Long-term outcomes of elderly hairy cell leukemia patients treated with cladribine.

Hairy cell leukemia (HCL) is a rare hematologic disorder characterized by pancytopenia and splenomegaly for which a single course of cladribine is highly effective in inducing complete remissions. However, there is limited real-world data on outcomes and complications among geriatric patients with HCL treated with cladribine. We conducted a retrospective review of all patients 70 years or older within the Scripps Clinic HCL Database at the time of first treatment with cladribine. Of the 45 patients meeting inclusion criteria, 32 (71%) achieved CR and 4 (9%) achieved PR. Of the 9 remaining patients, 7 achieved normalization of peripheral blood counts after a single course of cladribine (complete hematologic response, CHR) and 2 had no response. The median duration of response for all responders was 119 months. Nine (20%) patients relapsed with a median time to first relapse of 28 months. Ten patients subsequently developed 12 primary malignancies with an excess frequency (observed-to-expected ratio) of 0.85 (95% confidence interval, 0.48-1.49). Median overall survival for the entire cohort was 166 months from time of HCL diagnosis and 119 months from time of first cladribine administration. Forty patient deaths were observed; the standardized mortality ratio (observed-to-expected ratio) was 1.42 (95% confidence interval, 1.03-1.96), representing a statistically significant increase in the risk of death (P = .03). This study supports the high rate of complete and durable responses following a single course of cladribine in geriatric patients.

Malignant Melanoma With Neuroendocrine Differentiation: A Case Report and Literature Review.

BACKGROUND: Melanoma has a wide range of histologic variants and cytomorphologic features that make its diagnosis challenging. Melanoma can also rarely have neuroendocrine markers adding further diagnostic uncertainty particularly given that unrelated tumor types, such as prostate cancer, can also display focal neuroendocrine differentiations. CASE PRESENTATION: Our patient is a 74-year-old Caucasian man found to have a lung mass. Initial biopsy revealed typical microscopic morphology and neuroendocrine differentiation consistent with small cell carcinoma. Despite standard chemoradiation treatment, the patient continued to progress with new metastasis in the brain, liver and bone. Subsequent chest wall biopsy revealed golden-brown pigment associated with melanin. Further tumor immunohistochemistry revealed extensive neuroendocrine differentiation with CD56, synaptophysin, and INSM1, as well as strong immunoreactivity for melanocyte markers including SOX10, S100, PRAME, and MITF, consistent with metastatic melanoma with neuroendocrine differentiation. Genomic testing revealed increased tumor mutational burden and alterations in NF1, BRAF, CDKN2A/B, TERT. The patient was transitioned to checkpoint inhibitor therapy with nivolumab and ipilimumab and had resolution of his intracranial mass and decrease in size of other metastatic lesions. CONCLUSION: Often the combination of anatomic findings such as a lung mass, typical microscopic morphology, and confirmation of neuroendocrine differentiation correctly identifies a patient with small cell carcinoma. However, in a patient who fails to respond to treatment, a broader immunohistochemical workup along with molecular testing with additional tissue may be warranted.

Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer.

Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

TRK Inhibitors: Clinical Development of Larotrectinib.

PURPOSE OF REVIEW: In this review, we highlight the pre-clinical development, recent clinical studies, and future directions of larotrectinib in patients with NTRK fusion-positive tumors. RECENT FINDINGS: The tropomyosin receptor kinase family, TrkA, TrkB, and TrkC, transmit extracellular signals via a variety of intracellular pathways to promote normal neuronal development. TrkA, B, and C are encoded by NTRK1, 2, and 3, respectively. NTRK chromosomal alterations, most commonly gene fusions, have been identified as driver mutations in a broad range of malignancies. Small molecule tyrosine kinase inhibitors of Trk, including larotrectinib, have shown broad clinical activity across multiple tumor types with NTRK fusion events. Although the prevalence of NTRK alterations is low, the exceptional activity of larotrectinib makes NTRK alterations an important predictive biomarker to screen for in any cancer.

Simultaneous Loss of Both Atypical Protein Kinase C Genes in the Intestinal Epithelium Drives Serrated Intestinal Cancer by Impairing Immunosurveillance.

Serrated adenocarcinoma, an alternative pathway for colorectal cancer (CRC) development, accounts for 15%-30% of all CRCs and is aggressive and treatment resistant. We show that the expression of atypical protein kinase C ζ (PKCζ) and PKCλ/ι was reduced in human serrated tumors. Simultaneous inactivation of the encoding genes in the mouse intestinal epithelium resulted in spontaneous serrated tumorigenesis that progressed to advanced cancer with a strongly reactive and immunosuppressive stroma. Whereas epithelial PKCλ/ι deficiency led to immunogenic cell death and the infiltration of CD8+ T cells, which repressed tumor initiation, PKCζ loss impaired interferon and CD8+ T cell responses, which resulted in tumorigenesis. Combined treatment with a TGF-ß receptor inhibitor plus anti-PD-L1 checkpoint blockade showed synergistic curative activity. Analysis of human samples supported the relevance of these kinases in the immunosurveillance defects of human serrated CRC. These findings provide insight into avenues for the detection and treatment of this poor-prognosis subtype of CRC.

