Consolidative radiotherapy for residual fluorodeoxyglucose activity on day +30 post CAR T-cell therapy in non-Hodgkin lymphoma.

Majority of non-Hodgkin lymphoma (NHL) patients who achieve partial response (PR) or stable disease (SD) to CAR T-cell therapy (CAR T) on day +30 progress and only 30% achieve spontaneous complete response (CR). This study is the first to evaluate the role of consolidative radiotherapy (cRT) for residual fluorodeoxyglucose (FDG) activity on day +30 post- CAR T in NHL. We retrospectively reviewed 61 patients with NHL who received CAR T and achieved PR or SD on day +30. Progression-free survival (PFS), overall survival (OS), and local relapse-free survival (LRFS) were assessed from CAR T infusion. cRT was defined as comprehensive - treated all FDG-avid sites - or focal. Following day +30 positron emission tomography scan, 45 patients were observed and 16 received cRT. Fifteen (33%) observed patients achieved spontaneous CR, and 27 (60%) progressed with all relapses involving initial sites of residual FDG activity. Ten (63%) cRT patients achieved CR, and four (25%) progressed with no relapses in the irradiated sites. The 2-year LRFS was 100% in the cRT sites and 31% in the observed sites (P<0.001). The 2-year PFS was 73% and 37% (P=0.025) and the 2-year OS was 78% and 43% (P=0.12) in the cRT and observation groups, respectively. Patients receiving comprehensive cRT (n=13) had superior 2- year PFS (83% vs. 37%; P=0.008) and 2-year OS (86% vs. 43%; P=0.047) compared to observed or focal cRT patients (n=48). NHL patients with residual FDG activity following CAR T are at high risk of local progression. cRT for residual FDG activity on day +30 post-CAR T appears to alter the pattern of relapse and improve LRFS and PFS.

Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration.

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.

Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma.

Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR T failure. The median number of lines of therapy between CAR T infusion and alloHCT was one (range, 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range, 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis, <2 lines of intervening therapy between CAR T and alloHCT and complete response at time of alloHCT were associated with better outcomes. In conclusion, alloHCT after CAR T failure can provide durable remissions in a subset of patients.

DTRMWXHS-12, a novel Bruton tyrosine kinase inhibitor, in combination with everolimus and pomalidomide in patients with relapsed/refractory lymphomas: An open-label, multicenter, phase 1a/1b study.

Preclinical studies have shown augmented activity when combining Bruton tyrosine kinase inhibitors (BTKi) with inhibitors of mammalian target of rapamycin (mTOR) and immunomodulatory agents (IMiD). We conducted a phase 1, open-label study at five centers in USA to evaluate the safety of triplet BTKi/mTOR/IMiD therapy. Eligible patients were adults aged 18 years or older with relapsed/refractory CLL, B cell NHL, or Hodgkin lymphoma. Our dose escalation study used an accelerated titration design and moved sequentially from single agent BTKi (DTRMWXHS-12), doublet (DTRMWXHS-12 + everolimus), and then to triplet therapy (DTRMWXHS-12 + everolimus + pomalidomide). All drugs were dosed once daily on days 1-21 of each 28-day cycle. The primary goal was to establish the recommended phase 2 dose of the triplet combination. Between September 27, 2016, and July 24, 2019, a total of 32 patients with a median age of 70 years (range 46 to 94 years) were enrolled. No MTD was identified for monotherapy and the doublet combination. The MTD for the triplet combination was determined to be DTRMWXHS-12 200 mg + everolimus 5 mg + pomalidomide 2 mg. Responses across all studied cohorts were seen in 13 of 32 (41.9%). Combining DTRMWXHS-12 with everolimus and pomalidomide is tolerable and shows clinical activity. Additional trials could confirm benefit of this all-oral combination therapy for relapsed/refractory lymphomas.

Covid-19 associated pulmonary aspergillosis with extensive cavitary pneumonia: A case report.

