How I use next-generation sequencing-MRD to plan approach and prevent relapse after HCT for children and adults with ALL.

ABSTRACT: Measurable residual disease (MRD) evaluation by multiparameter flow cytometry (MFC) or quantitative polymerase chain reaction methods is an established standard of care for assessing risk of relapse before or after hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL). Next-generation sequencing (NGS)-MRD has emerged as a highly effective approach that allows for the detection of lymphoblasts at a level of <1 in 106 nucleated cells, increasing sensitivity of ALL detection by 2 to 3 logs. Early studies have shown superior results compared with MFC and suggest that NGS-MRD may allow for the determination of patients in whom reduced toxicity transplant preparative approaches could be deployed without sacrificing outcomes. Many centers/study groups have implemented immune modulation approaches based on MRD measurements that have resulted in improved outcomes. Challenges remain with NGS-MRD, because it is not commercially available in many countries, and interpretation of results can be complex. Through patient case review, discussion of relevant studies, and detailed expert opinion, we share our approach to NGS-MRD testing before and after HCT in pediatric and adult ALL. Improved pre-HCT risk classification and post-HCT monitoring for relapse in bone marrow and less invasive peripheral blood monitoring by NGS-MRD may lead to alternative approaches to prevent relapse in patients undergoing this challenging procedure.

Hematopathologic Correlates of CAR T-Cell Therapy.

CD19-targeting chimeric antigen rector (CAR) T-cell products are used for the treatment of relapsed/refractory B-acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and mantle cell lymphoma. The success of CD19-CAR-T cells has led to the investigation of CAR T-cell products targeting different antigens in other hematological malignancies and solid tumors. Clinical laboratories play an important role in the manufacture, distribution, and monitoring of CAR T-cell therapy. Hence, it is important for laboratory professionals to be cognizant of clinicopathologic aspects of CAR T-cell therapy.

Association of psychological distress and religious coping tendencies in parents of children recently diagnosed with cancer: A cross-sectional study.

PURPOSE: Parents of children with cancer exhibit high levels of psychological distress. Parents of children with serious illness report religion and spirituality are important coping resources. We sought to describe characteristics of religion, religious coping, social support, and resiliency in parents of children newly diagnosed with cancer and examine associations between psychological distress and self-reported religious coping, religiosity, resiliency, and social support. PATIENTS AND METHODS: Cross-sectional observational study of 100 parents of 81 unique children recently diagnosed with cancer. Parents provided demographic information and completed measures of psychological distress, importance of religion, religious coping, resiliency, and social support. Patients' type of tumor and intensity of treatment were collected by medical record abstraction. RESULTS: Compared to nationally reported data for adults, parents of children with cancer reported high scores for psychological distress but similar levels of religiosity, religious coping, and resiliency. Negative religious coping (feelings of negativity related to the divine) was associated with higher levels of psychological distress. This effect was most prominent in parents who reported the highest levels of religiosity. Positive religious coping, religiosity, and social support were not associated with levels of psychological distress. DISCUSSION: Findings confirm high levels of distress for parents of children with cancer. Negative religious coping was associated with higher levels of psychological distress but positive religious coping, religiosity, and other coping factors were not found to be significantly associated with distress. Further assessment of negative religious coping to inform interventions to promote resiliency is warranted as they may impact parental decision-making and care.

The Histopathology of Oral Cancer Pain in a Mouse Model and a Human Cohort.

Oral cancer patients often have severe, chronic, and mechanically induced pain at the site of the primary cancer. Oral cancer pain is initiated and maintained in the cancer microenvironment and attributed to release of mediators that sensitize primary sensory nerves. This study was designed to investigate the histopathology associated with painful oral cancers in a preclinical model. The relationship of pain scores with pathologic variables was also investigated in a cohort of 72 oral cancer patients. Wild-type mice were exposed to the carcinogen, 4-nitroquinoline 1-oxide (4NQO). Nociceptive (pain) behavior was measured with the dolognawmeter, an operant device and assay for measuring functional and mechanical allodynia. Lesions developed on the tongues and esophagi of the 4NQO-treated animals and included hyperkeratoses, papillomas, dysplasias, and cancers. Papillomas included lesions with benign and dysplastic pathological features. Two histologic subtypes of squamous cell carcinomas (SCCs) were identified-SCCs with exophytic and invasive components associated with papillary lesions (pSCCs) and invasive SCCs without exophytic histology (iSCCs). Only the pSCC subtype of tongue cancer was associated with nociceptive behavior. Increased tumor size was associated with greater nociceptive behavior in the mouse model and more pain experienced by oral cancer patients. In addition, depth of invasion was associated with patient-reported pain. The pSCC histology identifies 4NQO-induced tongue cancers that are expected to be enriched for expression and release of nociceptive mediators.

