Caspase-Mediated Cleavage of the Transcription Factor Sp3: Possible Relevance to Cancer and the Lytic Cycle of Kaposi's Sarcoma-Associated Herpesvirus.

The open reading frame 50 (ORF50) protein of Kaposi's sarcoma-associated herpesvirus (KSHV) is the master regulator essential for initiating the viral lytic cycle. Previously, we have demonstrated that the ORF50 protein can cooperate with Sp3 to synergistically activate a set of viral and cellular gene promoters through highly conserved ORF50-responsive elements that harbor a Sp3-binding motif. Herein, we show that Sp3 undergoes proteolytic cleavage during the viral lytic cycle, and the cleavage of Sp3 is dependent on caspase activation. Since similar cleavage patterns of Sp3 could be detected in both KSHV-positive and KSHV-negative lymphoma cells undergoing apoptosis, the proteolytic cleavage of Sp3 could be a common event during apoptosis. Mutational analysis identifies 12 caspase cleavage sites in Sp3, which are situated at the aspartate (D) positions D17, D19, D180, D273, D275, D293, D304 (or D307), D326, D344, D530, D543, and D565. Importantly, we noticed that three stable Sp3 C-terminal fragments generated through cleavage at D530, D543, or D565 encompass an intact DNA-binding domain. Like the full-length Sp3, the C-terminal fragments of Sp3 could still retain the ability to cooperate with ORF50 protein to activate specific viral and cellular gene promoters synergistically. Collectively, our findings suggest that despite the proteolytic cleavage of Sp3 under apoptotic conditions, the resultant Sp3 fragments may retain biological activities important for the viral lytic cycle or for cellular apoptosis. IMPORTANCE The ORF50 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) is the key viral protein that controls the switch from latency to lytic reactivation. It is a potent transactivator that can activate target gene promoters via interacting with other cellular DNA-binding transcription factors, such as Sp3. In this report, we show that Sp3 is proteolytically cleaved during the viral lytic cycle, and up to 12 caspase cleavage sites are identified in Sp3. Despite the proteolytic cleavage of Sp3, several resulting C-terminal fragments that have intact zinc-finger DNA-binding domains still retain substantial influence in the synergy with ORF50 to activate specific gene promoters. Overall, our studies elucidate the caspase-mediated cleavage of Sp3 and uncover how ORF50 utilizes the cleavage fragments of Sp3 to transactivate specific viral and cellular gene promoters.

Lymphoma in Pediatric-Onset Inflammatory Bowel Disease Treated with Infliximab Monotherapy: A Case Series.

BACKGROUND: Inflammatory bowel diseases (IBD) are often treated with anti-tumor necrosis factor alpha (anti-TNFα) medications. Concomitant treatment of IBD with anti-TNFα agents and immunomodulators appears to be associated with an increased risk for lymphoma. METHODS: Patients who developed lymphoma while on monotherapy with an anti-TNFα agent were identified at three centers. Institutional Review Board approval was obtained. RESULTS: Five adolescents and young adult patients with pediatric-onset IBD who were treated with infliximab (IFX) without exposure to thiopurines were subsequently diagnosed with lymphoma. Three of the five patients had bone involvement at presentation. Epstein-Barr virus was positive in 2 cases. Median time from diagnosis of IBD and exposure to IFX prior to diagnosis of lymphoma was 5 and 4.3 years, respectively. CONCLUSIONS: This case series reports long-term follow-up for young patients with IBD who were treated with IFX monotherapy and developed lymphoma. Three of the five patients had bone involvement. In general, the risk of lymphoma following exposure to anti-TNFα medications alone remains low, but the incidence of primary bone lymphomas in IBD has not been reported. Studies examining longer exposure times may be needed to determine the true lymphoma risk in patients treated with IFX monotherapy.

KSHV transactivator-derived small peptide traps coactivators to attenuate MYC and inhibits leukemia and lymphoma cell growth.

In herpesvirus replicating cells, host cell gene transcription is frequently down-regulated because important transcriptional apparatuses are appropriated by viral transcription factors. Here, we show a small peptide derived from the Kaposi's sarcoma-associated herpesvirus transactivator (K-Rta) sequence, which attenuates cellular MYC expression, reduces cell proliferation, and selectively kills cancer cell lines in both tissue culture and a xenograft tumor mouse model. Mechanistically, the peptide functions as a decoy to block the recruitment of coactivator complexes consisting of Nuclear receptor coactivator 2 (NCOA2), p300, and SWI/SNF proteins to the MYC promoter in primary effusion lymphoma cells. Thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM seq) with target-transcriptional analyses further confirm that the viral peptide directly attenuates MYC and MYC-target gene expression. This study thus provides a unique tool to control MYC activation, which may be used as a therapeutic payload to treat MYC-dependent diseases such as cancers and autoimmune diseases.