Covid-19 associated pulmonary aspergillosis (CAPA) is a new entity and is associated with high morbidity and mortality. Covid-19 is a pro-inflammatory and immunosuppressive disease, provoking fungal infections, especially by Aspergillus species. We describe the case of a critically ill Covid-19 female patient, who was diagnosed with CAPA infection and acute respiratory distress syndrome (ARDS). She was given intravenous Remdesivir. Her chest X-ray a few days after admission showed multiple cavities. Her condition initially improved but deteriorated again, with worsening hypoxia and pneumothorax and multiple cavitary lesions on HRCT of the chest. Despite optimal treatment, she could not recover. Interestingly, she had no predisposing risk factor for pulmonary aspergillosis, such as chronic lung disease, diabetes or use of immunosuppressants such as Tocilizumab. CAPA is an emerging entity with worsening hypoxia, and failure to improve can be an early sign. Early identification and treatment can improve survival and outcomes in Covid-19 patients.

Post-relapse survival in Waldenstrom macroglobulinemia patients experiencing therapy failure following autologous transplantation.

Waldenström macroglobulinemia (WM) is a rare B-cell lymphoproliferative malignancy. Autologous hematopoietic cell transplantation (auto-HCT) is considered in a subset of WM patients with relapsed disease. While registry data has shown a benefit for auto-HCT in relapsed WM, there is a paucity of data on outcomes of patients relapsing after auto-HCT. Eligibility criteria included adult patients with relapsed/refractory WM who underwent auto-HCT between 2007 and 2017. The primary endpoint was post-relapse overall survival (PR-OS). Secondary endpoints were to identify factors prognostic of PR-OS. Of the 48 patients with WM who underwent auto-HCT, 22 (46%) experienced relapse following auto-HCT. Median PR-OS of relapsed WM patients after auto-HCT (n = 22) was not reached (NR) (95% confidence interval [CI]: 17.5 months-NR). Among patients who relapsed <1 year versus ≥1 year from auto-HCT, the median PR-OS was 18.4 months (95%CI: 0.8-NR) months and NR (95%CI: 17.5-NR), respectively (p = 0.06). Of note, disease status at the time of transplant, CR/VGPR versus partial remission did not appear to impact PR-OS. The median PR-OS was significantly longer in patients who received ibrutinib in the post-transplant setting compared to those who did not (NR vs. 18.4 months, 95%CI: 9.1-NR, p = 0.02). On univariable analysis, the presence of complex karyotype (RR = 4.87, 95% CI = 1.22-19.53) and a higher number of prior lines of therapy (RR = 1.81, 95% CI = 1.23-2.67) were associated with a significantly higher risk of relapse. This is the only study to date that evaluated outcomes of WM patients who relapsed following auto-HCT and provides a benchmark for future trials evaluating survival following auto-HCT relapse.

Clinical characteristics, prognostic indicators, and survival outcomes in intravascular lymphoma: Mayo Clinic experience (2003-2018).

Intravascular lymphoma (IVL) is a rare extranodal non-Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003-2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS-IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non-CNS-IVL patients with abnormal FDG-PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS-IVL and 63.5% (35/55) had non-CNS-IVL. CNS-IVL group consists of clinically isolated CNS involvement (CNS-only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M-IVL) (14.5%; 8/55). Non-CNS-IVL group consists of clinically isolated skin involvement (skin-only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P-IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B-cell IVL. Rituximab + high-dose methotrexate-based regimen were used in 75% (12/16) of CNS-IVL patients and RCHOP in 60% (17/28) of non-CNS-IVL patients. Estimated 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin-only IVL was associated with excellent survival. Platelet count <150x109 /L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies.

Impact of Benzodiazepine Use on Length of Stay and 30-Day ED Visits among Hospitalized Hematopoietic Stem Cell Transplant Recipients.

OBJECTIVES: This study assesses the impact of benzodiazepine (BNZ) use on length of stay (LOS) and 30-day emergency department (ED) visits after hematopoietic stem cell transplant (HSCT). METHODS: Adult patients (18 years and older) who underwent an allogeneic or an autologous HSCT from 2015 to 2018 at the study site were included. Five multivariable models were used for both allogeneic and autologous HSCT: BNZ-naïve status, diazepam equivalent daily dosage (DEDD; 0 vs any), DEDD (excluding 0), ED visits, and LOS. RESULTS: BNZ-naïve autologous HSCT recipients were less likely to use any BNZs in the hospital (odds ratio [OR] 0.07, P < 0.001). If prescribed BNZs, then they used a lesser amount (incidence rate ratio 0.39, P < 0.001). BNZ-naïve autologous HSCT recipients were less likely to experience a 30-day ED visit (OR 0.17, P = 0.009). BNZ-naïve allogeneic HSCT recipients were also less likely to use any BNZ than previous users (OR 0.11, P = 0.014). Patient characteristics influenced BNZ naïvety, DEDD usage, LOS for autologous patients, and BNZ naïvety and DEDD for allogeneic patients. CONCLUSIONS: BNZ use resulted in increased 30-day ED visits after autologous HSCT. BNZ-naïve recipients were less likely to use BNZs during hospital stays; if they required BNZs, then it was in lower dosages.