Validated image ordering guidelines for odontogenic infections.

Overuse of computed tomography (CT) is a prevalent problem across multiple disciplines in healthcare and is common in the workup of odontogenic infections. To address this problem, an imaging pathway was created through collaboration of the oral maxillofacial surgery and emergency medicine departments to reduce unnecessary CT orders. A prospective study was implemented to assess the success of the imaging pathway to guide in the selection of the most appropriate radiological imaging modality when managing an odontogenic infection. Subjects included were adults, presenting through the emergency department for confirmed odontogenic infection. The primary outcome was the rate of unnecessary CT scans performed after the introduction of the pathway. Statistics were performed via the t-test, χ2 test, and multiple regression analysis; P < 0.05 was considered significant. Between February 1 and December 15, 2019, 100 patients met the inclusion criteria and were enrolled. The rate of unnecessary CT scans was 25.6%, compared to 56.6% prior to the introduction of the imaging pathway. The pathway did not misclassify any patient to not receive a CT when it was medically necessary. Use of the imaging pathway has the potential to reduce unnecessary CT imaging for odontogenic infections, without negatively affecting patient outcomes.

Treatment protocol for secondary esophageal reconstruction using 'supercharged' colon interposition flaps.

Locoregional esophageal cancer is currently treated with induction chemoradiotherapy, followed by esophagectomy with reconstruction, using a gastric conduit. In cases of conduit failure, patients are temporized with a cervical esophagostomy and enteral nutrition until gastrointestinal continuity can be established. At our institution, we favor reconstruction, using a colon interposition with a 'supercharged' accessory vascular pedicle. Consequently, we sought to examine our technique and outcomes for esophageal reconstruction, using this approach. We performed a retrospective review of all patients who underwent esophagectomy at our center between 2008 and 2018. We identified those patients who had a failed gastric conduit and underwent secondary reconstruction. Patient demographics, perioperative details, and clinical outcomes were analyzed after our clinical care pathway was used to manage and prepare patients for a second major reconstructive surgery. Three hundred and eighty eight patients underwent esophagectomy and reconstruction with a gastric conduit. Seven patients (1.8%) suffered gastric conduit loss and underwent a secondary reconstruction using a colon interposition with a 'supercharged' vascular pedicle. Mean age was 70.1 (±7.3) years, and six patients were male. The transverse colon was used in four cases (57.1%), left colon in two cases (28.6%), and right colon in one case (14.3%). There were no deaths or loss of the colon interposition at follow-up. Three patients (42.9%) developed an anastomotic leak, which resolved with conservative management. All patients had resumption of oral intake within 30 days. Utilizing a 'supercharging' technique for colon interposition may improve the perfusion to the organ and may decrease morbidity. Secondary reconstruction should occur when the patient's oncologic, physiologic, and psychosocial condition is optimized. Our outcomes and preoperative strategies may provide guidance for those centers treating this complicated patient population.

Targeted TNF-α Overexpression Drives Salivary Gland Inflammation.

Chronic inflammation of the salivary glands from pathologic conditions such as Sjögren's syndrome can result in glandular destruction and hyposalivation. To understand which molecular factors may play a role in clinical cases of salivary gland hypofunction, we developed an aquaporin 5 (AQP5) Cre mouse line to produce genetic recombination predominantly within the acinar cells of the glands. We then bred these mice with the TNF-αglo transgenic line to develop a mouse model with salivary gland-specific overexpression of TNF-α; which replicates conditions seen in sialadenitis, an inflammation of the salivary glands resulting from infection or autoimmune disorders such as Sjögren's syndrome. The resulting AQP5-Cre/TNF-αglo mice display severe inflammation in the salivary glands with acinar cell atrophy, fibrosis, and dilation of the ducts. AQP5 expression was reduced in the salivary glands, while tight junction integrity appeared to be disrupted. The immune dysregulation in the salivary gland of these mice led to hyposalivation and masticatory dysfunction.

Ultrasound-guided adductor canal block: a cadaver study investigating the effect of a thigh tourniquet.

