Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based nonintensive therapy.

ABSTRACT: Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype. We analyzed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved complete remission (CR)/CR with incomplete hematological recovery following treatment with venetoclax and hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity, and a further 14 (18%) achieved a reduction of ≥4 log10 from baseline as their best response, with no difference between HMAs and LDAC. The cumulative rates of BM MRD negativity by the end of cycles 2, 4, and 6 were 25%, 47%, and 50%, respectively. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive. On multivariable analyses, MRD negativity was the strongest prognostic factor. A total of 22 patients electively stopped therapy in BM MRD-negative remission after a median of 8 cycles, with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information.

FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML.

Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure.  This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated.  We identified 56 patients treated with FLT3i at molecular failure.  The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69-93) and molecular event-free survival 56% (95%CI 44-72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.

Defective T-cell response to COVID-19 vaccination in acute myeloid leukaemia and myelodysplastic syndromes.

Limited data exist on COVID-19 vaccination efficacy in patients with acute myeloid leukemia and myelodysplasia with excess blasts (AML/MDS-EB2). We report results from a prospective study, PACE (Patients with AML and COVID-19 Epidemiology). 93 patients provided samples post-vaccine 2 or 3 (PV2, PV3). Antibodies against SARS-COV-2 spike antigen were detectable in all samples. Neutralization of the omicron variant was poorer than ancestral variants but improved PV3. In contrast, adequate T-cell reactivity to SARS-COV-2 spike protein was seen in only 16/47 (34%) patients PV2 and 23/52 (44%) PV3. Using regression models, disease response (not in CR/Cri), and increasing age predicted poor T cell response.

Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry.

Introduction: COVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. Methods: This study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic. Results: The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 - 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022. Discussion: Although the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.

Molecular MRD status and outcome after transplantation in NPM1-mutated AML.

Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABL in the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P < .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P = .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P < .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P = .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P = .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).

Complications associated with surgical treatment of sleep-disordered breathing among hospitalized U.S. adults.

The purpose of this cross-sectional study is to examine the relationship between surgical treatments for sleep-disordered breathing (SDB) and composite measure of surgical complications in a nationally representative sample of hospital discharges among U.S. adults. We performed secondary analyses of 33,679 hospital discharges from the 2002-2012 Nationwide Inpatient Sample that corresponded to U.S. adults (≥18 years) who were free of head-and-neck neoplasms, were diagnosed with SDB and had undergone at least one of seven procedures. Multivariate logistic regression models were constructed to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI), controlling for age, sex, race/ethnicity, obstructive sleep apnea (OSA) and obesity diagnoses. Positive associations were found between composite measure of surgical complications and specific procedures: palatal procedure (aOR = 12.69, 95% CI: 11.91,13.53), nasal surgery (aOR = 6.47, 95% CI: 5.99,6.99), transoral robotic assist (aOR = 5.06, 95% CI: 4.34-5.88), tongue base/hypopharynx (aOR = 4.24, 95% CI: 3.88,4.62), maxillomandibular advancement (MMA) (aOR = 3.24, 95% CI: 2.74,3.84), supraglottoplasty (aOR = 2.75, 95% CI: 1.81,4.19). By contrast, a negative association was found between composite measures of surgical complications and tracheostomy (aOR = 0.033, 95% CI: 0.031,0.035). In conclusion, most procedures for SDB, except tracheostomy, were positively associated with complications, whereby palatal procedures exhibited the strongest and supraglottoplasty exhibited the weakest association.

Redirection to the bone marrow improves T cell persistence and antitumor functions.

A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.

Lateral dissemination and inter-patient transmission of blaKPC-3: role of a conjugative plasmid in spreading carbapenem resistance.

OBJECTIVES: The objective of this study was to describe the nosocomial spread of carbapenemase-producing enterobacteria and characterize a plasmid involved in KPC dissemination. METHODS: Two Klebsiella pneumoniae, one Escherichia coli and one Citrobacter freundii isolated from two patients were studied. Susceptibility profiles were obtained using Etest. Carbapenemase activity was detected using the Carba NP test. ß-Lactamase gene content was screened by PCR and sequencing. K. pneumoniae isolates were genotyped by MLST and PFGE. KPC plasmid sizes were estimated by S1-DNA digestion and PFGE-Southern blot. Plasmids were sequenced using Illumina's technology and Sanger sequencing. RESULTS: Two patients sharing a room on a surgical unit were positive for carbapenemase-producing K. pneumoniae. One patient was also colonized with carbapenemase-producing C. freundii and E. coli. Neither patient had known risk factors for carbapenemase acquisition, although one patient had recent surgery at another Toronto hospital; the other patient's husband had surgery in New York City 3 years prior to her presentation. An extensive investigation was conducted at both hospitals, but no additional cases were identified. blaKPC-3 was detected in all clinical isolates. Variable carbapenem resistance levels were observed. Both K. pneumoniae belonged to the same clone by PFGE and MLST (ST277). pKPC-SMH (∼ 53 kb) was identified in all the clinical isolates, showing identity only with structurally similar IncN plasmids. CONCLUSIONS: We describe intra- and inter-patient dissemination of blaKPC. The involvement of a clone related to the successful K. pneumoniae ST258 and the blaKPC-3 gene detected in an active Tn4401 transposon carried on a conjugative broad-host-range plasmid increased the potential for this horizontal transmission.

