Lung adenocarcinoma metastasis within a pituitary neuroendocrine tumor: a case report with review of literature.

Collision tumors involving the metastasis of malignant neoplasms to pituitary neuroendocrine tumors (PitNETs) are extremely rare. We herein report a case involving a patient with lung adenocarcinoma metastasis within a PitNET who exhibited relatively rapid progression of neurological symptoms. A 75-year-old man who underwent tumor resection 36 and 18 years prior to presentation for bladder and colon cancer, respectively, without recurrence presented with bitemporal hemianopsia, ptosis, and diplopia of the right eye. Subsequent magnetic resonance imaging (MRI) revealed a tumor 3.2 cm in diameter that extended from the anterior pituitary gland to the suprasellar region. Gadolinium-enhanced MRI of the tumor showed heterogeneous contrast enhancement. Considering the relatively rapid progression of neurological symptoms, semi-emergency endoscopic endonasal transsphenoidal surgery was performed. Histopathological examination revealed a group of thyroid transcription factor-1- and napsin A-positive papillary proliferating cells intermingled with α-subunit- and steroidogenic factor-1-positive PitNET cells. Thus, the patient was diagnosed with lung adenocarcinoma metastasis within a gonadotroph PitNET. Genetic testing revealed the presence of an EGFR (Ex-19del) mutation, after which chemotherapy was initiated. Additional stereotactic radiotherapy was performed for the residual tumor in the sella turcica. With continued chemotherapy, good control of both the primary and metastatic tumors was noted after 24 months after surgery. Cases of malignant neoplasm metastasis within a PitNET are difficult to diagnose. In the case of a sella turcica tumor with relatively rapid progression of neurological symptoms, early surgical intervention is recommended given the possibility of a highly proliferative tumor and the need to obtain pathologic specimens.

Concurrent IgG4-related hypophysitis and clinically nonfunctioning gonadotroph pituitary neuroendocrine tumor.

BACKGROUND: Some patients develop immunoglobulin G4 (IgG4)-related hypophysitis associated with systemic diseases. More than 30 cases of IgG4-related hypophysitis have been reported. However, biopsy has rarely been performed in these patients, and none have had an associated pituitary neuroendocrine tumor (PitNET). We present a case of concurrent IgG4-related hypophysitis and PitNET. CASE PRESENTATION: A 56-year-old Japanese man arrived at the hospital with visual impairment, bitemporal hemianopia, and right abducens nerve palsy. Magnetic resonance imaging revealed pituitary body and stalk swelling as well as a small poorly enhanced right anterior lobe mass. Laboratory and loading test results suggested hypopituitarism. Because IgG4 level was elevated, a systemic examination was performed; multiple nodules were found in both lung fields. The diagnosis was based on an endoscopic transnasal biopsy of the pituitary gland. A histopathological examination revealed a marked infiltration of plasma cells into the pituitary gland, which was strongly positive for IgG4. The histological features of the resected tumor were consistent with those of gonadotroph PitNET, which was immunohistochemically positive for follicle-stimulating hormone-ß and steroidogenic factor-1, and no plasma cell infiltration was observed. Based on the histopathological examination results, steroid therapy was initiated, which reduced pituitary gland size and serum IgG4 levels. DISCUSSION AND CONCLUSIONS: This is the first reported case of IgG4-related hypophysitis with PitNET. Although no pathological findings indicating a relationship between the two conditions were found, we were able to preoperatively differentiate multiple lesions via detailed diagnostic imaging.

A brief review of the WHO reporting system for lung cytopathology.

The International Academy of Cytology has joined with the International Agency for Research on Cancer to bring together a group of experts in lung cytopathology to develop a WHO Reporting System for Lung Cytopathology (WHO System). This System aims to improve and standardize the reporting of cytopathology, facilitate communication between cytopathologists and clinicians, and improve patient care. The WHO System describes 5 categories for reporting lung cytopathology: 'Insufficient/Inadequate/Nondiagnostic', 'Benign', 'Atypical', 'Suspicious for malignancy', and 'Malignant', each one with a clear descriptive term, a definition, a risk of malignancy, and a suggested management algorithm. The key diagnostic cytopathologic features of each of the lesions within each category have been established by consensus through an Expert Editorial Board, who are also the authors of this review and selected for each reporting system and chosen based on their expertise in the field and/or diversity of geographical representation. Many other co-authors from around the world also contributed. The assignment of writing and editing responsibilities used the same model as that used for the WHO Classification of Tumours (https://whobluebooks.iarc.fr/about/faq/). The WHO System provides the best practice application of ancillary testing, including immunocytochemistry and molecular pathology, and guides in sampling and processing techniques to optimize the handling and preparation of specimens. The WHO System was created by the authors to be applicable globally and is based on cytomorphology with possibilities for additional diagnostic management of the patient. The authors are aware that local medical and pathology resources would differ, especially in low- and middle-income countries. The WHO Tumour Classification for Thoracic Tumors, Fifth Edition, is directly accessible through the online WHO System.