Comprehensive genomic profiling identifies novel NTRK fusions in neuroendocrine tumors.

CGP results from >60,000 cases were screened to identify NTRK fusion events from cases of neuroendocrine tumors. 2417 NET patients from diverse anatomic sites were identified. From this dataset, six cases harbored NTRK fusions which included intra- and inter-chromosomal translocations. A NTRK fusion frequency of approximately 0.3% was found across all subtypes of NETs. Three cases involved translocations of NTRK1 with unique fusion partners (GPATCH4, PIP5K1A, CCDC19). Co-occurring alterations occurred in five cases. NTRK alterations were identified in nearly the full spectrum of NETs, including from the small intestine, pancreas, lung, and others. With the late stage clinical development of NTRK TKIs (including entrectinib and larotrectinib), these findings may further inform targeted approaches to therapy in NET.

Reversible intrahepatic cholestasis in metastatic prostate cancer: An uncommon paraneoplastic syndrome.

As with other genitourinary malignancies, a variety of paraneoplastic syndromes have been revealed to occur in patients with prostate cancer. Stauffer's Syndrome is a well-described clinical syndrome which manifests via intrahepatic cholestasis in patients with renal cell carcinoma. Less common is intrahepatic cholestasis occurring in association with prostate cancer. The current case report discusses a 67-year-old man presenting with liver failure secondary to intrahepatic cholestasis co-existing with metastatic prostate adenocarcinoma. The patient's liver failure completely resolved with androgen-deprivation therapy suggesting an association between these two entities. The case report evaluates existing literature on this uncommon syndrome including the clinical presentation, natural history, and potential pathophysiology.

Tumor Mutational Burden Guides Therapy in a Treatment Refractory POLE-Mutant Uterine Carcinosarcoma.

Gynecologic carcinosarcomas, previously known as malignant mixed Müllerian tumors, are uncommon malignancies that demonstrate an aggressive biology and lack a standard therapeutic approach. Molecular analyses have revealed recurrent alterations in chromatin remodeling genes, but clinical support for therapeutic significance is lacking. We prospectively identified a patient with refractory uterine carcinosarcoma whose tumor was subject to molecular profiling at diagnosis and again at radiographic progression. Initial molecular testing did not assess tumor mutational burden, DNA polymerase ɛ (POLE), or microsatellite status. After the failure of several lines of chemotherapy, comprehensive genomic profiling of a repeat biopsy identified two missense mutations of the exonuclease domain of POLE (P286R and T323A). Tumor mutational burden was elevated (169 mutations per DNA megabase), consistent with an ultramutator phenotype. As seen in previously reported POLE-endometrioid cases, our patient harbored alterations in PIK3CA, ARID1A, and PTEN and was microsatellite stable, with appreciable tumor-infiltrating lymphocytes. She achieved an ongoing durable response with pembrolizumab. This is the first report of programmed cell death protein 1 response in uterine carcinosarcoma. KEY POINTS: Uterine carcinosarcoma is an uncommon and aggressive histologic variant of endometrial carcinoma with a poor prognosis.Inactivating DNA polymerase ɛ (POLE) mutations have been associated with high tumor mutational burden (TMB) and response to immune checkpoint inhibition.To the authors' knowledge, this is the first report of response to immune checkpoint inhibitor therapy in a patient with uterine carcinosarcoma.This case further supports expanding genomic profiling to include assessment of tumor mutational burden across tumor types, given the potential for immune checkpoint inhibitor therapy in TMB-high tumors.

Low ATM expression and progression-free and overall survival in advanced gastric cancer patients treated with first-line XELOX chemotherapy.

BACKGROUND: Gastric cancer (GC) is a leading cause of cancer-specific mortality with limited biologically informed treatments. The ataxia telangiectasia mutated (ATM) gene is critically involved in the repair of double-stranded DNA breaks and a component of DNA damage repair (DDR) pathways. Platinum salts are hypothesized to have increased efficacy in tumors deficient in DDR pathways. We sought to investigate an association between ATM status and response to XELOX in a homogenous first line GC patient cohort. METHODS: A clinically annotated cohort of 137 Korean patients with advanced GC treated with first-line XELOX was retrospectively examined for ATM status by immunohistochemistry. Correlation between ATM expression and clinicopathologic variables was performed by two-tailed, unpaired t-tests and Fisher's exact tests. Kaplan-Meier survival analysis curves and Cox proportional hazards models were used to evaluate for independent predictors of disease-free survival (DFS) and overall survival (OS). RESULTS: Low ATM expression was observed in 19.0% (26/137) of patients and was not associated with clinicopathologic features or response rate to XELOX. Univariate, but not multivariable, logistic regression and Cox analysis identified ATM as an independent risk factor influencing OS and DFS. A higher ECOG score independently predicted worse survival [hazard ratio (HR) 2.96, P=0.016] and complete surgical resection independently protected against progression of disease (HR 0.69, P=0.007). CONCLUSIONS: Low ATM expression was not associated with increased response rates to XELOX in a single-institution cohort of advanced GC patients. Similarly, ATM status did not predict DFS or OS after platinum-based chemotherapy.