Long term follow-up of BEAM-autologous and BEAM-alemtuzumab allogeneic stem cell transplantation in relapsed advanced stage follicular lymphoma.

This is an analysis in 171 patients comparing BEAM-Auto and BEAM-Allo (alemtuzumab)-hematopoietic stem cell transplantation in relapsed follicular lymphoma. BEAM-Allo group had a lower 10 years cumulative incidence of relapse(31.4% vs 55.1%, p=0.042), a trend to a plateau in survival but no statistical differences in OS or DFS, and a TRM of 24%. When transplanted in CR BEAM-Allo patients had better OS and DFS. Incidence of acute and chronic GVHD was 16.6% and 22%. 29% of BEAM-Allo patients received DLI (all but two remain in CR and alive). Our data supports Allo-HSCT as a potential curative treatment for selected patients with FL.

PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement.

We investigated whether positron emission tomography combined with computed tomography (PET-CT) identifies clinically important bone marrow involvement by diffuse large B-cell lymphoma (DLBCL) with sufficient accuracy to replace routine staging bone marrow biopsy. All patients from a single centre diagnosed as DLBCL since 2005 had data extracted from staging PET-CT, marrow biopsy, and treatment records. Of 130 patients, 35 (27%) were judged to have marrow involvement; 33 were identified by PET-CT compared with 14 by marrow histology. PET identified all clinically important marrow lymphoma, while biopsy did not upstage any patient. Sensitivity and specificity were 94% and 100% for PET-CT and 40% and 100% for marrow biopsy. As a secondary aim, we compared the prognosis of marrow involvement, as detected by PET-CT or biopsy. Cases with marrow deposits identified by PET-CT but not biopsy had progression-free survival (PFS) and overall survival similar to stage IV disease without involved marrow. Positive biopsy conferred significantly inferior PFS (P = .003); these cases frequently had other markers of poor-risk disease. These data confirm that in experienced hands PET-CT has a high level of accuracy for identifying marrow disease in DLBCL, and provide new insight into the nature and clinical significance of marrow involvement.

Rapid control of a scabies outbreak at a tertiary care hospital without ward closure.

BACKGROUND: Although scabies outbreaks in hospitals are frequent, the optimal approach to management of these outbreaks has not yet been defined. We describe a hospital scabies outbreak that was successfully controlled without ward closure. METHODS: An outbreak of scabies at a teaching hospital and subsequent control measures were investigated. Outcomes included the number of cases affecting patients and staff, number of patients and staff requiring prophylaxis, duration of the outbreak, and cost of the outbreak. Outcomes were compared with those in a similar outbreak occurring at the same hospital 20 years earlier and with other published descriptions of hospital scabies outbreaks. RESULTS: In January 2010, a patient who had undergone renal transplantation was admitted 3 times to St. Michael's Hospital, but a diagnosis of scabies was not considered until the final admission. Widespread exposure of patients and staff on 2 wards prompted the establishment of an outbreak management team. Initial interventions focused on isolation and treatment of the index case and on contact tracing to identify and treat secondary cases and to offer prophylaxis to direct contacts. Five symptomatic staff members and 2 patient cases were quickly identified, an outbreak was declared, and mass simultaneous prophylaxis was initiated on the 2 involved wards. A single case occurred 2 weeks after the mass prophylaxis program in a staff member who had not received the prophylaxis. Six weeks after the onset of symptoms, the end of the outbreak was declared. No additional cases have been reported up to the time of publication. The total cost of the outbreak was $20,000. CONCLUSIONS: Early recognition of crusted scabies is essential to prevent outbreaks. Once an outbreak occurs, prompt control of the index patient and rapid tracing of contacts to identify secondary cases are necessary. When prolonged exposure to a case of crusted scabies results in multiple secondary cases, institution of simultaneous mass prophylaxis is the most efficient strategy for terminating the outbreak and can be implemented without ward closure.

Let off the leash: kala-azar following the use of tumour necrosis factor antibodies.

A 74-year-old woman with a history of psoriatic arthritis was referred to the Hospital for Tropical Diseases following investigation of a skin lesion that had failed to heal after a visit to Malta 2 years previously. Skin biopsy had revealed invasion of Leishmania amastigotes. She reported a recent history of weight loss, dry cough and dyspnoea, and was investigated for pancytopenia and hepatosplenomegaly. Bone marrow biopsy confirmed the diagnosis of visceral leishmaniasis and she responded well to treatment with intravenous liposomal amphotericin B. Recent rheumatological treatment with adalimumab, a monoclonal antibody to tumour necrosis factor α, was thought to be the factor responsible for causing the cutaneous lesion to become disseminated. This case highlights an unexpected adverse effect of novel immunosuppressants. As the use of biologics becomes widespread, there is an increasing need for clinical surveillance.

