Evidence‐based recommendations for the optimal duration and sequencing of temozolomide‐based treatments in advanced neuroendocrine neoplasms are lacking. Here, we conducted a systematic review of the ...literature for a descriptive analysis of temozolomide‐associated myelodysplasias and leukemias to guide treatment planning. A database search of PubMed and Embase was conducted to identify case reports and/or case series reporting secondary myelodysplasias or leukemias in the setting of temozolomide therapy. Key data items extracted from the studies were the temozolomide dose and duration, latency to hematological disorder, type of secondary malignancy and cytogenetics. Reported cases were summarized graphically. A total of 16 studies with 27 patient cases of therapy‐related hematologic neoplasms were identified, all of which were case reports or case series. The median treatment duration and cumulative dose were 19 months and 18,000 mg/m2, respectively. Most patients (21/27) were diagnosed on, or after, 12 months, while only one patient was diagnosed before 6 months of treatment. Most of the patients were diagnosed, while still on treatment with temozolomide. Graphically, cases clustered around a cumulative dose of 10,000 to 30,000 mg/m2 and a latency period of 10 to 40 months which translates to an approximate treatment duration of 12.5 to 37.5 months. Taken together, most reported treatment‐related hematological neoplasms appear to develop on or beyond the 12‐month mark, while patients are still on treatment with temozolomide. For patients with neuroendocrine neoplasms, where sequencing of multiple therapies is important, we suggest an approach to optimizing treatment duration by establishing disease response at 6 months before continuing further treatment and restricting treatment to or establishing closer vigilance beyond 12 months.
Capecitabine and temozolomide (CAPTEM) has established efficacy in advanced neuroendocrine neoplasms (NEN). Unlike in patients with primary neoplasms of the brain, where temozolomide is also commonly used, patients with NEN have a much longer expected overall survival and consequently may be exposed to longer durations of temozolomide which is typically given until unacceptable toxicity, disease progression, or death. While relatively well tolerated, especially with regards to acute toxicity, temozolomide is associated with cumulative risk of therapy‐related hematologic toxicity including therapy‐related leukemias, which is particularly relevant given the potential prolonged exposure. Here, we review the literature to help inform the optimal duration of temozolomide therapy taking into context the risk of long‐term therapy‐related hematologic toxicity.
Background
Limited data exist regarding the characteristics and survival outcomes of older adults with non–small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors in routine oncology ...practice.
Methods
Using the Surveillance, Epidemiology, and End Results–Medicare linked database, we identified 1256 patients aged ≥65 years who were diagnosed with pathologically confirmed stage I to stage IV NSCLC between 2002 and 2015 and initiated nivolumab or pembrolizumab in 2016. We examined patient characteristics and overall survival from the time of immune checkpoint inhibitor initiation through December 31, 2017.
Results
The median patient age at the time of immune checkpoint inhibitor initiatiton was 75.3 years (interquartile range, 8.5). A substantial percentage of patients were initially diagnosed with stage IV disease (42.6%) and had ≥2 comorbid conditions (48.7%). Using a claims‐based proxy, 11.5% of patients had poor performance status and 12.6% had a history of autoimmune conditions. The median overall survival after initiation of immune checkpoint inhibitor was 9.3 months (95% CI, 8.5‐10.5 months). The 1‐year survival rate was 43.0% (95% CI, 40.2‐45.7%). In multivariable analyses, multiple comorbid conditions, squamous histology, a history of nonplatinum doublet systemic therapy, recent radiotherapy, and a shorter time from initial diagnosis to treatment initiation were found to be statistically significantly associated with an increased hazard of death. Demographics, poor performance status, and prior autoimmune conditions were not significantly associated with the hazard of death.
Conclusions
Many older adults with NSCLC who initiated immune checkpoint inhibitors had multiple comorbidities, a history of autoimmune disease, or poor performance status. Factors associated with poor prognosis among patients with advanced NSCLC were also associated with worse survival in older adults treated with immune checkpoint inhibitors.
Many older adults with non–small cell lung cancer (NSCLC) who initiate treatment with immune checkpoint inhibitors in routine oncology practice have multiple comorbidities or a history of autoimmune disease. Factors associated with poor prognosis among patients with advanced NSCLC also appear to be predictive of decreased survival in older adults who are treated with immune checkpoint inhibitors.
