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Background/Aims: Paediatric primary follicular lymphoma of the testis (PPFLT) is exceptional: the few reported cases seem to lack BCL-2 gene rearrangement and/or protein expression. The aim of this study was [...]

Summary: Background: The presence of ulceration has been recognized as an adverse prognostic factor in primary cutaneous melanoma (PCM). Objectives: To investigate whether the extent of ulceration (EoU) predicts relapse‐free survival (RFS) and overall survival (OS) in PCM. Materials and methods: We retrieved data for 477 patients with ulcerated PCM from databases of the Italian Melanoma Intergroup. Univariate and multivariable Cox proportional hazard models were used to assess the independent prognostic impact of EoU. Results: A significant interaction emerged between Breslow thickness (BT) and EoU, considering both RFS (P < 0·0001) and OS (P = 0·0006). At multivariable analysis, a significant negative impact of EoU on RFS [hazard ratio (HR) (1‐mm increase) 1·26, 95% confidence interval (CI) 1·08–1·48, P = 0·0047] and OS [HR (1‐mm increase) 1·25, 95% CI 1·05–1·48, P = 0·0120] was found in patients with BT ≤ 2 mm, after adjusting for BT, age, tumour‐infiltrating lymphocytes, sentinel lymph node status and mitotic rate. No impact of EoU was found in patients with 2·01–4 mm and > 4 mm BT. Conclusions: This study demonstrates that EoU has an independent prognostic impact in PCM and should be recorded as a required element in pathology reports. What is already known about this topic? Ulceration is a well‐known prognostic factor in melanoma.There are conflicting results on the prognostic value of the extent of ulceration. What does this study add? The extent of ulceration is an independent prognostic factor in primary cutaneous melanoma with Breslow thickness (BT) ≤ 2 mm.The extent of ulceration should be incorporated into the pathology report as a required, core element.Patients with extensive ulceration with a BT ≤ 2 mm are at high risk of recurrence and should be included in prospective adjuvant trials. Linked Comment: Wilkinson and Gyorki. Br J Dermatol 2021; 184:192–193. [ABSTRACT FROM AUTHOR]

A case study a 75-year-old man with skin rash and lymphadenopathy and with chills, myalgia and diffuse arthralgias is presented. Presence of hepatosplenomegaly and diffuse lymphoadenopathy were revealed on physical examination. Epstein Barr virus (EBV) DNA were diagnosed in the patient's plasma and interstitial and perivascular infiltrates of lymphocytes were revealed in histopathology of a skin biopsy.

Competing Interests: Competing interests: None declared.

No prospective study has validated molecular classification to guide adjuvant treatment in endometrial cancer (EC), and not even retrospective data are present for patients with morphological low-risk EC. We conducted a retrospective, multicenter, observational study including 370 patients with low-risk endometrioid EC to evaluate the incidence and prognostic role of p53 abnormal expression (p53abn) in this specific subgroup. Among 370 patients, 18 had abnormal expressions of p53 (4.9%). In 13 out of 370 patients (3.6%), recurrences were observed and two were p53abn. When adjusting for median follow-up time, the odds ratio (OR) for recurrence among those with p53abn versus p53 wild type (p53wt) was 5.23-CI 95% 0.98-27.95, p = 0.053. The most common site of recurrence was the vaginal cuff (46.2%). One recurrence occurred within the first year of follow-up, and the patient exhibited p53abn. Both 1-year and 2-year DFS rates were 94.4% and 100% in the p53abn and p53wt groups, respectively. One patient died from the disease and comprised p53wt. No difference in OS was registered between the two groups; the median OS was 21.9 months (16.4-30.1). Larger multicenter studies are needed to tailor the treatment of low-risk EC patients with p53abn. Performing molecular classification on all EC patients might be cost-effective, and despite the limits of our relatively small sample, p53abn patients seem to be at greater risk of recurrence, especially locally and after two years since diagnosis.

Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is the key genetic event of CML, whereas JAK2/MPL/CALR mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of BCR::ABL1 and JAK2 has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or JAK2 aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, BCR::ABL1 translocation occurs in patients with a history of JAK2 -positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient's treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of BCR::ABL1 and JAK2 co-occurrence. The interaction between JAK2 and BCR::ABL1 clones during the disease course as well as therapy and outcome are presented., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zanelli, Bisagni, Sanguedolce, Broggi, Fragliasso, Zizzo, Palicelli, Martino, Cresta, Caprera, Corsi, Gentile, Gozzi, Trombetta, Parente, Caltabiano, Koufopoulos, Cimino, Cavazza, Fraternali Orcioni and Ascani.)

Microcystic/reticular (MRV) schwannoma has been described since 2008, but remains a rarely encountered entity. MRV has a predilection for visceral locations and has variable histologic appareances. Given its rarity and anatomic variability, this entity could raise differential diagnostic issues with other tumours and malignancies., We describe the case of a 69-year-old male followed at IRCCS Ospedale Policlinico San Martino of Genoa for his previous history of non-Hodgkin lymphoma. A para-aortic mass was discovered during follow-up, which -due to its stability, also after chemotherapy- had been hypothesized to be a non-lymphomatous lesion; given the dimensions and the site, the mass was removed. Histological evaluation showed a nodule limited by a slight fibrous capsule and characterized by a proliferation of medium-sized fusiform cells, with elongated nuclei and scarce eosinophilic cytoplasm. Given the lack of malignant signs and the strong expression of protein S-100, a diagnosis of mesenchymal neoplasia with expression of neural markers compatible with reticular schwannoma was made. The neoplasm has not recurred since its removal., The case we present is, at our best knowledge, the first described in the retroperitoneum, a site where the exclusion of other mesenchymal malignancies is mandatory. The rarity and variability of presentations could create problems of differential diagnosis both with mucinous-producing carcinomas or with other soft tissue tumours, with myxoid or reticular structure. The description of this case could help raise information on this rare neoplasm and help distinguish it from other malignancies, especially in unusual sites., (Copyright © 2022 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Varices are the main clinical manifestation of portal hypertension, and their bleeding is the predominant cause of mortality from this condition. Periumbilical varices are known as "caput medusae." Reports of their bleeding are rare, with only three fatal cases described in the literature. The antemortem diagnosis is relatively simple, while the postmortem diagnosis is more complex. This paper is the first report of fatal hemorrhage from a caput medusae for which the diagnosis was made postmortem, thanks to a complete diagnostic process including scene and circumstances, medical history, and autopsy with detailed histology. The circumstantial analysis showed the presence of a large amount of blood at the scene, blood which originated from a small abdominal wound; an analysis of the subject's clinical data reported that he was affected by portal hypertension. The autopsy revealed some dilated and convoluted veins in the subcutaneous tissue of the umbilical region; a fistula between these veins and the abdominal wound was detected. The histological study confirmed the presence of periumbilical varices, one of them ruptured and connected with the overlying skin. The cause of death was attributed to a massive hemorrhage generated by a periumbilical varix in a patient affected by portal hypertension., (© 2020 American Academy of Forensic Sciences.)

Acute myeloid leukemia (AML) is characterized by the rapid growth of abnormal white blood cells in the bone marrow that interferes with the production of normal blood cells. This disease is burdened by a high risk of bleeding complications involving central nervous system hemorrhages, purpura, gingival bleeding, and gastrointestinal bleeding. In this article, the authors report a case of a fatal intracerebral hemorrhage in a 21-year-old man who was affected by an undiagnosed AML. The subject practiced a combat sport (Muay Thai), and 2 days before his last training, he was involved in a fight where the aggressor punched him in the face; however, after the fight, he did not claim of any symptoms. The current case highlights the importance of the role of the forensic pathologist because only through a careful and complete circumstantial, autoptic, and histological analysis it is possible to date the origin of a cerebral hemorrhage and establish whether it is spontaneous or posttraumatic in subjects with undiagnosed preexisting diseases. Through an integrated study, it is also important to date the lesion and identify the traumatic event responsible of the bleeding. Finally, this case has a relevant clinical importance relatively to sports medicine, where it would be appropriate that athletes undergo blood test as a preventive measure. In fact, in presence of an acute hematological disease, such as AML, even mild traumatic injuries may be fatal.