BACKGROUND: Placement of local anaesthetic within the adductor canal using ultrasonography is an alternative to femoral nerve blocks for postoperative pain relief after knee joint replacement surgery. However, the effect of an inflated thigh tourniquet on the distribution of local anaesthetic within the adductor canal is unknown. The aim of this cadaveric study was to compare the distribution of radio-opaque dye within the adductor canal in the presence or absence of an inflated thigh tourniquet. METHODS: Bilateral ultrasound-guided adductor canal blocks were performed on the thawed lower limbs of five fresh frozen human cadavers. The left and right lower cadaver limbs were randomised to receive or not receive a thigh tourniquet inflated to 300 mm Hg for 1 h. X-rays with iohexol radio-opaque dye were obtained in four views, and fiducial markers inserted as reference points. Virtual editing technology was used to recreate outlines representing the distribution of the radio-opaque dye and superimpose these on anatomical images. RESULTS: Radio-opaque dye was distributed on the medial aspect of the thighs with entire and well circumscribed margins. The majority of the radio-opaque dye was confined within the adductor canal. Superior-inferior dye distribution was 315 mm [95% confidence intervals (CI) 289-342] and 264 mm (95% CI 239-289) in the presence and absence of an inflated thigh tourniquet, respectively (diff 95% CI -80.46 to -22.22, P=0.0081). Image analysis using the recreated radio-opaque outlines suggested that the most proximal point of the radio-opaque dye was 100 mm (95% CI 82-117) or 117 mm (95% CI 62-171) below the inguinal ligament in the presence and absence of an inflated thigh tourniquet, respectively (diff 95% CI -38 to 72, P=0.456). CONCLUSIONS: Application and inflation of thigh tourniquets significantly increased the combined superior-inferior dye distribution within the adductor canal of cadaveric limbs. There was insufficient evidence to suggest significant proximal spread of 25 ml of local anaesthetic to involve the motor branches of the femoral nerve. In some patients, the local anaesthetic may reach the popliteal fossa in close approximation to the sciatic nerve.

Orofacial cleft management by short-term surgical missions in South America: literature review.

There is a growing demand for surgical care in South America, particularly for patients with congenital orofacial clefts (OFCs). Short-term surgical missions (STSMs) have emerged as a means to deliver surgical expertise and alleviate this demand. The aim of this study was to review the quantity and quality of peer-reviewed reports on OFC repairs performed by STSMs in South America. A literature search was conducted using the PubMed, Embase, Web of Science, and SciELO databases. The search was limited to articles published in English and Spanish. Descriptive statistics were used for the data analysis. The search yielded 65 studies related to OFCs. Eight (12.3%) were selected for full-text review. Only five (7.7%) articles met the inclusion criteria. The diverse study designs and heterogeneous types of data assessment among the selected studies hindered a comparison between them. This review found a sparse number of publications pertaining to OFC missions to South America. The articles that were included demonstrated inconsistencies in reporting patient care data. There is a need for a more efficient, streamlined method of reporting humanitarian missions for OFC repairs in order for healthcare professionals to fulfill research and ethical obligations and offer the best practices in patient-centered care.

Neoadjuvant chemoradiotherapy with concurrent cisplatin/5-fluorouracil is associated with increased pathologic complete response and improved survival compared to carboplatin/paclitaxel in patients with locally advanced esophageal cancer.