Pathology of Crooke Cells in the Human Pituitaries: A Timely Review.

Crooke cell change was first found in the regressed and suppressed corticotroph (adrenocorticotropic hormone-producing) cells, and now is known to occur in pituitary tumors. The tumor cells of this type can be recognized by morphology with immunohistochemistry, and are well known to predict aggressive behavior such as invasion and rare metastases. This is one of the representative neuroendocrine tumors in the pituitary which is now considered to have malignant potential as proposed in the pancreas and gastrointestinal tracts. It is important to emphasize the pituitary tumor pathology such as Crooke cell change for prognostication and appropriate therapies. This review article describes the evolution from the Crooke cells to Crooke cell tumors which is timely along with the Fifth WHO classification 2022 published online.

The World Health Organization Reporting System for Lung Cytopathology.

The International Academy of Cytology has joined with the International Agency for Research on Cancer (IARC) to bring together a group of experts in lung cytopathology to develop a WHO Reporting System for Lung Cytopathology (WHO System). This WHO System defines five categories for reporting lung cytopathology, that is, "Insufficient"/"Inadequate"/"Non-diagnostic," "Benign," "Atypical," "Suspicious for malignancy," and "Malignant," each with a clear descriptive term for the category, a definition, a risk of malignancy and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category have been established by consensus and will be presented more fully in a subsequent IARC e-book and published hard cover book.The WHO System provides the best practice application of ancillary testing, including immunocytochemistry and molecular pathology, and provides a review to guide sampling and processing techniques to optimize the handling and preparation of the cytopathology sample emphasizing the cytomorphological differential diagnosis to aid low-resourced settings. The authors recognize that local medical and pathology resources will vary, particularly in low- and middle-income countries, and have developed the WHO System to make it applicable worldwide based on cytomorphology with options for further diagnostic management of the patient.The online WHO System provides a direct link to the WHO Tumour Classification for Thoracic Tumours 5th Edition. It will raise the profile and use of cytopathology by increasing awareness of its current role and its potential role in the era of personalized medicine based on molecular pathology utilizing "small biopsies." Ultimately, the System will improve patient care and outcomes.This System aims to improve and standardize the reporting of cytopathology, facilitate communication between cytopathologists and clinicians and improve patient care. The System is based on the current role of lung cytopathology and synthesizes the existing evidence while highlighting areas requiring further research and the future potential role of lung cytopathology.

Analysis of Insulinoma-Associated Protein 1 Expression in Pituitary Neuroendocrine Tumors.

Insulinoma-associated protein 1 (INSM1) is a representative diagnostic marker of neuroendocrine neoplasms (NENs); however, it has not yet been used to diagnose pituitary neuroendocrine tumors (PitNETs), according to the 2022 World Health Organization (WHO) classification of pituitary tumors. This study aimed to examine the expression of INSM1 using immunohistochemistry, in the various cell lineages of PitNET classified by hormone secretion and transcription factor expression. INSM1 expression in PitNETs (different subtypes) and normal pituitary tissues was immunohistochemically assessed. The results were interpreted as scores of 0 (negative), 1 (focally positive), or 2 (frankly positive), depending on the proportion of cell staining. Twenty-eight of 35 PitNET cases (80%) showed INSM1 positivity in their nuclei. The staining in each histological subtype of PitNETs was as follows: somatotroph tumors, score 0 = 3/5, score 1 = 1/5, score 2 = 1/5; lactotroph tumors, score 0 = 2/5, score 1 = 1/5, score 2 = 2/5; thyrotroph tumors, score 2 = 5/5; corticotroph tumors: score 1 = 1/9, score 2 = 8/9; gonadotroph tumors, score 0 = 2/10, score 1 = 0/10, score 2 = 8/10; and unclassifiable tumor, score 1 = 1/1. INSM1 expression in most PitNETs was obtained, similar to that in the normal pituitary gland; thus, INSM1 may maintain the characteristics of anterior pituitary cells and pituitary tumors.

Overview of the 2022 WHO Classification of Pituitary Tumors.