Background: Immunoglobulin M multiple myeloma and Waldenström macroglobulinemia are two different hematological diseases with the common finding of an immunoglobulin M monoclonal gammopathy of unknown significance. However, clinical characteristics of the two entities can overlap., Case Presentation: In this report, we describe two cases of immunoglobulin M neoplasm with the same histological bone marrow presentation but with different clinical behavior, cytogenetics, and biological assessment. On the basis of comprehensive diagnostic workup, these patients were considered to have different diseases and treated accordingly with different approaches. Patient 1 (Caucasian man) presented with increased serum protein and immunoglobulin M (7665 mg/L) with an M-spike electrophoresis of 4600 mg/L. His bone marrow biopsy revealed a small-cell immunoglobulin M multiple myeloma. The result of testing for the MYD88 L265P mutation was negative, while fluorescence in situ hybridization analysis showed translocation t(11,14). A diagnosis of immunoglobulin M-κ multiple myeloma was made. Patient 1 was a candidate for bortezomib plus thalidomide and dexamethasone, followed by autologous stem cell transplant consolidation. Patient 2 (Caucasian man) showed an M-spike by protein electrophoresis (300 mg/L, 4.9%), with serum immunoglobulin M level of 327 mg/L. His bone marrow biopsy revealed immunoglobulin M-κ multiple myeloma. Computed tomography showed many enlarged lymph nodes and splenomegaly. Patient 2's clinical features were suggestive of Waldenström macroglobulinemia, in contrast to the bone marrow biopsy results. The result of testing for the MYD88 L265P mutation was positive. Patient 2 was diagnosed with Waldenström macroglobulinemia and received rituximab, cyclophosphamide, and dexamethasone., Conclusions: A correct differential diagnosis between immunoglobulin M multiple myeloma and Waldenström macroglobulinemia is a critical point in the setting of a new immunoglobulin M monoclonal gammopathy onset. These patients should undergo a complete diagnostic workup with pathological, radiological, and serological examinations to establish the diagnosis and plan the most appropriate treatment in order to improve the prognosis.

Intravascular lymphoma (IVL) is a rare subtype of extranodal lymphomas that is characterized by the selective growth of neoplastic cells within the lumen of small vessels. Authors document the case of an unexpected death caused by an undiagnosed intravascular large B-cell lymphoma with multi-organ involvement, which had initially manifested as an infection and then as an unclarified central nervous system pathology. Histological examination showed a diffuse intravascular large B-cell brain lymphoma with prominent cerebral involvement. The relevance of the case report reveals the importance of an autopsy of an extremely rare and threatening pathology that in most cases is diagnosed only postmortem. As a result, the role of the forensic pathologist becomes particularly important. When specifically performing an in-depth autopsy evaluation with a specific histologic analysis, it is possible to identify the intravascular lymphoma and declare a more accurate cause of death., (© 2019 American Academy of Forensic Sciences.)

3,4-Methylenedioxymethamphetamine (MDMA), more commonly known as "ecstasy," is a semi-synthetic entactogenic phenylethylamine. In recent years it has gained popularity as a recreational drug whose use has registered an upward trend especially among adolescents and young adults. Despite its unwarranted reputation of being a "safe" drug, the actual scientific data denote that it actually leaves a trail of cardio-toxicity, above and beyond its neurotoxicity and other somatic effects. Both experimental and clinical data, in fact, indicate that ecstasy can alter cardiac function leading to rhythm disturbances, myocardial infarction, and even sudden cardiac death. We reviewed and summarized the bio-medical literature on the cardiovascular response to MDMA both in humans and laboratory animals. The aim was to elucidate the various pathophysiological mechanisms involved, as well as the clinical, autoptic, and experimental findings underlying MDMA-induced cardio-toxicity. Finally, an illustrative case report of ecstasy-induced adolescent death due to acute cardio-toxicity was described so as to highlight some key features.