18F-FDG PET/CT imaging in the diagnosis of drug-induced lung disease and pulmonary infection in lymphoma.

OBJECTIVE: Lymphoma is a hematological disease with high prevalence. Multi-cycle chemotherapy (CHT) or local radiotherapy is applied usually; however, adverse events have been reported, such as drug-induced lung disease (DILD). Positron emission tomography/computed tomography (PET/CT) is often used to evaluate the lesion, treatment effect, and prognosis of lymphoma. We investigated DILD and pulmonary infection (PI) after multi-cycle CHT in lymphoma patients, to identify DILD and PI, provide guidance for later treatment for them. METHODS: In all, 677 patients diagnosed with lymphoma and who underwent CHT were included. These patients underwent 18fluorodeoxyglucose (18F-FDG) PET/CT before and after CHT at Shandong Cancer Hospital (affiliated with Shandong University) between April 2015 and November 2019. Fifty patients developed DILD, 41 patients had lung infections; lesion characteristics were analyzed based on clinical characteristics, laboratory examinations, and PET/CT imaging. RESULTS: Among the 677 lymphoma patients, there were 50 cases of DILD, with an incidence rate of 7.4%. PET/CT showed an elevated 18fluorodeoxyglucose uptake lung background, septal thickening and reticulation, multiple ground glass-like shadows, and grid-shaped blur shadows, which were more common in the lung periphery and under the pleura. The maximum standardized uptake value in the lung was 2.45 ±â€Š0.52. Pulmonary infections occurred in 41 patients, and the maximum standardized uptake value was 4.05 ±â€Š1.42. Age, sex, CHT cycle, Ann-Arbor stage, and lymphocyte levels were not significantly different between DILD and PI patients. Leukocyte and neutrophils showed significant differences; the PI patients had increased laboratory indexes of leukocyte and neutrophils. The mean number of CHT cycles was 4 cycles for DILD and PI. CONCLUSIONS: PET/CT imaging has high sensitivity and detection rates for primary and metastatic lymphoma lesions. DILD mostly occurs in the middle and late stages of CHT. Laboratory tests and PET/CT can evaluate the lesions and treatment effects, and provide guidance for subsequent treatment plans for patients.

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic.

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.

Primary extraperitoneal rectum lymphoma in AIDS patient / Linfoma primário de reto extraperitoneal em paciente SIDA

ABSTRACT Introduction The gastrointestinal lymphoma can be classified in primary or secondary, and this is important regarding diagnosis and subsequent treatment. Primary gastrointestinal lymphoma of the rectum is rare and therefore lacks data in medical literature. Its incidence has been increasing and that fact may be related to a higher incidence in immunosuppressive therapy and immunosuppressive diseases (such as AIDS). Metodology 19 articles have been reviewed, searched online on the Scielo and PubMed databases. The goal was to increase data available regarding this pathology and improve its therapy. Discussion Primary GI lymphoma of the rectum presents as hematochezia, rectal pain, change in bowel habits. PET/CT is the first choice exam to pursue investigation; however abdominal CT and MRI reveal sufficient information and are much more available in daily practice. Plasmablastyc lymphoma is an aggressive subtype and is usually associated with AIDS patients. There are no available treatment protocols for this specific type of lymphoma and colonic lymphoma's therapy is usually used for this patient (such as ECHOP and CHOP). Conclusion As rare as this pathology is, this article aims to improve the available data and provide useful information regarding diagnosis and therapy.

