Treatment of adult patients with acute lymphoblastic leukemia in the Czech Republic in the period 2007-2020.

BACKGROUND: Pediatric-inspired protocols with prospective monitoring of minimal residual disease (MRD) are considered the standard of intensive treatment for adults with acute lymphoblastic leukemia (ALL). They have been used in the Czech Republic since 2007. PATIENTS AND METHODS: Two hundred and ninety-seven patients aged 18-65 years were treated at five hematology centers between 2007-2020 according to the GMALL 07/2003 protocol. This is a retrospective analysis of their treatment outcomes. RESULTS: In the Ph-negative cohort, 189 (93.1%) patients achieved complete remission, 5 (2.4%) patients were refractory, and early mortality was 3.0%. Seventy (34.5%) patients experienced relapse in a median of 10.6 months. Overall survival (OS) at 3 and 5 years was 63.5% and 55.9%, disease-free survival (DFS) at 3 and 5 years was 54.5% and 49.7%, respectively. Young adults under 35 years of age (P = 0.015), patients without initial CNS infiltration (P = 0.016), with MRD negativity before consolidation treatment (P < 0.001), transplanted in the 1st complete remission (P < 0.001), and subjects treated after 2012 (P = 0.05) had significantly better overall survival. In a multivariate analysis, MRD at week 11 was the only independent factor affecting OS (HR 3.06; P = 0.006). For DFS, baseline CNS infiltration (HR 2.08; P = 0.038) and MRD at week 11 (HR 2.15; P = 0.020) were significant. In the Ph-positive cohort, 84 (89.4%) patients achieved complete remission, 1 (1.0%) patient was refractory, early mortality was 4.3%. Twenty-six (27.7%) patients relapsed in a median of 8.6 months. Survival at 3 and 5 years was 57.2% and 52.4% for OS and 50.2% and 44.9% for DFS, respectively. Transplanted patients and patients diagnosed after 2012 had statistically better overall survival (P < 0.001). CONCLUSION: The introduction of pediatric-inspired protocols with treatment intensification according to MRD levels resulted in a significant improvement in the survival outcomes of adult patients with ALL.

Therapy of Relapsed/Refractory Acute Lymphoblastic Leukemia Today and Tomorrow.

BACKGROUND: New diagnostics and treatments, including the use of new drugs, have advanced considerably the treatment of acute lymphoplastic leukemia (ALL) in the past few years. Monoclonal antibodies and immunoconjugates targeting antigens CD19 and CD22 show greater efficacy and more favourable toxicity profiles than standard salvage chemotherapeutic protocols. Two of these drugs - blinatumomab and inotuzumab ozogamicin - have already made their way into clinical practice. Ponatinib and other new generation tyrosine kinase inhibitors allow dose reduction of intensive cytostatic regimens in Ph-positive ALL patients and slowly start to overshadow the importance of allogeneic hematopoietic cell transplants. For the time being, their use is reserved for relapsed/refractory ALL, but they are already available as a first line therapy in clinical trials. An entirely new group of living drugs is emerging for the treatment of ALL - chimeric antigen receptor T-cells produced by genetic modification of native human cells. Chimeric antigen receptor T-cells can be looked upon as in vitro trained professional blast killers. They show an efficacy never seen before for the treatment of relapsed/refractory ALL. On the other hand, this treatment still presents significant risks, mainly due to cytokine release syndrome. Ruxolitinib, mTOR inhibitors, bortezomib, and other drugs for targeted treatment of ALL are currently being evaluated in clinical trials. PURPOSE: The article focuses on current options and news in the field of relapsed and refractory ALL treatment. This work was created at Masaryk University as part of the project “New Approaches in Research, Diagnostics and Therapy of Hematological Malignancies VI”, number MUNI/A/1105/2018, supported by Czech Ministry of Education, Youth and Sports in 2019.  The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 28. 8. 2018 Accepted: 10. 1. 2019.

Reasons for non-adherence to nicotine patch therapy during the first month of a quit attempt.