Background: Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is a rare Epstein-Barr virus (EBV) positive lymphoproliferative disorder included in the current World Health Organization (WHO) classification. It arises within fibrinous material in the context of hematomas, pseudocysts, cardiac myxoma or in relation with prosthetic devices. In these clinical settings the diagnosis requires an high index of suspicion, because it does not form a mass itself, being composed of small foci of neoplastic cells. Despite overlapping features with diffuse large B-cell lymphoma associated with chronic inflammation, it deserves a separate classification, being not mass-forming and often following an indolent course., Case Presentation: A 64-year-old immunocompetent woman required medical care for cerebral hemorrhage. Computed Tomography (CT) angiography identified an aneurysm in the left middle cerebral artery. A FA-DLBCL was incidentally identified within thrombotic material in the context of the arterial aneurysm. After surgical removal, it followed a benign course with no further treatment., Conclusions: The current case represents the first report of FA-DLBCL identified in a cerebral artery aneurysm, expanding the clinicopathologic spectrum of this rare entity. A complete literature review is additionally made.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that ectopically secretes fibroblast growth factor 23, a bone cell-derived protein that regulates phosphate homeostasis. The overproduction of fibroblast growth factor 23 causes a paraneoplastic syndrome characterized by hyperphosphaturia, hypophosphatemia, hypovitaminosis D, and vitamin D refractory rickets/osteomalacia, effects that disappear with tumor removal. The PMT may occur in several anatomic regions, mainly in the limbs, usually involving both soft tissue and bone. Acral locations occur in 10% to 15% of the cases, mostly in the feet, with 95 cases reported in this anatomic region to date. We report a case of a PMT in a young adult male who presented in 2007 with the classic constellation of signs and symptoms. A small soft-tissue tumor was detected in his right heel, 3 years after exhaustively seeking for it by various imaging techniques performed at different institutions. Before the tumor was detected, attempts to manage this patient's osteomalacia with phosphate and vitamin D (both calcitriol and ergocalciferol) supplementation were unsuccessful. Following surgical resection, the patient experienced prompt correction of the phosphaturia and gradual reconstitution of his bone mineralization. The pathologic diagnosis was (benign) PMT, mixed connective tissue type. In 2019, 12 years after resection, the patient is asymptomatic, and his bone mineral homeostasis has been restored.

Rationale: Spontaneous esophageal rupture (Boerhaave syndrome) is a rare, though frequently fatal, event. It is generally caused by a sudden increase in pressure inside the esophagus. In some cases, full-thickness perforations of the esophagus may develop from previous lesions that initially involve only the esophageal mucosa (Mallory-Weiss syndrome) and which, following further triggering events, give rise to a transmural lesion., Patient Concerns: Here, we present the case of a 45-year-old subject who suddenly died of acute cardio-respiratory failure, an autopsy was performed to identify the cause of death., Diagnosis, Interventions, and Outcomes: The autopsy examination revealed a full-thickness rupture of the esophageal wall. Through the integration of necroscopy findings, anamnestic data, and histopathological examination, it has been possible to establish that complete esophageal rupture resulted from the evolution of a previous partial lesion of the esophageal wall, and that an untreated Mallory-Weiss syndrome evolved into a rapidly fatal Boerhaave syndrome., Lessons: This case shows that distal esophageal tears, rather than constituting a distinct entity, may be part of a spectrum of diseases and that a partial lesion of the esophageal wall caused by barogenic injury may evolve into a full-thickness rupture following further barotraumas.

Cysts of the pineal gland are benign lesions. Often asymptomatic, in the majority of cases they are discovered incidentally during brain magnetic resonance imaging or autopsy. Sporadically, however, they may cause such symptoms as chronic headache, loss of consciousness, corticospinal and sensory impairment, and, in some cases, even sudden death. A 45-year-old woman, in apparently good health, collapsed and died suddenly, after reaching orgasm while engaged in sexual intercourse. According to the circumstantial account of her relatives, the woman suffered from severe headaches, which were exacerbated by certain types of physical strain, such as sexual activity. Postmortem examination revealed no external injuries or internal diseases except for a cystic lesion of the pineal gland. Microscopically, the wall of the cyst consisted of a layer of glial tissue surrounded by an area of pineal elements. A complete forensic approach concluded that the cause of death was fatal cardiorespiratory failure resulting from midbrain compression due to a nonneoplastic pineal gland cyst, exacerbated by sexual activity. In this case, the intracranial pressure increase, secondary to Valsalva maneuver during climax, may further aggravate compression on the brainstem, thus concurring to determine the death.