RESUMO Introdução O linfoma do TGI pode ser dividido entre primário e secundário, com importância diagnóstica e terapêutica. O linfoma primário de reto é patologia rara, pouco relatada em literatura médica. Sua incidência tem aumentado e possivelmente esse fenômeno esteja associado ao aumento no numero de pacientes com imunossupressão (seja por SIDA ou drogas imunossupressoras). Metodologia Foram revisados 19 artigos nas bases de dados Scielo e PubMed, com o objetivo de aumentar o número de relatos dessa patologia e consequentemente expandir o conhecimento disponível, visando melhorar a terapêutica e, principalmente, o diagnóstico desse tipo de linfoma. Discussão Quando o linfoma tem seu sítio primário no reto, as principais manifestações são sangramento, dor retal, tenesmo e mudança nos hábitos intestinais (diarreia ou constipação). O exame de investigação de escolha é o PET/CT, porém a TC e RNM fornecem as informações necessárias e são mais disponíveis na prática clínica. O linfoma plasmablástico é um subtipo bastante agressivo e associado aos pacientes com SIDA. Não existem ainda protocolos definidos para o tratamento do linfoma primário de reto, sendo optado por seguir a mesma terapêutica dos linfomas de cólon com esquemas EPOCH e CHOP. Conclusão Por se tratar de patologia rara e pouco descrita na literatura, espera-se que este relato contribua na formação de protocolos de tratamento específicos.

Cervical lymphadenopathy in children: a diagnostic tree analysis model based on ultrasonographic and clinical findings.

OBJECTIVES: To establish a diagnostic tree analysis (DTA) model based on ultrasonography (US) findings and clinical characteristics for differential diagnosis of common causes of cervical lymphadenopathy in children. METHODS: A total of 242 patients (131 boys, 111 girls; mean age, 11.2 ± 0.3 years; range, 1 month-18 years) with pathologically confirmed Kikuchi disease (n = 127), reactive hyperplasia (n = 64), lymphoma (n = 24), or suppurative lymphadenitis (n = 27) who underwent neck US were included. US images were retrospectively reviewed to assess lymph node (LN) characteristics, and clinical information was collected from patient records. DTA models were created using a classification and regression tree algorithm on the basis of US imaging and clinical findings. The patients were randomly divided into training (70%, 170/242) and validation (30%, 72/242) datasets to assess the diagnostic performance of the DTA models. RESULTS: In the DTA model based on all predictors, perinodal fat hyperechogenicity, LN echogenicity, and short diameter of the largest LN were significant predictors for differential diagnosis of cervical lymphadenopathy (overall accuracy, 85.3% and 83.3% in the training and validation datasets). In the model based on categorical parameters alone, perinodal fat hyperechogenicity, LN echogenicity, and loss of fatty hilum were significant predictors (overall accuracy, 84.7% and 86.1% in the training and validation datasets). CONCLUSIONS: Perinodal fat hyperechogenicity, heterogeneous echotexture, short diameter of the largest LN, and loss of fatty hilum were significant US findings in the DTA for differential diagnosis of cervical lymphadenopathy in children. KEY POINTS: • Diagnostic tree analysis model based on ultrasonography and clinical findings would be helpful in differential diagnosis of pediatric cervical lymphadenopathy. • Significant predictors were perinodal fat hyperechogenicity, heterogeneous echotexture, short diameter of the largest LN, and loss of fatty hilum.

Impact of the Conditioning Regimen Dose Intensity Before Autologous Stem Cell Transplantation on the Pulmonary Function Test Abnormalities in Patients With Lymphoma and Multiple Myeloma: Single Center Experience.

BACKGROUND: Most studies addressing the impact of hematopoietic stem cell transplantation (SCT) on pulmonary function test (PFT), and the various factors affecting that impact have been performed on the allogenic type. Few have addressed PFT changes in autologous SCT. This study describes PFT changes seen in autologous SCT recipients and addresses the various factors impacting these changes. PATIENTS AND METHODS: We reviewed the medical records of 223 consecutive adult autologous SCT recipients. We collected pre-transplant and post-transplant data, as well as PFT data and long-term mortality. RESULTS: A total of 123 patients with lymphoma receiving the BEAM (carmustine, etoposide, aracytin, and melphalan) conditioning regimen had a significant 5% drop in mean forced vital capacity and total lung capacity but no significant change in forced expiratory volume in one second/forced vital capacity ratio nor in diffusion lung capacity of carbon monoxide adjusted to volume. Fifteen percent of the patients with lymphoma had a clinically significant drop of 15% in their lung volume parameters. The patients with multiple myeloma receiving the melphalan conditioning regimen had no significant change in any of the PFT parameters. Smoking, baseline PFT parameters, and radiation did not affect lung function or mortality. CONCLUSIONS: Autologous SCT impact on lung function depends on the disease and conditioning regimen. It leads to a drop in lung volumes but no obstruction or decrease in diffusion in patients with lymphoma receiving the BEAM regimen. Autologous SCT did not affect lung functions in patients with multiple myeloma, and these patients may not need screening PFTs.