This review summarizes the changes in the 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors that relate to the pituitary gland. The new classification clearly distinguishes anterior lobe (adenohypophyseal) from posterior lobe (neurohypophyseal) and hypothalamic tumors. Other tumors arising in the sellar region are also discussed. Anterior lobe tumors include (i) well-differentiated adenohypophyseal tumors that are now classified as pituitary neuroendocrine tumors (PitNETs; formerly known as pituitary adenomas), (ii) pituitary blastoma, and (iii) the two types of craniopharyngioma. The new WHO classification provides detailed histological subtyping of a PitNET based on the tumor cell lineage, cell type, and related characteristics. The routine use of immunohistochemistry for pituitary transcription factors (PIT1, TPIT, SF1, GATA3, and ERα) is endorsed in this classification. The major PIT1, TPIT, and SF1 lineage-defined PitNET types and subtypes feature distinct morphologic, molecular, and clinical differences. The "null cell" tumor, which is a diagnosis of exclusion, is reserved for PitNETs with no evidence of adenohypophyseal lineage differentiation. Unlike the 2017 WHO classification, mammosomatotroph and acidophil stem cell tumors represent distinct PIT1-lineage PitNETs. The diagnostic category of PIT1-positive plurihormonal tumor that was introduced in the 2017 WHO classification is replaced by two clinicopathologically distinct PitNETs: the immature PIT1-lineage tumor (formerly known as silent subtype 3 tumor) and the mature plurihormonal PIT1-lineage tumor. Rare unusual plurihormonal tumors feature multi-lineage differentiation. The importance of recognizing multiple synchronous PitNETs is emphasized to avoid misclassification. The term "metastatic PitNET" is advocated to replace the previous terminology "pituitary carcinoma" in order to avoid confusion with neuroendocrine carcinoma (a poorly differentiated epithelial neuroendocrine neoplasm). Subtypes of PitNETs that are associated with a high risk of adverse biology are emphasized within their cell lineage and cell type as well as based on clinical variables. Posterior lobe tumors, the family of pituicyte tumors, include the traditional pituicytoma, the oncocytic form (spindle cell oncocytoma), the granular cell form (granular cell tumor), and the ependymal type (sellar ependymoma). Although these historical terms are entrenched in the literature, they are nonspecific and confusing, such that oncocytic pituicytoma, granular cell pituicytoma, and ependymal pituicytoma are now proposed as more accurate. Tumors with hypothalamic neuronal differentiation are classified as gangliocytomas or neurocytomas based on large and small cell size, respectively. This classification sets the standard for a high degree of sophistication to allow individualized patient management approaches.

High-risk pituitary adenomas and strategies for predicting response to treatment.

High-risk pituitary adenomas are aggressive. They show clinical and imaging features similar to those of carcinomas, including infiltration of the surrounding brain structures, but lack cerebrospinal or systemic metastases. In addition, they display distinct behavior, including tendency for fast growth and frequent recurrences, which are difficult to control. The term "high-risk" adenoma was first introduced in the 4th edition of the World Health Organization Classification of Endocrine Tumors in 2017. Five defined adenoma types belong to this category, including sparsely granulated somatotroph, lactotroph in men, Crooke cell, silent corticotroph, and plurihormonal PIT-1 positive adenomas. The morphological and immunohistochemical characteristics of high-risk adenomas are herein described in detail. In addition, the clinical features and the treatment options are presented. This review focuses on predictive markers assessed by immunohistochemistry, which help clinicians to design the appropriate treatment strategies for high-risk adenomas. Somatostatin receptor status predicts effectiveness of postsurgical treatment with somatostatin analogs, and MGMT expression predicts response to treatment with temozolomide. This comprehensive review presents the clinical and pathological features of high-risk pituitary adenomas, underlines the contribution of immunohistochemistry, and emphasizes the leading role of pathology in the design of optimal clinical management.

JNETS clinical practice guidelines for gastroenteropancreatic neuroendocrine neoplasms: diagnosis, treatment, and follow-up: a synopsis.

Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters-diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel-Lindau (VHL) disease-and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of "neuroendocrine tumor" (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published.

Molecular, functional, and histopathological classification of the pituitary neuroendocrine neoplasms.

