI (P=0.005) and cGvHD (P=0.01). This study confirms that a fraction of relapsed leukemias is cured with an allogeneic transplant: selection of patients with a blast count <30%, identification of young, human leukocyte antigen-matched donors and the use of total body radiation may significantly improve the outcome.

Factors predicting response and graft-versus-host disease after donor lymphocyte infusions: a study on 593 infusions.

In the present study, we analyze factors predicting graft-versus-host disease (GvHD) and response after donor lymphocyte infusions (DLI). A total of 100 patients received 593 DLI between June 1990 and December 2000 in a bulk dose (n=14) or in escalating dose infusions (n=86). Patients were analyzed after stratification for type of relapse: (1). molecular relapse (n=6), (2). cytogenetic relapse (n=20), (3). chronic phase of chronic myeloid leukemia (CML) or complete remission of other disease post chemotherapy (n=24), (4). CML in accelerated/blastic phase (n=14), (5). resistant disease not responding to chemotherapy (n=36). The proportion of responders to DLI in these five groups was 100, 90, 75, 36 and 0% (P<0.0001). Factors predicting response by multivariate analysis were type of relapse (P<0.0001), post-DLI GvHD (P=0.005), pancytopenia (P=0.008), and a diagnosis of CML (P=0.04). Acute GvHD (grades II-IV) occurred in 21 patients (21%), and correlated in multivariate analysis with pancytopenia and less than four DLI. Other predictors of GvHD were the number of CD3+cells/infusion and serum levels of gamma-glutamyl transferase (gammaGT). The actuarial probability of treatment-related mortality was 9% for HLA identical siblings and 44% for alternative donor transplants (P=0.006). Response to DLI is predicted by tumor burden and is associated with GvHD and pancytopenia.

Allogeneic bone marrow transplantation (BMT) for adults with acute lymphoblastic leukemia (ALL): predictive role of minimal residual disease monitoring on relapse.

We developed a PCR-based method to monitor clonogenic IgH VDJ rearrangement as a possible predictor of relapse in patients with acute B-ALL after allogeneic bone marrow transplantation (BMT). We studied 23 patients at diagnosis, before and after BMT. At the time of BMT, 13 patients were in first complete remission, eight in second complete remission and two in relapse. Four patients were PCR negative before BMT and remained PCR negative also after BMT (-/- pattern). They are still in remission after a median follow-up of 41 months. Nineteen patients were MRD-positive before BMT: three were PCR negative at first determination after BMT (+/- pattern) and maintain remission. Sixteen patients were PCR-positive at first determination after BMT (+/+ pattern): five became PCR negative (+/+/- pattern) (four with chronic graft-versus-host disease (GVHD) and two after donor lymphocyte infusions (DLI)). Nine patients remained PCR-positive (+/+/+ pattern) (four remain in remission, and six relapsed); two patients died before transplant. In conclusion, PCR negative patients before BMT remained negative post-BMT; many pre-BMT positive patients had initial MRD positivity after BMT: 37% of them achieved a molecular remission with cGVHD or DLI.

Prophylactic antithymocyte globulin reduces the risk of chronic graft-versus-host disease in alternative-donor bone marrow transplants.

We studied the impact of preparative regimens with or without antithymocyte globulin (ATG) on chronic GVHD in 160 patients undergoing marrow transplants from unrelated donors (n = 127) or partially mismatched related donors (n = 33). A conditioning regimen that included rabbit ATG, 7.5 to 15 mg/kg (Thymoglobuline; Sangstat, Lyon, France), was given to 102 patients, whereas a conditioning regimen without ATG was given to 58 patients. The median patient age was 34 years for the ATG group and 29 years for the non-ATG group (P = .002); otherwise the 2 groups were matched for disease phase, diagnosis, donor age, interval from diagnosis to transplantation, and number of cells infused at the time of transplant. Median follow-up for surviving patients was 4.5 years (range, l.5-9 years). The conditioning regimen was cyclophosphamide (CY) and total body irradiation (TBI) in 95 patients and CY-thiotepa in 65 patients; the source of stem cells was bone marrow for all patients. Acute GVHD grades II-IV and grades III-IV were reduced in patients receiving ATG compared to patients not receiving ATG (51% versus 74%, P = .004 and 14% versus 28%, P = .03, respectively). There were significantly fewer patients with chronic GVHD in the ATG group than in the non-ATG group at 6 months (14% versus 30%, P = .03), 1 year (7% versus 41%, P = .0001), 2 years (16% versus 36%, P = .02), and 4 years (5% versus 34%, P = .002) and beyond 4 years (0% in 19 patients at risk versus 29% in 24 patients at risk, P = .01). More patients in the ATG group than in the non-ATG group had a performance status (Karnowski score) greater than 90 at last follow-up (93% versus 56%, P = .01) and had discontinued cyclosporin treatment 2 years posttransplant (28% versus 3%, P = .003). Survival rates were comparable in the ATG and non-ATG groups for patients who received TBI (56% versus 59%, P = .7) and those who received thiotepa (33% versus 18%, P = .3). Transplant mortality and relapse rates were also comparable in the 2 groups for these patients. We conclude that pretransplant ATG administration reduces the risk of acute and chronic GVHD, improves quality of life, and increases the likelihood that discontinuation of immunosuppressive therapy will be possible.

Conventional hematopoietic stem cell transplants from identical or alternative donors are feasible in recipients relapsing after an autograft.

BACKGROUND AND OBJECTIVES: The risk of relapse after autologous bone marrow transplantation (ASCT) is high and is related to the type of malignancy and phase of the disease. The outcome for the patient who relapses after an autologous transplant is poor. Some of these patients achieve a remission with conventional chemotherapy, but it is usually short-lasting. Most of them succumb to the original disease. One further therapeutic possibility is an allogeneic transplant which would confer the potential advantage of a graft-versus-leukemia effect in addition to the lack of tumor contamination of the graft and to a high-dose intensity conditioning regimen. DESIGN AND METHODS: We have studied the outcome of 31 patients with hematologic malignancies who underwent an allogeneic hematopoietic stem cell transplant (HSCT) after failing an autologous transplant because of relapse (n=29) or persistent aplasia (n=2). The median age at allograft was 36 years (18-55) and the interval from autograft to allograft was 21 months (3-141). The source of stem-cells was unmanipulated bone marrow (n=26) or growth-factor-mobilized peripheral blood (n=5). The donor was an HLA-identical sibling (n=7), or an alternative donor (n=24) (family mismatched n=11, or matched unrelated n=13). The conditioning regimen was cyclophosphamide and thiotepa (n=22), or cyclophosphamide and total body irradiation (n=9) Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine (CyA) + methotrexate (MTX). RESULTS: Acute GvHD was scored as 0-I, II, or III-IV in 39%, 48%, and 13% of the patients, respectively. Sixteen patients died of transplant-related complications and one of progressive disease. With a median follow-up of 220 days (9-2104) the actuarial 2-year transplant-related mortality (TRM) was 51%, the actuarial relapse risk 37%, the actuarial survival 46%. Fifteen patients (48%) are alive in complete remission, with a median follow-up of 32 months (range 2-71). INTERPRETATION AND CONCLUSIONS: These data suggest that patients relapsing after an autotransplant should be screened for potential related or unrelated donors: although TRM remains high there is a definite chance of long-term disease-free survival if these patients are allografted.