Impact of extent and biochemical parameters of lymphoma on fertility preservation outcome.

OBJECTIVE: To evaluate the impact of lymphoma aggressiveness on ovarian response during fertility preservation treatment. DESIGN: Retrospective cohort study. SETTING: University-affiliated tertiary hospital. PATIENT(S): Women with lymphoma who underwent ovarian stimulation for fertility preservation in the period from 2009 to 2018. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome: the number of mature oocytes; secondary outcomes: the number of retrieved oocytes, estradiol level, and number of follicles >14 mm on the day of oocyte maturation trigger. RESULT(S): Patients with stage I-II lymphoid neoplasms (localized disease) were compared with those with stage III-IV lymphomas (advanced disease). Women with favorable levels of biochemical prognostic markers were also compared with those with unfavorable levels. Women with favorable levels of biochemical prognostic markers (n = 74) had a higher number of mature oocytes compared with patients with unfavorable serum levels (n = 67): 11 (7.8-16) versus 9 (5-11), respectively. The number of mature oocytes was similar between patients with localized (n = 75) and advanced (n = 66) lymphomas. Women with unfavorable combination of stage and biochemical factors had lower number of mature oocytes compared to patients with favorable combination: 8 (5-10) versus 11 (7-16), respectively. Multivariate logistic regression showed that favorable levels of biochemical markers as well as a combination of extent and biochemical parameters were statistically significantly associated with the result of over 10 mature oocytes. CONCLUSION(S): Highly-aggressive lymphoid neoplasms have a negative impact on ovarian function and response during fertility preservation treatment.

DNA-PKcs has KU-dependent function in rRNA processing and haematopoiesis.

The DNA-dependent protein kinase (DNA-PK), which comprises the KU heterodimer and a catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) factor1. KU binds to DNA ends, initiates cNHEJ, and recruits and activates DNA-PKcs. KU also binds to RNA, but the relevance of this interaction in mammals is unclear. Here we use mouse models to show that DNA-PK has an unexpected role in the biogenesis of ribosomal RNA (rRNA) and in haematopoiesis. The expression of kinase-dead DNA-PKcs abrogates cNHEJ2. However, most mice that both expressed kinase-dead DNA-PKcs and lacked the tumour suppressor TP53 developed myeloid disease, whereas all other previously characterized mice deficient in both cNHEJ and TP53 expression succumbed to pro-B cell lymphoma3. DNA-PK autophosphorylates DNA-PKcs, which is its best characterized substrate. Blocking the phosphorylation of DNA-PKcs at the T2609 cluster, but not the S2056 cluster, led to KU-dependent defects in 18S rRNA processing, compromised global protein synthesis in haematopoietic cells and caused bone marrow failure in mice. KU drives the assembly of DNA-PKcs on a wide range of cellular RNAs, including the U3 small nucleolar RNA, which is essential for processing of 18S rRNA4. U3 activates purified DNA-PK and triggers phosphorylation of DNA-PKcs at T2609. DNA-PK, but not other cNHEJ factors, resides in nucleoli in an rRNA-dependent manner and is co-purified with the small subunit processome. Together our data show that DNA-PK has RNA-dependent, cNHEJ-independent functions during ribosome biogenesis that require the kinase activity of DNA-PKcs and its phosphorylation at the T2609 cluster.

Lymphoma: Diagnosis and Treatment.

Lymphoma is a group of malignant neoplasms of lymphocytes with more than 90 subtypes. It is traditionally classified broadly as non-Hodgkin or Hodgkin lymphoma. Approximately 82,000 new U.S. patients are diagnosed with lymphoma annually. Any tobacco use and obesity are major modifiable risk factors, with genetic, infectious, and inflammatory etiologies also contributing. Lymphoma typically presents as painless adenopathy, with systemic symptoms of fever, unexplained weight loss, and night sweats occurring in more advanced stages of the disease. An open lymph node biopsy is preferred for diagnosis. The Lugano classification system incorporates symptoms and the extent of the disease as shown on positron emission tomography/computed tomography to stage lymphoma, which is then used to determine treatment. Chemotherapy treatment plans differ between the main subtypes of lymphoma. Non-Hodgkin lymphoma is treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab (R-CHOP), bendamustine, and lenalidomide. Hodgkin lymphoma is treated with combined chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), Stanford V (a chemotherapy regimen consisting of mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone), or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) with radiotherapy. Subsequent chemotherapy toxicities include neuropathy, cardiotoxicity, and secondary cancers such as lung and breast, and should be considered in the shared decision-making process to select a treatment regimen. Once remission is achieved, patients need routine surveillance to monitor for complications and relapse, in addition to age-appropriate screenings recommended by the U.S. Preventive Services Task Force. Patients should receive a 13-valent pneumococcal conjugate vaccine followed by a 23-valent pneumococcal polysaccharide vaccine at least eight weeks later with additional age-appropriate vaccinations because lymphoma is an immunosuppressive condition. Household contacts should also be current with their immunizations.