In 2017, WHO published an updated classification of the pituitary adenomas according to the lineages defined by the transcription factors, PIT1, SF1 and TPIT. Nomenclature of the pituitary tumors follows the mature cell types such as somatotroph (GH), lactotroph (LH), thyrotroph, corticotroph, and gonadotroph (FSH, LH). Null cell adenomas are defined by the absence of expression of any hormones and transcription factors. Not infrequently, the pituitary adenomas are invasive to the adjacent structures and are designated as aggressive adenomas. Knosp grading is often used to define the aggressiveness of the tumor. Sparsely granulated somatotroph adenomas and Crooke cell corticotroph adenomas are representative aggressive adenomas. Recently, genomics regarding various adenomas have been clarified, such as GNAS for somatotrophs and USP8 for corticotrophs. Familial pituitary adenomas are another aspect which has been clarified such as MEN1, Carney's complex, familial isolated pituitary adenoma and McCune-Albright syndrome. The pituitary adenomas often produce GH or PRL, hormones of PIT1 transcription factor. It has been agreed that the pituitary adenomas share the characteristics of neuroendocrine neoplasms. The terminology of pituitary neuroendocrine tumor has been discussed. This review article covers various aspects of pituitary adenomas.

Digital/Computational Technology for Molecular Cytology Testing: A Short Technical Note with Literature Review.

This short article describes the method of digital cytopathology using Z-stack scanning with or without extended focusing. This technology is suitable to observe such thick clusters as adenocarcinoma on cytologic specimens. Artificial intelligence (AI) has been applied to histological images, but its application on cytologic images is still limited. This article describes our attempt to apply AI technology to cytologic digital images. For molecular analysis, cytologic materials, such as smear, LBC, and cell blocks, have been successfully used for targeted single gene detection and multiplex gene analysis with next-generation sequencing. As a future perspective, the system can be connected to full automation by combining digital cytopathology with AI application to detect target cancer cells and to perform molecular analysis. The literature review is updated according to the subjects.

Survey of surgical resections for neuroendocrine liver metastases: A project study of the Japan Neuroendocrine Tumor Society (JNETS).

BACKGROUND/PURPOSE: Hepatic resection is considered the treatment of choice for neuroendocrine liver metastases (NELM). However, the safety and efficacy of resection have not been fully evaluated using a large cohort. The aim of the present study was to collect real-world data regarding hepatic resections for NELM. METHODS: A retrospective, multicenter survey was conducted. The background characteristics of patients undergoing an initial hepatic resection for NELM, the operative details, pathological findings, and patient outcomes were investigated. RESULTS: A total of 222 patients were enrolled from 30 institutions. The primary tumor site was the pancreas in 58.6%, and the presentation of NELM was synchronous in 63.1% of the cases. Concomitant resection of the primary tumor and liver metastases was performed for 66.4% of the synchronous metastases, and the 90-day morbidity and mortality rates were 12.6% and 0.9%, respectively. The operations resulted in R2 resections in 26.1% of the cases, and 83.4% of the patients experienced recurrence after R0/1 resections. However, the patients were treated using multiple modalities after R2 resection or recurrence, and the overall survival rate was relatively favorable, with 5-year and 10-year survival rates of 70.2%, and 43.4%, respectively. Univariable and multivariable analyses identified the tumor grading (G3) of the primary tumor as a significant prognostic factor for both the recurrence-free and overall survivals. CONCLUSIONS: The present data confirmed the safety of the surgical resection of NELM. Although recurrences were frequent, the survival outcomes after resection were favorable when a multi-disciplinary treatment approach was used.

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.

Histopathology and Cytopathology of Neuroendocrine Tumors and Carcinomas of the Breast: A Review.

Neuroendocrine tumors (NET) and carcinomas (NEC) of the breast are rare diseases, but NEC has attracted attention in both cytopathology and surgical pathology because of its specific management and prognosis. Fine-needle aspiration biopsy (FNAB) cytology can make the diagnosis in many cases particularly with high-grade NEC, with definitive diagnosis based on histopathology and immunohistochemistry. This review describes the characteristics of the disease based on the WHO classification 2012 and recent literature and -includes discussion related to the International Academy of Cytology Yokohama System of Reporting Breast FNAB -cytology.

A case of advanced pancreatic neuroendocrine tumor in which octreotide long-acting repeatable was effective after failure of everolimus and sunitinib.