Trimodal therapy consisting of neoadjuvant chemoradiation followed by esophagectomy has become the standard of care in North America for locally advanced esophageal cancer. While cisplatin/5-fluorouracil has been a common concurrent chemotherapy regimen since the 1980s, its utilization has declined in recent years as the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) trial regimen of carboplatin/paclitaxel has become widely adopted. The efficacy of the CROSS regimen compared to alternate chemotherapy choices, however, has rarely been evaluated when each is used as a component of a trimodal treatment approach. The aim of this study is to report our institutional experience with these two concurrent chemotherapy regimens at a specialized esophageal cancer center.We performed an Institutional Review Board-approved retrospective review of a prospectively maintained institutional foregut registry from a single National Cancer Institute-designated cancer center. Esophageal cancer patients who completed trimodal therapy with a chemotherapy regimen of either carboplatin/paclitaxel or cisplatin/5-fluorouracil were identified and divided into groups based on their chemotherapy regimens. Multivariable logistic regression was used to analyze pathologic complete response rates, while the Kaplan-Meier and Cox proportional hazards models were utilized to evaluate recurrence-free and overall survival. Analytical models were adjusted for age, clinical stage, radiation dose, histologic subtype (adenocarcinoma vs. squamous cell carcinoma), and time interval from completion of neoadjuvant therapy to surgery.One hundred and forty-two patients treated between January of 2000 and July of 2015 were identified as meeting inclusion criteria. Of this group, 87 had received the CROSS regimen of carboplatin/paclitaxel, while 55 had completed cisplatin/5-fluorouracil. Multivariable analysis demonstrated that the cisplatin/5-fluorouracil.group had an increased odds of pathologic complete response (odds ratio = 2.68, 95% confidence interval, P = 0.032), as well as significantly improved recurrence-free survival (hazard ratio = 0.39, 95% confidence interval 0.21-0.73, P = 0.003) and overall survival (hazard ratio = 0.46, 95% confidence interval 0.24-0.87, P = 0.016), compared to the carboplatin/paclitaxel group.Concurrent chemotherapy with cisplatin/5-fluorouracil in locally advanced esophageal cancer is associated with higher rates of pathologic complete response and improved recurrence-free and overall survival compared to the CROSS regimen of carboplatin/paclitaxel. This suggests that, for select patients, alternate neoadjuvant chemotherapy approaches, such as cisplatin/5-fluorouracil, merit reconsideration as potential primary treatment choices in the management of this highly morbid disease.

Persistent pain after caesarean section and its association with maternal anxiety and socioeconomic background.

BACKGROUND: Pain, both from the surgical site, and from other sources such as musculoskeletal backache, can persist after caesarean section. In this study of a predominantly socially deprived population we have sought to prospectively examine the association between antenatal maternal anxiety and socioeconomic background and the development of persistent pain of all sources after caesarean section. METHODS: Demographic details and an anxiety questionnaire were completed by 205 women before elective caesarean section. On the first postoperative day, pain scores were recorded, and at four months patients were asked to complete a Brief Pain Inventory and an Edinburgh Postnatal Depression Score. RESULTS: Of 205 parturients recruited, 186 records were complete at the hospital admission phase and 98 (52.7%) were complete at the four-month follow-up phase. At recruitment, 15.1% reported pain. At four months 41.8% (95% CI 32.1 to 51.6%) reported pain, of whom pain was a new finding in 35.7% (95% CI 26.2 to 45.2%). Antenatal anxiety was not a significant predictor of severity of new pain at four months (P=0.44 for state anxiety, P=0.52 for trait anxiety). However, four-month pain severity did correlate with social deprivation (P=0.011), postnatal depression (P<0.001) and pain at 24h (P=0.018). CONCLUSION: Persistent pain from a variety of sources after caesarean section is common. Our findings do not support the use of antenatal anxiety scoring to predict persistent pain in this setting, but suggest that persistent pain is influenced by acute pain, postnatal depression and socioeconomic deprivation.

Resolving Fine-Scale Heterogeneity of Co-seismic Slip and the Relation to Fault Structure.

Fault slip distributions provide important insight into the earthquake process. We analyze high-resolution along-strike co-seismic slip profiles of the 1992 Mw = 7.3 Landers and 1999 Mw = 7.1 Hector Mine earthquakes, finding a spatial correlation between fluctuations of the slip distribution and geometrical fault structure. Using a spectral analysis, we demonstrate that the observed variation of co-seismic slip is neither random nor artificial, but self-affine fractal and rougher for Landers. We show that the wavelength and amplitude of slip variability correlates to the spatial distribution of fault geometrical complexity, explaining why Hector Mine has a smoother slip distribution as it occurred on a geometrically simpler fault system. We propose as a physical explanation that fault complexity induces a heterogeneous stress state that in turn controls co-seismic slip. Our observations detail the fundamental relationship between fault structure and earthquake rupture behavior, allowing for modeling of realistic slip profiles for use in seismic hazard assessment and paleoseismology studies.

Conditional TNF-α Overexpression in the Tooth and Alveolar Bone Results in Painful Pulpitis and Osteitis.