Peptide receptor radionuclide therapy (PRRT) can be a very useful treatment for patients with neuroendocrine neoplasms and metastatic castration‐resistant prostate cancer but it is routinely avoided ...in those with advanced kidney disease because it can adversely affect the renal function. Accordingly, no clear guidelines exist on the use of PRRT for patients on hemodialysis (HD). We performed a literature review to identify publications on HD patients who received PRRT with Lutetium‐177 (Lu177) Dotatate and Y‐90 and obtained information on Lu177 pharmacokinetics and early testing data from the manufacturer. We also perused the most recent North American Neuroendocrine Tumor Society (NANETS)/European Neuroendocrine Tumor Society (ENETS) recommendations. Seven relevant publications with a total of 15 patients were included. Patients received dose‐adjusted fractions of PRRT with HD occurring usually within 24 h. There were no immediate or long‐term serious adverse events attributed to the radioligand, although data was limited. Using available evidence and input from a multidisciplinary group, we have created an institutional workflow. Dose‐adjusted PRRT can be offered to patients undergoing HD under careful, multidisciplinary supervision.
Context.--Hypergastrinemia states such as achlorhydria from gastric mucosal atrophy or a gastrin-producing tumor in humans have been associated with the development of enterochromaffin-like (ECL) ...cell hyperplasia and gastric neuroendocrine tumors (GNETs). Whether drugs that can elevate serum gastrin levels, such as proton pump inhibitors (PPIs), can produce the same tissue effect is not known, and there is no concrete evidence linking the use of PPIs to GNETs outside animal models and case reports. Objective.--To explore the clinicopathologic association for GNETs of presumed ECL cell origin that cannot be reliably placed into any of the 3 established categories currently recognized by the World Health Organization. Design.--This is a retrospective clinicopathologic study of GNETs in the body/fundus during a period of 15 years (2005-2019). Results.--Of a total of 87 cases, 57 (65.5%) were associated with atrophic gastritis, 2 (2.3%) were associated with Zollinger-Ellison syndrome, and 28 (32.2%) were unclassified. Of the latter, 11 were consistent with true sporadic/type 3 GNETs, while 17 had background mucosal changes of parietal cell and ECL cell hyperplasia but without underlying detectable gastrinoma, and 88.2% (15 of 17) of patients from this group had documented longterm PPI use. This subtype of GNETs was more commonly multifocal and of higher grade (P = .03) than "true" sporadic GNETs. Conclusions.--A subset of GNETs arises in the background of gastric mucosal changes suggestive of hypergastrinemia, but without underlying gastrinoma, and could be linked to long-term PPI use. (Arch Pathol Lab Med. 2022;146:366-371; doi: 10.5858/arpa.2020-0315-OA)
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
ONC201 is an oral selective antagonist of the dopamine D2 receptor and direct activator of caseinolytic protease P. In a phase II study, ONC021 was shown to be well tolerated with notable efficacy in ...patients with the rare neuroendocrine neoplasms pheochromocytomas-paragangliomas, although biomarkers for activity remain to be elucidated. See related article by Anderson et al., p. 1773.
Pancreatic neuroendocrine tumors (PanNETs) in familial tuberous sclerosis (
TSC
1 and
TSC
2 mutations) have been known and studied. However, little is known about PanNET patients harboring the very ...rare (less than 2%) sporadic
TSC
mutations. Some renal tumors have been shown to harbor sporadic
TSC
mutations, with a distinctive morphological correlate. We hereby describe this rather unusual molecular alteration in well-differentiated pancreatic neuroendocrine tumors (WD PanNETs) with a focus on their morphology and treatment outcomes. Six cases of WD PanNETs harboring sporadic
TSC
mutations were identified retrospectively. H&E slides and corresponding immunostains were reviewed for all cases. Clinical, molecular, and radiological information was obtained using the electronic medical records. Cohort consisted of 4 males and 2 females. Median age at diagnosis was 50 years (range 33–74 years). Origin of neoplasm was the pancreas and, in all but one, patient had liver metastasis by the time of presentation. Six out of six cases demonstrated a unique tumor morphology, with ample eosinophilic cytoplasm. Tumors were arranged in sheets and nests; prominent cystic change was noted in one case. Two cases were additionally biopsied post-treatment with capecitabine and temozolomide, and showed even more abundant oncocytic cytoplasm, eccentric nuclei, and a prominent cherry red nucleolus, and were arranged in a cluster of 3–4 cells, separated by stromal cells. Every patient had a different
TSC
2 variant with no cases of
TSC
1 mutations. Other common variants included
MEN1
(4/6),
DAXX
(2/6), and
TP53
(2/6). Per the WH0 2019 classification, tumors were graded as NET-G3 (
n
= 3) and NET-G2 (
n
= 3). Ki-67 s ranged from 7.2 to 60. All cases had retained MMR protein expression. The majority of patients (4/6) have expired. Although they received multiple treatments, a consistent pattern observed in patients was marked radiologic response to chemotherapy with capecitabine and temozolomide (offered in 5/6 patients) with duration of responses reaching 11 months in the majority of cases, with one patient showing near complete pathologic response of localized disease.