Aggressive Inflammatory Myofibroblastic Tumor without Anaplastic Lymphoma Kinase Gene Rearrangement in the Rectum with Liver Metastasis.

Inflammatory myofibroblastic tumor is a rare intermediate-grade tumor. We herein report the case of an 81-year-old man with rectal ulceration and abnormal retroperitoneal soft tissue with a high serum level of IgG4. The administration of prednisolone reduced the retroperitoneal lesion; however, the rectal ulceration expanded. Surgical resection was performed. A histopathological examination revealed proliferating spindle cells accompanied by inflammatory cells and plasma cells. Liver metastasis emerged two months after surgical resection, and the histology of the proliferating spindle cells sampled by a fine-needle biopsy was similar to that of the rectal tissue. The patient ultimately died of inflammatory myofibroblastic tumor.

Can antineutrophil cytoplasmic antibody positivity at diagnosis predict the poor outcomes of Sjögren's syndrome?

We investigated the clinical implication of ANCA positivity at diagnosis on the poor outcomes in patients with Sjögren's syndrome. The medical records of 606 Korean patients with Sjögren's syndrome were retrospectively reviewed. The results of perinuclear (P)-ANCA, myeloperoxidase (MPO)-ANCA, cytoplasmic (C)-ANCA, and proteinase 3 (PR3)-ANCA were collected and the frequencies of all-cause mortality, interstitial lung disease (ILD), end-stage renal disease (ESRD), and lymphoma were assessed as the poor outcomes of Sjögren's syndrome. Comparison of the cumulative patient survivals between the two groups was analysed by the Kaplan-Meier survival analysis. Of the 606 patients, ANCA was detected in 10.2% of Sjögren's syndrome patients without AAV. Twenty-one patients (3.5%) died, 99 patients (16.3%) suffered from ILD, and 8 patients had ESRD. Lymphoma occurred in 5 patients (0.8%) during 37.5 months. Sjögren's syndrome patients with ANCA positivity exhibited a lower cumulative ILD-free survival rate than those with ANCA negativity (P = 0.001). Sjögren's syndrome patients with P-ANCA positivity and those with MPO-ANCA (or P-ANCA) positivity showed a lower cumulative ILD-free survival rate than those without (P = 0.012 and P < 0.001). Also, Sjögren's syndrome patients with P-ANCA positivity exhibited a lower cumulative ESRD-free survival rate than those without (P = 0.043). ANCA positivity was associated with neither all-cause mortality nor lymphoma in Sjögren's syndrome patients. ANCA positivity and MPO-ANCA (or P-ANCA) positivity at diagnosis was associated with the development of ILD during follow-up in patients with Sjögren's syndrome.

Sperm DNA integrity in adult survivors of paediatric leukemia and lymphoma: A pilot study on the impact of age and type of treatment.

Childhood cancer survivors (CCS) are more likely than siblings to report low sperm count and to use assisted reproductive technologies. Yet, it is still unclear if the sperm produced many years after remission of cancer display DNA and chromatin damage linked to male infertility and poor embryo development. As well, the importance of the age at diagnosis in relation to puberty is poorly understood. In this pilot study, we compared reproductive parameters and sperm damage from adult survivors of childhood leukemia and lymphoma, sub-divided into those diagnosed before or after puberty, to men with no history of cancer. Our data indicate that CCS, independently of the age of diagnosis, have a high risk of low sperm count and when sperm are present, chances of DNA and chromatin abnormalities appear similar to those seen in the general population. Exposure to alkylating agents is correlated with low sperm count whereas exposure to anthracyclines, and doxorubicin in particular, could have long-term consequences on sperm integrity. This study highlights the need for further research on fertility among male CCS and the importance of informing families about the potential long-term impact of chemotherapy on male fertility regardless of age at diagnosis.

Do total parenteral nutrition and bowel rest reduce the risk for perforation in patients with gastrointestinal tract lymphoma receiving chemotherapy?