Tumor necrosis factor-α (TNF-α) is a proalgesic cytokine that is commonly expressed following tissue injury. TNF-α expression not only promotes inflammation but can also lead to pain hypersensitivity in nociceptors. With the established link between TNF-α and inflammatory pain, we identified its increased expression in the teeth of patients affected with caries and pulpitis. We generated a transgenic mouse model (TNF-α(glo)) that could be used to conditionally overexpress TNF-α. These mice were bred with a dentin matrix protein 1 (DMP1)-Cre line for overexpression of TNF-α in both the tooth pulp and bone to study oral pain that would result from subsequent development of pulpitis and bone loss. The resulting DMP1/TNF-α(glo) mice show inflammation in the tooth pulp that resembles pulpitis while also displaying periodontal bone loss. Inflammatory infiltrates and enlarged blood vessels were observed in the tooth pulp. Pulpitis and osteitis affected the nociceptive neurons innervating the orofacial region by causing increased expression of inflammatory cytokines within the trigeminal ganglia. With this new mouse model morphologically mimicking pulpitis and osteitis, we tested it for signs of oral pain with an oral function assay (dolognawmeter). This assay/device records the time required by a mouse to complete a discrete gnawing task. The duration of gnawing required by the DMP1/TNF-α(glo) mice to complete the task was greater than that for the controls; extended gnaw time in a dolognawmeter indicates reduced orofacial function. With the DMP1/TNF-α(glo) mice, we have shown that TNF-α expression alone can produce inflammation similar to pulpitis and osteitis and that this mouse model can be used to study dental inflammatory pain.

Significant understaging is seen in clinically staged T2N0 esophageal cancer patients undergoing esophagectomy.

This study aimed to determine the impact of preoperative staging on the treatment of clinical T2N0 (cT2N0) esophageal cancer patients undergoing esophagectomy. We reviewed a retrospective cohort of 27 patients treated at a single institution between 1999 and 2011. Clinical staging was performed with computed tomography, positron emission tomography, and endoscopic ultrasound. Patients were separated into two groups: neoadjuvant therapy followed by surgery (NEOSURG) and surgery alone (SURG). There were 11 patients (41%) in the NEOSURG group and 16 patients (59%) in the SURG group. In the NEOSURG group, three of 11 patients (27%) had a pathological complete response and eight (73%) were partial or nonresponders after neoadjuvant therapy. In the SURG group, nine of 16 patients (56%) were understaged, 6 (38%) were overstaged, and 1 (6%) was correctly staged. In the entire cohort, despite being clinically node negative, 14 of 27 patients (52%) had node-positive disease (5/11 [45%] in the NEOSURG group, and 9/16 [56%] in the SURG group). Overall survival rate was not statistically significant between the two groups (P = 0.96). Many cT2N0 patients are clinically understaged and show no preoperative evidence of node-positive disease. Consequently, neoadjuvant therapy may have a beneficial role in treatment.

Preoperative carboplatin and paclitaxel-based chemoradiotherapy for esophageal carcinoma: results of a modified CROSS regimen utilizing radiation doses greater than 41.4 Gy.

Trimodality therapy for resectable esophageal and gastroesophageal junction cancers utilizing preoperative radiotherapy with concurrent carboplatin and paclitaxel-based chemotherapy is being increasingly utilized secondary to the results of the phase III CROSS trial. However, there is a paucity of reports of this regimen as a component of chemoradiotherapy in North America. We aim to report on our clinical experience using a modified CROSS regimen with higher radiotherapy doses. Patients with advanced (cT2-cT4 or node positive) esophageal or gastroesophageal junction carcinoma who received preoperative carboplatin/paclitaxel-based chemoradiotherapy with radiation doses of greater than 41.4 Gray (Gy) followed by esophagectomy were identified from an institutional database. Patient, imaging, treatment, and tumor response characteristics were analyzed. Twenty-four patients were analyzed. All but one tumor had adenocarcinoma histology. The median radiation dose was 50.4 Gy. Pathologic complete response was achieved in 29% of patients, with all receiving 50.4 Gy. Three early postoperative deaths were seen, due in part to acute respiratory distress syndrome and all three patients received 50-50.4 Gy. With a median follow-up of 9.4 months (23 days-2 years), median survival was 24 months. Trimodality therapy utilizing concurrent carboplatin/paclitaxel with North American radiotherapy doses appeared to have similar pathologic complete response rates compared with the CROSS trial, but may be associated with higher toxicity. Although the sample size is small and further follow-up is necessary, radiation doses greater than 41.4 Gy may not be warranted secondary to a potentially increased risk of severe radiation-induced acute lung injury.