Attribution of death to myocarditis continues to be a controversial issue in forensic pathology, despite the existence of established histopathological criteria as well as complementary investigations. The aim of the study was two-fold: (a) to retrospectively analyse the data obtained from a series of clinical and forensic autopsies in order to assess the number of cases with death attributed to myocarditis, and (b) to reevaluate these cases in order to assess how properly the histopathological diagnosis of myocarditis conformed to established criteria and therefore how accurately these were used on the basis of all postmortem investigation findings to conclude the cause of death. 2474 clinical and forensic autopsies were taken into consideration. Myocarditis was recorded as the official, underlying cause of death in 48 cases. Of those, 8 cases were considered to accurately conform to the histopathological Dallas criteria for the presence of myocarditis and could therefore be classified as cases of fatal myocarditis. In 19 out of 48 cases, description of focal myocarditis was considered to accurately fulfill the histopathological Dallas criteria for the presence of myocarditis. However, data provided by histological analysis and virology testing result reevaluation allowed alternative causes of death to be speculated. In another 21 out of 48 cases, description of focal myocardial inflammation was considered to inaccurately meet the histopathological Dallas criteria for the presence of myocarditis. The findings of our own study appear to be in agreement with previous observations in similar study groups and highlight that since myocarditis may occur in association with many diseases, a great deal of evidence is required before settling on categorical conclusions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A bezoar is a mass of undigested, or partially digested, material forming in the lumen of the gastroenteric tract, causing occlusive or subocclusive events. The most frequent types of bezoars are those composed of vegetable fibers, also called phytobezoars, which, by virtue of their high content in cellulose, hemicellulose, and lignin, remain undigested in the stomach and intestines and, from there, can migrate and occlude the narrowest portions of the bowel. The areas that are most frequently affected by occlusive phenomena related to the presence of bezoars are the stomach and the small intestine, although colic localizations are extremely rare. In this article, we have studied the case of a fatal colic obstruction caused by a phytobezoar in an 84-year-old woman who was found dead at her home. The autopsy revealed that the cause of the obstruction was a large artichoke fragment occluding the central part of the descending colon. Additional histological examinations confirmed that the death was attributable to bowel obstruction resulting in acute peritonitis.

Suicide by hanging inside a motor vehicle is a rare occurrence. A 48-year-old woman suffering from major depression was found having agonal breathing inside her automobile. A 20-mm diameter blue nylon rope was wrapped tightly around her neck, with its other end tied to a nearby wooden fence post. Despite resuscitation attempts, she was declared deceased after several minutes. The vehicle was located in an area with a slight downward slope. The motor was off. It was in neutral gear, with the parking brake disengaged. Consequently, the gravitational forces, attributable to the mass of the vehicle and the declivity of the terrain, caused the rope to tighten.The dynamics fulfill the criteria for a partial hanging, given the difference in height between the point at which the rope was secured to the post and woman's neck, which in turn presented the typical oblique upward groove.This case, thus, represents a unique mode of partial hanging inside a passenger vehicle, rarely reported in the literature. The relative lack of internal injury is also noteworthy, along with the fact that the victim was discovered while still alive. The latter feature can be explained by the absence of the sudden or violent acceleration forces that can be generated with the engine on.

We describe a rare case of intracranial malignant triton tumor (MTT) arising in the middle cranial fossa in a 74-year-old female patient who had previously been exposed to radiation in the Chernobyl disaster. The patient underwent a surgical subtotal removal of the mass and radiation therapy, but the progression-free survival was only 2.5 months and death occurred four months after the onset of symptoms. MTTs are rare aggressive tumors arising from the nerve sheath showing rhabdomyosarcomatous differentiation and associated with a poor prognosis. The intracranial location is very rare, and only 10 cases, including the present report, have been described so far. Among intracranial MTTs, the cerebellopontine angle is the most common location. Neurofibromatosis type 1 (NF-1) and radiation exposure are risk factors as for MTTs located in other sites. The gold standard therapy is surgical excision followed by radiation therapy, but the prognosis is usually very poor.