Efficacy of proteasome inhibitor-based maintenance following autologous transplantation in multiple myeloma: A systematic review and meta-analysis.

INTRODUCTION: Lenalidomide maintenance, commonly prescribed in the postautologous transplantation (AHCT) setting for multiple myeloma (MM), is associated with development of secondary primary malignancies (SPM). Proteasome inhibitor maintenance (PIM) has also been evaluated in MM. We conduct a systematic review/meta-analysis to assess the efficacy of PIM in MM. METHODS: Performing a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 11, 2019, we extracted data on clinical outcomes related to benefits (OS, PFS, and depth of hematologic response [DOHR]) and harms (SPM and adverse events). 2144 references were identified; three studies were eligible for inclusion. RESULTS: A total of 1760 patients were included in the analysis; 507 patients received bortezomib and 395 received ixazomib maintenance. Control arms were either placebo (n = 261) or thalidomide (n = 358). PIM did not improve OS (HR 0.88, 95% CI 0.73-1.05, P = .15) but improved PFS (HR 0.77, 95% CI 0.69-0.86, P ≤ .00001) and DOHR (HR 0.88, 95% CI 0.79-0.98, P = .02) compared with control. There were no significant differences between PIM and control regarding SPM (p = NS) and ≥grade 3 peripheral neuropathy (PN) (p = NS). CONCLUSIONS: PIM following AHCT in MM improves PFS and DOHR without an increase in development of SPM or severe PN compared with placebo/thalidomide.

Efficacy of Allogeneic Hematopoietic Cell Transplantation in Cutaneous T Cell Lymphoma: Results of a Systematic Review and Meta-Analysis.

Mycosis fungoides and Sézary syndrome are the most common types of primary cutaneous T cell lymphomas. The clinical presentation of mycosis fungoides is generally indolent, whereas Sézary syndrome represents a more aggressive disease variant. Stage at diagnosis is the most important determinant of long-term survival outcome. Although most patients present with early-stage disease, those who develop progressive disease or have an advanced stage represent a therapeutic challenge because of a lack of effective therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) has been used as a potentially curative treatment modality with encouraging long-term outcomes. However, a lack of randomized controlled data remains, and the published literature is limited to mostly retrospective studies. We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE, and Cochrane reviews on September 13, 2018. We extracted data on clinical outcomes related to benefits (overall [OS] and progression-free [PFS] survival) and harms (relapse and nonrelapse mortality [NRM]) independently by 2 authors. Our search strategy identified 289 references. Five studies (266 patients) were included in this systematic review and meta-analysis. Reduced-intensity and nonmyeloablative regimens were more commonly prescribed (76%). Mobilized peripheral blood stem cells were the preferred graft source (78%). The pooled OS and PFS rates were 59% (95% confidence interval [CI], 50% to 69%) and 36% (95% CI, 27% to 45%), respectively. Pooled relapse rate was 47% (95% CI, 41% to 53%) and pooled NRM rate 19% (95% CI, 13% to 27%). Results of this systematic review and meta-analysis show that allo-HCT yields encouraging OS and PFS rates; however; relapse remains a significant cause of allo-HCT failure. Novel strategies to further improve outcomes should focus on offering allo-HCT before the development of resistant disease and reducing relapse by incorporating post-transplant maintenance therapies.

Impact of Depression and Anxiety on Opioid Use in Hospitalized Hematopoietic Cell Transplantation Recipients.