OBJECTIVES: Gastrointestinal tract (GIT) lymphoma is associated with a risk for perforation while the patient is receiving chemotherapy. The role of total parenteral nutrition (TPN) and bowel rest in preventing perforation is unknown. The aim of this study was to examine the clinical outcomes of TPN and bowel rest in patients with GIT lymphoma who were receiving chemotherapy. METHODS: We reviewed all patients with GIT biopsy-proven lymphoma in our institution between 2013 and 2017. Patients were stratified into two groups, with and without TPN and bowel rest during chemotherapy. We identified 158 patients with GIT lymphoma. Of these, 47 (29.7%) received TPN and bowel rest before chemotherapy. Patients who received TPN were younger, more likely to have aggressive lymphoma in the small or large bowel. The primary outcome was to compare the perforation rate between the two groups. Secondary outcome analysis included infection rate and survival. RESULTS: Patients with perforation had significantly poorer survival. Perforation rate was similar between the TPN and the non-TPN groups (8.5% versus 2.7%, P = 0.197). Overall survival was similar between the two groups (P = 0.659). The TPN group had a higher infection rate (odds ratio, 5.32; 95% confidence interval, 1.36-20.8) after adjustment for covariates (age, types of lymphoma, and location of lymphoma). CONCLUSION: The present study demonstrated that TPN and bowel rest did not reduce the risk for perforation among patients with GIT lymphoma who were receiving chemotherapy. As the practice of prophylactic TPN and bowel rest was associated with higher infection risk and longer hospitalization, we do not recommend such practice for all patients with GIT lymphoma receiving chemotherapy.

Impact of organ motion on volumetric and dosimetric parameters in stomach lymphomas treated with intensity-modulated radiotherapy.

PURPOSE: Interplay effects may influence dose distributions to a moving target when using dynamic delivery techniques such as intensity-modulated radiotherapy (IMRT). The aim of this study was to evaluate the impact of organ motion on volumetric and dosimetric parameters in stomach lymphomas treated with IMRT. METHODS: Ten patients who had been treated with IMRT for stomach lymphomas were enrolled. The clinical target volume (CTV) was contoured as the whole stomach. Considering interfractional uncertainty, the internal target volume (ITV) margin was uniformly 1.5 cm to the CTV and then modified based on the 4DCT images in case of the large respiratory motion. The planning target volume (PTV) was created by adding 5 mm to the ITV. The impact of organ motion on the volumetric and dosimetric parameters was evaluated retrospectively (4D simulation). The organ motion was reproduced by shifting the isocenter on the radiation treatment planning system. Several simulation plans were created to test the influence of the beam-on timing in the respiration cycle on the dose distribution. The homogeneity index (HI), volume percentage of stomach covered by the prescribed dose (Vp ), and D99 of the CTV were evaluated. RESULTS: The organ motion was the largest in the superior-inferior direction (10.1 ± 4.5 mm [average ± SD]). Stomach volume in each respiratory phase compared to the mean volume varied approximately within a ± 5% range in most of the patients. The PTV margin was sufficiently large to cover the CTV during the IMRT. There was a significant reduction in Vp and D99 but not in HI in the 4D simulation in free-breathing and multiple fractions compared to the clinically-used plan (P < 0.05) suggesting that interplay effects deteriorate the dose distribution. The absolute difference of D99 was less than 1% of the prescribed dose. CONCLUSIONS: There were significant interplay effects affecting the dose distribution in stomach IMRT. The magnitude of the dose reduction was small when patients were treated on free-breathing and multiple fractions.

Max deletion destabilizes MYC protein and abrogates Eµ-Myc lymphomagenesis.

Although MAX is regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is poorly defined. We show that B-cell-specific deletion of Max has a modest effect on B-cell development but completely abrogates Eµ-Myc-driven lymphomagenesis. While Max loss affects only a few hundred genes in normal B cells, it leads to the global down-regulation of Myc-activated genes in premalignant Eµ-Myc cells. We show that the balance between MYC-MAX and MNT-MAX interactions in B cells shifts in premalignant B cells toward a MYC-driven transcriptional program. Moreover, we found that MAX loss leads to a significant reduction in MYC protein levels and down-regulation of direct transcriptional targets, including regulators of MYC stability. This phenomenon is also observed in multiple cell lines treated with MYC-MAX dimerization inhibitors. Our work uncovers a layer of Myc autoregulation critical for lymphomagenesis yet partly dispensable for normal development.