Objective response to mTOR inhibition in a metastatic collision tumor of the liver composed of melanoma and adenocarcinoma with TSC1 loss: a case report.

BACKGROUND: Collision tumors are uncommon but well described clinical entities composed of distinct tumor histologies occurring within the same anatomic site. Optimal management of patients with collision tumors remains highly variable and depends on clinical characteristics such as the involved tumor types, predominant histology, as well as the extent of disease. Comprehensive genomic profiling is a means of identifying genomic alterations to suggest benefit from targeted therapy. CASE PRESENTATION: A 78-year-old woman presented to medical oncology with liver metastases occurring within the background of a 1-year history of uveal melanoma. Biopsy of the liver metastases revealed presence of adenocarcinoma along with nests of malignant melanoma consistent with a collision tumor. The disease was refractory to several lines of conventional cytotoxic chemotherapy, and the patient later developed pulmonary metastases while on chemotherapy. The patient's tumor tissue was assayed by comprehensive genomic profiling which revealed presence of a TSC1 partial loss. The patient was subsequently initiated on temsirolimus 15 mg intravenously weekly for 4 months. Restaging imaging demonstrated a partial response to therapy by RECIST 1.1 criteria and clinical benefit for 6 months until the patient passed away secondary to unrelated causes. CONCLUSIONS: We report the first case of a collision tumor composed of adenocarcinoma and melanoma with a TSC1 mutation that objectively and durably responded to mTOR inhibition.

Acute Respiratory Distress Syndrome in Lemierre's Syndrome.

Lemierre's syndrome is an infectious disease defined by the presence of septic thrombophlebitis with associated embolic phenomenon, most commonly to the lungs. Here we present two cases from a single institution of acute respiratory distress syndrome (ARDS) developing as a result of Lemierre's syndrome in previously healthy young adult men. ARDS can occur as a consequence of pulmonary septic emboli and sepsis, both of which are well-described consequences of Lemierre's syndrome. We describe important diagnostic and management considerations in the care of patients with hypoxemic respiratory failure and Lemierre's syndrome. Essential components of management include prompt antibiotic therapy, lung-protective ventilation strategies, and supportive care.

Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers.

Valganciclovir has been reported to improve physical and cognitive symptoms in patients with chronic fatigue syndrome (CFS) with elevated human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) IgG antibody titers. This study investigated whether antibody titers against HHV-6 and EBV were associated with clinical response to valganciclovir in a subset of CFS patients. An uncontrolled, unblinded retrospective chart review was performed on 61 CFS patients treated with 900 mg valganciclovir daily (55 of whom took an induction dose of 1,800 mg daily for the first 3 weeks). Antibody titers were considered high if HHV-6 IgG ≥ 1:320, EBV viral capsid antigen (VCA) IgG ≥ 1:640, and EBV early antigen (EA) IgG ≥ 1:160. Patients self-rated physical and cognitive functioning as a percentage of their functioning prior to illness. Patients were categorized as responders if they experienced at least 30% improvement in physical and/or cognitive functioning. Thirty-two patients (52%) were categorized as responders. Among these, 19 patients (59%) responded physically and 26 patients (81%) responded cognitively. Baseline antibody titers showed no significant association with response. After treatment, the average change in physical and cognitive functioning levels for all patients was +19% and +23%, respectively (P < 0.0001). Longer treatment was associated with improved response (P = 0.0002). No significant difference was found between responders and non-responders among other variables analyzed. Valganciclovir treatment, independent of the baseline antibody titers, was associated with self-rated improvement in physical and cognitive functioning for CFS patients who had positive HHV-6 and/or EBV serologies. Longer valganciclovir treatment correlated with an improved response.

Severe encephalomyelitis in an immunocompetent adult with chromosomally integrated human herpesvirus 6 and clinical response to treatment with foscarnet plus ganciclovir.

Human herpesvirus 6 has rarely been identified as a cause of encephalitis in immunocompetent adults. We describe a patient who had severe encephalomyelitis, hypoglycorrhachia, and human herpesvirus 6 identified in his cerebrospinal fluid and serum and who recovered after treatment with foscarnet and ganciclovir. Human herpesvirus 6 should be considered in immunocompetent patients with encephalitis.