BACKGROUND: Hematopoietic cell recipients are reported to have a high prevalence of depression and anxiety. The impact of depression and anxiety on opioid use has not been well characterized. This is of significance as the opioid epidemic continues, and over 60% of deaths secondary to drug overdose involve the use of opioids. OBJECTIVE: In this retrospective, single-center study of 275 patients who underwent hematopoietic cell transplantation (HCT) (allogeneic and autologous) for hematological malignancies, we explore the impact of depression and anxiety on opioid use. RESULTS: Patients who were both anxious and depressed at admission for HCT had increased odds of receiving an opioid (odds ratio of 4.50 [95% confidence interval: 1.75, 11.56]) compared with patients who were neither depressed nor anxious. However, patients who were either depressed or anxious did not have different odds of receiving an opioid compared with those who were neither depressed nor anxious. Autologous HCT recipients had reduced odds of receiving an opioid (odds ratio of 0.17 [95% confidence interval: 0.08, 0.38]) compared with patients undergoing allogeneic HCT. Patients with lower Karnofsky performance status (<90 on a scale of 1-100) had an increased incidence of receiving a higher Morphine milligram equivalent daily dosage (incidence rate ratio of 2.59 [95% confidence interval: 1.18, 5.67]) when modeled by zero truncated negative binomial regression. CONCLUSION: Presence of depression and anxiety impacts opioid use in patients undergoing HCT.

Efficacy of Allogeneic Hematopoietic Cell Transplantation in Human T Cell Lymphotropic Virus Type 1-Associated Adult T Cell Leukemia/Lymphoma: Results of a Systematic Review/Meta-Analysis.

Human T cell lymphotropic virus type 1 (HTLV1)-associated adult T cell leukemia/lymphoma (ATLL) is an aggressive malignant disorder. Intensive conventional chemotherapy regimens and autologous hematopoietic cell transplantation (HCT) have failed to improve outcomes in ATLL. Allogeneic HCT (allo-HCT) is commonly offered as front-line consolidation despite lack of randomized controlled trials. We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE, and Cochrane reviews on September 10, 2018. We extracted data on clinical outcomes related to benefits (complete response [CR], overall survival [OS], and progression-free survival [PFS]) and harms (relapse and nonrelapse mortality [NRM]), independently by 2 authors. Our search strategy identified a total of 801 references. Nineteen studies (n = 2446 patients) were included in the systematic review; however, only 18 studies (n = 1767 patients) were included in the meta-analysis. Reduced intensity conditioning regimens were more commonly prescribed (52%). Bone marrow (50%) and peripheral blood (40%) were more frequently used as stem cell source. The pooled post-allografting CR, OS, and PFS rates were 73% (95% confidence interval [CI], 57% to 87%), 40% (95% CI, 33% to 46%), and 37% (95% CI, 27% to 48%), respectively. Pooled relapse and NRM rates were 36% (95% CI, 28% to 43%) and 29% (95% CI, 21% to 37%), respectively. The heterogeneity among the included studies was generally high. These results support the use of allo-HCT as an effective treatment for patients with ATLL, yielding pooled OS rates of 40%, but relapse still occurs in over one-third of cases. Future studies should evaluate strategies to help reduce relapse in patients with ATLL undergoing allo-HCT.

Correlation between Internet addiction, depression, anxiety and stress among undergraduate medical students in Azad Kashmir.

OBJECTIVE: To find out the correlation between internet addiction and depression, anxiety, and stress among undergraduate medical students in Azad Kashmir. METHODS: A cross-sectional study including 210 undergraduate medical students (first to the fifth year) was done in Poonch Medical College, Azad Kashmir. The data collection tools were DASS21 questionnaire and Young's internet addiction questionnaire. Spearman rank correlation test was done to see the correlation between internet addiction and depression, anxiety, and stress. Data were analyzed by SPSS v23 at a 95% confidence interval. RESULTS: A very high prevalence (52.4%) of moderate to extremely severe internet addiction was observed among the respondents. The mild positive correlation between internet addiction and depression was identified (p <.001) and similar type of correlation was observed between internet addiction and stress (p .003). However, anxiety and internet addiction were not significantly correlated. The prevalence of anxiety and depression among the males were higher than the females, whilst the stress level was almost the same across gender. CONCLUSION: Internet addiction has been found to be associated with various psychiatric diseases. In this study, we also observed such correlation. We have also observed a very high level of internet addiction among medical students. The prevalence of internet addiction may further increase in the coming years as the internet will become more cheap, available and include more high quality psychologically addictive contents.