INTRODUCTION: Prior research has shown that the transdermal nicotine patch is a safe and effective aid to smoking cessation, but adherence to the directed use of the nicotine patch is often low. Few studies have examined participant-reported reasons for non-adherence to nicotine patch therapy during a quit attempt. AIMS: The aim of this study was to evaluate adherence to nicotine patch therapy and to identify participant-reported reasons for non-adherence. METHODS: Participants were 201 current daily smokers who were offered 6-weekly group treatment sessions and were asked to report nicotine patch use and barriers to use. RESULTS: Seventy-one (35.3%) participants were adherent for the first 28 days of treatment and 130 (64.7%) participants were non-adherent. Commonly reported reasons for non-adherence were forgetting to put the patch on (30%), not liking the experienced side effects (15%), resuming smoking (10%) and difficulty affording the cost of the patches (7%). CONCLUSIONS: Participant- reported barriers to adherence of nicotine patch therapy can be mitigated with advice from healthcare providers. Some examples of advice to patients could include carrying an extra patch, using community resources to obtain free or reduced cost nicotine patches, reviewing the effectiveness of nicotine replacement, and explaining side effects associated with the use of the nicotine patch.

Once bitten, twice shy: concern about gaining weight after smoking cessation and its association with seeking treatment.

BACKGROUND: Concern about weight gain after quitting smoking is often cited as a barrier to smokers making a quit attempt or seeking treatment. AIM: To identify whether smokers who are non-treatment seekers (NTS) are more concerned about weight gain and have lower confidence to maintain weight after quitting smoking as compared with treatment-seeking smokers (TS). METHODS: Participants were smokers recruited from Penn State Hershey Medical Center and family practice outpatient clinics. A total of 102 NTS and 186 TS, who participated in a smoking cessation trial, completed a survey regarding tobacco use, weight concern and diet. Stepwise logistic regression was used to identify variables associated with treatment seeking, overall and stratified by those who gained and did not gain weight on a previous quit attempt. RESULTS: Fifty three per cent of the overall sample (47.1% NTS vs. 56.5% TS, p = 0.127) had gained weight on a prior quit attempt. Among smokers who had gained weight, higher weight gain concern (WGC) and lower confidence in ability to maintain weight were significantly associated with being a NTS after adjusting for other factors. CONCLUSION: Among smokers who gained weight on a previous quit attempt, NTS had greater concern about gaining weight and less confidence in their ability to maintain their weight after quitting than treatment seekers. Clinicians can identify smokers for whom WGC may be a barrier to seeking treatment by asking if they gained weight on a previous quit attempt. These smokers should be assured that this issue will be addressed in treatment.

Immunosuppressive effects of silicon phthalocyanine photodynamic therapy.

The purpose of this study was to determine if silicon phthalocyanine 4 (Pc 4), a second-generation photosensitizer being evaluated for the photodynamic therapy (PDT) of solid tumors, was immunosuppressive. Mice treated with Pc 4 PDT 3 days before dinitrofluorobenzene sensitization showed significant suppression of their cell-mediated immune response when compared to mice that were not exposed to PDT. The response was dose dependent, required both Pc 4 and light and occurred at a skin site remote from that exposed to the laser. The immunosuppression could not be reversed by in vivo pre-treatment of mice with antibodies to tumor necrosis factor-alpha or interleukin-10. These results provide evidence that induction of cell-mediated immunity is suppressed after Pc 4 PDT. Strategies that prevent PDT-mediated immunosuppression may therefore enhance the efficacy of this therapeutic modality.

Preoperative and postoperative skin care with laser resurfacing.

Laser resurfacing has become a commonly used technique for the treatment of a variety of skin conditions including facial actinic damage, rhytides, and acne scarring. Although the procedure has the ability to deliver consistently good results with an excellent safety profile, complications do occur even in the best of hands. Independent of the type of laser used or the surgical technique, the risk of complications and the final outcome can be greatly influenced by the care of the skin before and after the procedure. This article will focus on the preoperative assessment of the patient, the concept of preconditioning the skin, and postoperative wound management after laser resurfacing. Various occlusive dressing products will be discussed, as well as their role in wound healing. A pre- and posttreatment skin care regimen will be provided to use as a guide in the management of patients undergoing laser resurfacing.

Phthalocyanine photodynamic therapy: disparate effects of pharmacologic inhibitors on cutaneous photosensitivity and on tumor regression.