TSC
2 mutations may confer distinctive appearance in WD PanNETs, reminiscent of their effects in renal tumors. Although not entirely specific, this distinct morphological pattern with abundant eosinophilic cytoplasm in WD PanNETs could be reflective of an associated
TSC
mutation, with suggestions of significant therapeutic response to a specific cytotoxic chemotherapy.
Hypergastrinemia states such as achlorhydria from gastric mucosal atrophy or a gastrin-producing tumor in humans have been associated with the development of enterochromaffin-like (ECL) cell ...hyperplasia and gastric neuroendocrine tumors (GNETs). Whether drugs that can elevate serum gastrin levels, such as proton pump inhibitors (PPIs), can produce the same tissue effect is not known, and there is no concrete evidence linking the use of PPIs to GNETs outside animal models and case reports.
To explore the clinicopathologic association for GNETs of presumed ECL cell origin that cannot be reliably placed into any of the 3 established categories currently recognized by the World Health Organization.
This is a retrospective clinicopathologic study of GNETs in the body/fundus during a period of 15 years (2005-2019).
Of a total of 87 cases, 57 (65.5%) were associated with atrophic gastritis, 2 (2.3%) were associated with Zollinger-Ellison syndrome, and 28 (32.2%) were unclassified. Of the latter, 11 were consistent with true sporadic/type 3 GNETs, while 17 had background mucosal changes of parietal cell and ECL cell hyperplasia but without underlying detectable gastrinoma, and 88.2% (15 of 17) of patients from this group had documented long-term PPI use. This subtype of GNETs was more commonly multifocal and of higher grade (P = .03) than "true" sporadic GNETs.
A subset of GNETs arises in the background of gastric mucosal changes suggestive of hypergastrinemia, but without underlying gastrinoma, and could be linked to long-term PPI use.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Both metachronous and synchronous tumors pose a diagnostic and clinical challenge, more so when one of the specimens demonstrates the rare neuroendocrine histology. We describe a patient with ...sarcoidosis who was treated for endometrial and ovarian neoplasm, recurred with two separate histologies (adenocarcinoma and high grade neuroendocrine), both associated with microsatellite instability (MSI)‐high status. Targeted next‐generation sequencing of tumor with synonymous somatic alterations pointed to a common ancestry of all three tumors and patient was successfully treated with a tailored immunotherapy regimen. Her sarcoidosis worsened only slightly, and immunotherapy did not need to be discontinued. This case highlights the importance of molecular testing for the optimal therapy of complex synchronous tumors and the need for communication between surgical and medical oncologists in patients with MSI‐high cancer.
Key Points
The case of a patient with a recurrent gynecological cancer presenting as microsatellite instability (MSI)‐high endometrial adenocarcinoma and MSI‐high neuroendocrine tumor is reported.
This case demonstrated a common genetic lineage with good response to checkpoint inhibition without clinical worsening of autoimmune disease.
This article adds to the literature, suggesting tumor evolution with neuroendocrine differentiation in some cancers, and argues that a molecular‐based approach to treatment might achieve better understanding and possibly superior treatment outcomes.
This case report highlights the importance of molecular testing for optimal therapy of complex synchronous tumors and the need for communication between surgical and medical oncologists in cases of high microsatellite instability cancer.
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