Rapid control of a methicillin resistant Staphylococcus aureus (MRSA) outbreak in a medical surgical intensive care unit (ICU).

BACKGROUND: Outbreaks of methicillin resistant Staphylococcus aureus in the intensive care unit setting can be prolonged and difficult to control. This report describes the rapid control of an outbreak of methicillin resistant Staphylococcus aureus in a 24-bed open-concept medical surgical intensive care unit with a baseline methicillin resistant Staphylococcus aureus acquisition rate of 1.5 cases per 1000 patient days. INTERVENTIONS/RESULTS: This institution's infection control policy mandates an outbreak investigation if two cases of hospital-acquired methicillin resistant Staphylococcus aureus colonization or infection are identified in an intensive care unit within a four-week period. In July 2007, methicillin resistant Staphylococcus aureus was identified in the sputum of two patients within a one-week period. Screening of all patients in the intensive care unit identified one additional case and a fourth case was identified from a clinical specimen before control measures were implemented. Initial control measures included healthcare worker education, enhanced surveillance, patient cohorting, and enhanced environmental cleaning. Despite these measures, three more cases occurred. All patients were then placed in contact isolation, healthcare workers were screened, and the nursing staff was cohorted. After two weeks without a case, two additional cases were identified. Decolonization of all positive patients was initiated. No further cases occurred over a five-week period and the outbreak was declared over. The outbreak resulted in nine cases of methicillin resistant Staphylococcus aureus colonization (n = 8) or infection (n = 1) over an 11-week period. Only one of 175 healthcare workers was colonized and it was not the outbreak strain. CONCLUSIONS: Early detection and the stepwise addition of infection control measures resulted in the rapid control of an outbreak of methicillin resistant Staphylococcus aureus in a medical surgical intensive care unit without unit closure. A low threshold of suspicion and the rapid initiation of unit wide surveillance were the key steps in limiting the size of the outbreak. Complete cessation of transmission occurred after the initiation of decolonization for all positive patients.

The upper lip lift using the 'bull's horn' approach.

Our lift lip technique consists of an excision of the white part of the upper lip directly beneath the nose in the shape of a 'bull's-horn', with advancement of the inferior border of the incision to the area directly beneath the nose. Pre-operative markings on the skin ensure the lip lift is approximately symmetric. Advancement of the inferior edge of skin directly beneath the nasal base lifts the lip, producing more visible vermilion and about 3 mm of tooth show at rest. The position of the final incision is such that it is located within the shadow of the nose. Meticulous technique produces an almost invisible scar. The amount and width of skin excised is individualized depending on the desired aesthetic goals. The procedure is straightforward and is usually performed under local anesthetic. Abdominal fat is frequently injected into both the upper and lower lips to increase the volume and improve the rejuvenation. Lip lifts using this technique provide an immediate, dramatic, and permanent result.

Persistent primary hyperparathyroidism caused by adenomas identified in pharyngeal or adjacent structures.

Abnormalities in the normal migration of the parathyroid glands during embryological development of the head and neck may result in considerable variability in the location of parathyroid tissue. Ectopic parathyroid adenomas present diagnostic and technical challenges and are frequently the cause of persistent primary hyperparathyroidism (HPT) after unsuccessful initial parathyroid surgery. We report a series of eight patients with persistent primary HPT who had adenomas in rare and unusual locations associated with various pharyngeal structures. Four were located within the epineurium of the vagus nerve at or above the level of the carotid bifurcation, and four were located within the paranasopharyngeal space or oropharynx. Noninvasive and invasive preoperative imaging studies were crucial in localizing the neoplasms in these patients and permitted the use of a direct surgical approach, resulting in cure in all patients and a low complication rate. The location of parathyroid glands in high pharyngeal and cervical structures is a consequence of anomalous or arrested descent through developing pharyngeal structures and illustrates the remarkable spectrum of ectopic parathyroid adenomas that occur secondary to this phenomenon.

Minimizing Upper Lip and Incisor Teeth Paresthesias in Approaches to Transsphenoidal Surgery.

Currently popular transsphenoidal approaches to the pituitary include sublabial, external rhinoplasty, alotomy, and transnasal techniques. The conventional sublabial approach remains the workhorse method despite postoperative lip edema, potential difficulty for denture wearers, and troublesome persistent upper lip and incisor teeth numbness. We traced the courses of the nasopalatine, infraorbital, and anterior superior alveolar nerves in 41 cadaveric half-head dissections to determine the exact contribution to upper lip and incisor teeth innervation. We then conducted a retrospective patient survey of 25 sublabial, 28 external rhinoplasty, 23 alotomy, and 12 transnasal approaches to the hypophysis to assess the incidence of upper lip and incisor teeth paresthesias lasting longer than 1 month. We conclude that rhinoplastic techniques are superior to the sublabial approach in limiting upper lip and incisor teeth numbness without compromising neurosurgical exposure for hypophysectomy.