The phthalocyanines are promising second-generation photosensitizers that are being evaluated for the photodynamic therapy (PDT) of malignant tumors. In vivo studies with the silicon phthalocyanine Pc 4 have shown that it is highly effective at causing regression of RIF-1 tumors in C3H/HeN mice in PDT protocols. Because cutaneous photosensitivity is the major complication of photosensitizers used for PDT, experiments were performed to evaluate the effect of inhibitors of the inflammatory response (cyproheptadine, dexamethasone, pentoxifylline, and tumor necrosis factor alpha [TNF-alpha] antibodies) on Pc 4-induced cutaneous photosensitivity and tumor regression. The C3H/HeN mice were injected with either Pc 4 or Photofrin and were exposed to 86 J/cm2 of filtered radiation emitted from a solar simulator. Animals were irradiated at 1, 3, 7, 10, 14 and 28 days postinjection. Cutaneous photosensitivity was assessed using the murine ear-swelling response. Cyproheptadine, dexamethasone, pentoxifylline and TNF-alpha antibodies were administered prior to illumination to assess their ability to block Pc 4-induced cutaneous photosensitivity and to evaluate whether such treatment adversely influenced Pc 4 PDT-induced tumor regression. Compared to Photofrin, Pc 4 produced cutaneous photosensitivity that was transient, resolving within 24 h, and that could be elicited for only 10 days after administration. In contrast, Photofrin caused photosensitivity that required 4 days to resolve and could be elicited for at least 1 month after it was administered. The Pc 4-induced cutaneous photosensitivity could be blocked by corticosteroids and an inhibitor of vasoactive amines (cyproheptadine). The TNF-alpha gene transcription was found to increase in keratinocytes following treatment with Pc 4 and light. The anti-TNF-alpha antibodies and pentoxifylline, an inhibitor of cytokine transcription, also prevented cutaneous photosensitivity, implicating TNF-alpha in the pathogenesis of Pc 4-induced cutaneous photosensitivity. None of these agents had any effect on Pc 4 PDT-induced tumor regression. Cyproheptadine, dexamethasone, pentoxifylline and TNF-alpha antibodies may be valuable pharmacologic agents in the management of cutaneous photosensitivity associated with PDT without altering the efficacy of this new therapeutic modality. The findings suggest that it should be possible to devise PDT protocols that block cutaneous photosensitivity without impairing the anti-tumor response to the agents.

Basal cell carcinomas display extensive abnormalities in the hemidesmosome anchoring fibril complex.

We have employed a panel of antibodies directed against several newly-defined and well-characterized components of the epidermal basement membrane (BM) to investigate the biology of basal cell carcinoma (BCC) by indirect immunofluorescence and to determine whether alterations in BM components may play a significant role in BCC tumor invasion. We found that the 230 KD bullous pemphigoid antigen (BPA) was either not detected (13/16) or significantly diminished (3/16) in BCC tumor BM. While the 180 KD BPA revealed less intense staining of the normal overlying epidermal BM than did the 230 KD BPA, the 180 KD BPA was uniformly undetectable in BCC tumor BM (16/16). Epiligrin was either not detected (9/15) or minimally detected (6/15) in BCC tumor BM. alpha 6 integrin was not detected (15/16) or minimally detected (1/16) in BCC tumor BM, whereas beta 4 integrin was uniformly undetectable in BCC tumor BM (16/16). Type VII collagen was also not detected (9/16) or was significantly diminished (4/16) in BCC tumor BM. Laminin and type IV collagen were both at least as strong in BCC tumor BM as in adjacent normal BM. All of these components were present both in the epidermis of normal skin as well as in the normal epidermal BM overlying BCC tumor nests. Our findings reveal extensive alterations in numerous components of the hemidesmosome anchoring fibril complex of BCC's. As this complex is thought to play an important part in epidermal cell adhesion to the BM, our findings suggest that these extensive BM abnormalities may facilitate or contribute to BCC tumor invasion.

Acute myocardial infarction and sudden death in Sioux Indians.

While some Indian tribes have low rates of acute myocardial infarction, Northern Plains Indians, including the Sioux, have rates of morbidity and mortality from acute myocardial infarction higher than those reported for the United States population in general. In a review of diagnosed cases of acute myocardial infarction over a 3-year period in 2 hospitals serving predominantly Sioux Indians, 8% of cases were found misclassified, and 22% failed to meet rigorous diagnostic criteria, although the patients did indeed have ischemic heart disease. Patients had high frequencies of complications and risk factors and a fatality rate of 16% within a month of admission. Sudden deaths likely due to ischemic heart disease but in persons not diagnosed as having acute myocardial infarction by chart review occurred 3 times more frequently than deaths occurring within a month of clinical diagnosis.