Molecular targeted drugs, such as everolimus and sunitinib, have shown efficacy against advanced pancreatic neuroendocrine tumors. Octreotide, a somatostatin analogue, improves the hormone-related symptoms in patients with neuroendocrine tumors. Furthermore, it has been reported that octreotide has antitumor activity in patients with metastatic midgut neuroendocrine tumors. However, whether octreotide has anti-proliferative effects in patients with advanced pancreatic neuroendocrine tumors is not fully understood. We report a 71-year-old man with multiple liver metastases of pancreatic neuroendocrine tumor. He was treated with everolimus 10 mg daily and sunitinib 25 mg daily on days 1-14 every 3 weeks at the physician's discretion. However, these molecular targeted drugs were discontinued due to disease progression or severe adverse effects. Octreotide long-acting repeatable was administered continuously from the initiation of everolimus treatment. The tumor marker level markedly decreased and the metastatic liver lesions showed shrinkage with octreotide treatment. Immunohistochemistry of tumor specimens obtained before treatment showed that somatostatin receptor 2, a high-affinity receptor for octreotide, was highly expressed. The clinical course of this patient suggested that octreotide long-acting repeatable may be a treatment option for advanced pancreatic neuroendocrine tumors after failure of everolimus and sunitinib. Further clinical trials are warranted to determine whether the expression of somatostatin receptor 2 in tumor tissues is predictive of octreotide efficacy.

The International Academy of Cytology Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy Cytopathology.

The International Academy of Cytology (IAC) gathered together a group of cytopathologists expert in breast cytology who, working with clinicians expert in breast diagnostics and management, have developed the IAC Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy (FNAB) Cytology. The project was initiated with the first cytopathology group meeting in Yokohama at the 2016 International Congress of Cytology. This IAC Yokohama System defines five categories for reporting breast cytology, each with a clear descriptive term for the category, a definition, a risk of malignancy (ROM) and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category will be presented more fully in a subsequent atlas. The System emphasizes that the crucial requirements for diagnostic breast FNAB cytology are a high standard for the performance of the FNAB and for the making of direct smears, and well-trained experienced cytopathologists to interpret the material. The performance indicators of breast FNAB, including specificity and sensitivity, negative predictive value, positive predictive value and ROM stated in this article have been derived from the recent literature. The current practice of breast FNAB has evolved with the increasing use of ultrasound guidance and rapid on-site evaluation. Two recent publications have shown a range of ROM for the insufficient/inadequate category of 2.6-4.8%, benign 1.4-2.3%, atypical 13-15.7%, suspicious of malignancy 84.6-97.1%, and malignant 99.0-100%. The management algorithm in the System provides options because there are variations in the management of breast lesions using FNAB and core-needle biopsy in those countries utilizing the "triple test" of clinical, imaging, and FNAB assessment, and also variations in the availability of CNB and imaging in low- and middle-income countries. The System will stimulate further discussion and research, particularly in the cytological diagnostic features of specific lesions within each category and in management recommendations. This will lead to continuing improvements in the care of patients with breast lesions and possible modifications to the IAC Yokohama System.

Phase II Trial of Trastuzumab and Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2-Positive Salivary Duct Carcinoma.

PURPOSE: Clinical evidence demonstrating the effectiveness of systemic therapy for advanced salivary duct carcinoma (SDC) is lacking because of the disease's rarity. We assessed the efficacy and toxicity of trastuzumab plus docetaxel in patients with locally advanced and/or recurrent or metastatic human epidermal growth factor receptor 2-positive SDC. PATIENTS AND METHODS: This was a single-center, single-arm, open-label, phase II study in Japan. The patients received trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Docetaxel 70 mg/m2 was administrated every 3 weeks. The primary end point was the overall response rate; the secondary end points included the clinical benefit rate, progression-free survival, overall survival, and toxicity. This study is registered with the University Hospital Medical Information Network Clinical Trials Registry (Identification No. UMIN000009437). RESULTS: Fifty-seven eligible patients with SDC were enrolled. The overall response rate was 70.2% (95% CI, 56.6% to 81.6%), and the clinical benefit rate was 84.2% (95% CI, 72.1% to 92.5%). Median progression-free and overall survival times were 8.9 months (95% CI, 7.8 to 9.9 months) and 39.7 months (95% CI, not reached), respectively. The most frequent adverse event was anemia (52 patients [91%]), followed by a decreased WBC count (51 patients [89%]) and neutropenia (50 patients [88%]). The most frequently observed grade 4 adverse event was a decreased neutrophil count (34 patients [60%]). Grade 3 febrile neutropenia was reported in eight patients (14%). No grade 2 or greater adverse events of heart failure or left ventricular ejection fraction decline to less than 50% occurred. CONCLUSION: Our data show encouraging efficacy of trastuzumab plus docetaxel therapy in patients with human epidermal growth factor receptor 2-positive SDC, with a manageable toxicity profile.