Interleukin (IL)-25, a member of the IL-17 cytokine superfamily, is produced by immune and non-immune cells and exerts type 2 pro-inflammatory effects in vitro and in vivo . The IL-25 receptor(R) is composed of the IL-17RA/IL-17RB subunits. Previous work showed that germinal centre (GC)-derived B-cell non Hodgkin lymphomas (B-NHL) expressed IL-17AR, formed by IL-17RA and IL-17RC subunits, and IL-17A/IL-17AR axis promoted B-NHL growth by stimulating neoangiogenesis. Here, we have investigated expression and function of IL-25/IL-25R axis in lymph nodes from human GC-derived B-NHL, i.e. Follicular Lymphoma (FL,10 cases), Diffuse Large B Cell Lymphoma (6 cases) and Burkitt Lymphoma (3 cases). Tumor cells expressed IL-25R and IL-25 that was detected also in non-malignant cells by flow cytometry. Immunohistochemical studies confirmed expression of IL-25R and IL-25 in FL cells, and highlighted IL-25 expression in bystander elements of the FL microenvironment. IL-25 i) up-regulated phosphorylation of NFkBp65, STAT-1 and JNK in B-NHL cells; ii) inhibited in vitro proliferation of the latter cells; iii) exerted anti-tumor activity in two in vivo B-NHL models by dampening expression of pro-angiogenic molecules as VEGF-C, CXCL6 and ANGPT3. In conclusion, IL-25, that is intrinsically pro-angiogenic, inhibits B-NHL growth by reprogramming the angiogenic phenotype of B-NHL cells.

Hodgkin Lymphoma (HL) is a tumor of B-cell origin characterized by Hodgkin and Reed-Stenberg (H/RS) cells embedded in an inflammatory tissue where numerous cytokines/chemokines contribute to shape the microenvironment, leading to the typical clinical symptoms. We investigated: i) the expression of Interleukin-IL-31 (IL-31) and Thymic Stromal Lymphopoietin (TSLP), two Th2-related cytokines with tumor-promoting and pruritogenic functions, and of the respective receptors in HL invaded lymph nodes by flow cytometry, and ii) the potential association of IL-31/TSLP plasma concentrations with clinical characteristics by ELISA. H/RS cells and the major immune cell types infiltrating HL lymph nodes expressed intracytoplasmic and surface IL-31/TSLP, and their receptors. A subgroup of patients showing at diagnosis elevated IL-31 and TSLP plasma levels had an International Prognostic Score>2, indicative of high risk of relapse, and a subsequent positive interim PET-scan, indicative of insufficient response to chemotherapy. No correlation was found between IL-31/TSLP plasma levels and overall or event-free survival. In conclusion, IL-31/TSLP and their receptors are expressed in HL cells and in immune cells infiltrating affected lymph nodes, where both cytokines may contribute to local immune suppression. The clinical impact of IL-31 and TSLP plasma levels has to be further defined in larger patient cohorts., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing financial interests in relation to the work described.

Purpose: Nicotinamide phosphoribosyltransferase (Nampt) regulates intracellular NAD + pool and is highly expressed in a number of malignancies. FK866, a selective inhibitor of Nampt, depletes intracellular NAD + levels, thereby blocking cellular metabolism and triggering sensitization to other drugs and cell death. Here we characterized the antitumor effects of Nampt inhibition in Waldenström macroglobulinemia., Experimental Design: We investigated Nampt role in MW cells using both mRNA and protein expression analyses. We have also used loss-of-function approaches to investigate the growth and survival effects of Nampt on MW cells and further tested the anti-MW activity of dual Nampt and BTK inhibition in vitro and in vivo RESULTS: We found that Waldenström macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenström macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenström macroglobulinemia cell death, regardless of MYD88 and CXCR4 mutational status. Cell death was associated with: (i) activation of caspase-3, PARP and downregulation of Mcl-1, (ii) enhanced intracellular ATP and NAD + depletion, (iii) inhibition of NF-κB signaling, and (iv) inhibition of multiple prosurvival signaling pathways. In a murine xenograft Waldenström macroglobulinemia model, low-dose combination FK866 and ibrutinib is well tolerated, significantly inhibits tumor growth, and prolongs host survival., Conclusions: Our results show intracellular NAD + level as crucial for proliferation and survival of Waldenström macroglobulinemia cells, and provides the mechanistic preclinical rationale for targeting Nampt, either alone or with Ibrutinib, to overcome drug resistance and improve patient outcome in Waldenström macroglobulinemia. Clin Cancer Res; 22(24); 6099-109. ©2016 AACR., (©2016 American Association for Cancer Research.)