Phytochemical screening and antibacterial activity of different solvent extracted samples of Arisaema jacquemontii.

The current research was carried out to assess the antibacterial activities and phytochemical analysis of the methanol, n-hexane, ethyl acetate, n-butanol soluble fractions and aqueous extracts of the tubers of Arisaema jacquemontii. All the extracts were tested for their antibacterial potential at 1, 2 and 3 mg disc-1 concentrations against 6 bacterial strains through disc diffusion suseptibility assay. The data suggested that different extracts showed varying degree of growth inhibition against the tested microbes. Statistical analysis revealed that n-hexane and ethyl acetate soluble fractions significantly inhibited the growth of all the bacterial strains at the tested concentrations. Moderate activities were recorded for n-butanol and methanolic extracted samples at different concentrations against all the tested strains of bacteria. P. aeruginosa, S. aureus and X. campestris showed resistance to all the tested concentrations of the aqueous extract. B. subtilis and K. pneumoniae were resistant at 1 and 2 mg disc-1 concentrations of the aqueous extract and 3 mg disc-1 of the same extract reduced the growth of the same bacteria. Phytochemical analysis of the different solvent extracted samples suggested the presence or absence of various metabolites including alkaloids, saponins, tannins, sterols, flavonoids, protein, carbohydrates and fats.

ASSOCIATION BETWEEN PLACENTAL ABRUPTION AND CAESAREAN SECTION AMONG PATIENTS AT KHYBER TEACHING HOSPITAL PESHAWAR.

BACKGROUND: Ante partum haemorrhage remains to be a major cause of morbidity and mortality.30% of this haemorrhage is attributed to placental abruption. Along with other adverse maternal outcomes, it increases the risk of Caesarean sections in patients, which is a public health concern. This study was conducted to find out whether any significant association exists between placental abruption and C-section in our set up. METHODS: A cross-sectional study was conducted from July 26th, 2011 to May 1st, 2013 (i.e., 21 months) in the Department of Obstetrics and Gynaecology, Khyber Teaching Hospital Peshawar on a sample of 334 patients who presented with antepartum haemorrhage after 28 weeks of gestation. All those patients with and without placental abruption were followed throughout pregnancy and labour to detect the risk of caesarean section. RESULTS: Among study participants, parity had the highest dispersion while gestational age had the lowest. Caesarean section was performed on 26.3% (95% CI) of the study participants. Proportion of placental abruption among patients presenting with ante partum haemorrhage was 20.6%, (95% CI) out of which 7.5% underwent C-section. Association between placental abruption and C-section was found significant at α = 0.05 (p = 0.03). CONCLUSION: Risk of caesarean section is increased in pregnancies complicated by placental abruption as compared to pregnancies complicated by other causes of ante partum haemorrhage.

Effect of the silicone heel pad on plantar fasciitis.

OBJECTIVE: To evaluate the effect of silicone heel pad in the management of pain in plantar fasciitis patients. METHODS: The descriptive case series study was conducted at Hope Rehabilitation Centre, Lahore, from March 1 to September 30, 2013, and comprised patients aged > 18 years with symptomatic plantar fasciitis who were treated with silicone heel pad. All patients were assessed at one month and six months for pain relief measured on % Maximum Total Pain Relief and Pain Intensity Difference percentage scales. Data was analysed using SPSS 20. RESULTS: Out of 100 patients, 37(37%) were male and 63(63%) were female. The mean age of the patients was 44.25±12.75 years. Five (5%) patients were lost to follow-up during the study, while 7(7%) patients changed their initial treatment because they did not experience relief. Silicone heel pad reported a better outcome measure associated with the patient\'s heel pain as 74(84.09%) patients resolved their condition or reached a tolerance level and showed preferable reduction in heel pain .There were statistically significant difference between pain relieved and treatment duration (p=0.039). CONCLUSIONS: Conservative intervention with silicone heel pad showed relief from heel pain and it allowed the patient to manage the condition more effectively with no complications but for shortterm. It was less effective in the long term.