You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Introduction
============

Von Hippel-Lindau disease (VHL) is a hereditary syndrome with an autosomal dominant feature due to a germline mutation of the *VHL* tumor suppressor gene residing in chromosome 3p25.5 ([@B1]). Patients with VHL are at risk of developing various neoplasms, such as central nervous system (CNS) tumors and renal cell carcinoma. Pancreatic neuroendocrine neoplasms are another manifestation associated with VHL. Approximately 10-17% of VHL patients will develop PNET ([@B2]); however, the rate of advanced cases of VHL-related pancreatic neuroendocrine tumor (PNET) with metastasis is reported to be lower than that in patients with sporadic PNET ([@B3]).

According to the WHO 2017 classification (a proliferation-based grading system), PNETs are categorized as NET G1 \[mitotic count, \<2 per 10 high-power fields (HPFs) and/or a Ki67 index of \<2%\], NET G2 (mitotic count 2-20 per 10 HPFs and/or a Ki67 index of 3-20%), NET G3 (well-differentiated type; mitotic count. \>20 per 10 HPFs and/or a Ki67 index of 20%) and NEC G3 (poorly differentiated type: mitotic count, \>20 per 10 HPFs and/or a Ki67 index of 20%). Among the three grades, G3 tumors, which account for 7.5% of all PNETs in Japan, generally tend to progress most aggressively ([@B4]). Due to their rarity, there is currently no consensus on the therapy for advanced VHL-related PNET, especially on cases corresponding to G3.

We herein report a case of VHL-associated PNET G3 that progressed rapidly in spite of molecular targeted therapies.

Case Report
===========

A 45-year old Japanese woman was referred to our hospital for the management of a pancreatic tumor and multiple liver tumors. At 17 years of age, she underwent surgical resection of a cerebellar hemangioblastoma and was diagnosed with VHL following a genetic examination. Genome sequencing revealed a nonsense mutation c.394C\>T(p.Gln132X) in exon 2. There was no evidence of a family history of VHL. She experienced multiple recurrent cerebellar hemangioblastoma and underwent three additional surgical operations. She also had a history of surgery of retinal hemangioblastoma and adrenalectomy for pheochromocytoma at age of 26 and 30 age years of age, respectively.

She presented no symptoms at admission to our hospital. The initial abdominal physical examination revealed no palpable mass and there was no pronounced tenderness.

Routine blood tests revealed no abnormal findings, with the exception of anemia and mildly elevated alkaline phosphatase (ALP) 412 U/L and gamma-glutamyl transpeptidase (γ-GTP)164 U/L levels. Her serum level of chromogranin A 57.8 ng/mL (normal range, \<47 mg/mL) and neuron-specific enolase (NSE) was 15.4 ng/mL (normal range, \<15.1 mg/mL).

Abdominal CT revealed a 4-cm mass with ring enhancement in the pancreatic tail and multiple liver tumors ([Fig. 1a](#g001){ref-type="fig"}), and also showed diffuse pancreatic cystic lesions, which were compatible with simple cysts or neoplasms, as the pancreatic involvement of VHL ([Fig. 1b](#g001){ref-type="fig"}). ^18^F-fluorodeoxy glucose positron emission tomography (FDG-PET)-CT imaging showed the increased uptake in both the pancreatic and liver tumors with maximal standardized uptake values (SUV-max) of 14.0 and 21.1 respectively ([Fig. 1c](#g001){ref-type="fig"}). The examination of a percutaneous liver tumor biopsy specimen led to a diagnosis of NET G3 (Ki-67 index, 40%; mitotic count, \<2 per 10 HPFs) according to the 2017 World Health Organization (WHO) classification. Hematoxylin and Eosin (HE) staining of the specimen should features that were more likely well-differentiated than poorly-differentiated. Immunohistochemically, the tumor cells were positive for synaptophysin, CD56, AE1/AE3, CAM5.2 and negative for chromogranin A.

![Images on the first admission. a: Computed tomography (CT) showed a hyper-vascular mass with a hypo-vascular lesion in the center of the pancreatic tail (arrow) and liver masses (arrowhead). b: CT also showed multiple pancreatic cysts (arrow), which were compatible with simple cysts or serous neoplasms. c: ^18^F-fluorodeoxy glucose-positron emission tomography showed the abnormal uptake of the mass lesions.](1349-7235-57-2007-g001){#g001}

We suggested the treatment choices to the patient, including systematic chemotherapy using a platinum-based regimen and molecular targeted therapy. She selected the latter using everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Everolimus was started at a daily dose of 10 mg and no severe adverse events were observed. CT image at 3 months after the initiation of everolimus showed no progression of the primary or metastatic tumors. However, a further 3 months later, her liver metastases increased in size. As a second-line therapy, she was given a multi-tyrosine kinase inhibitor sunitinib. Sunitinib as administered at the initial dose of 37.5 mg, daily for 2 weeks; the dose was then reduced to 25 mg daily because of adverse events (hypertension and facial edema). A one month after the dose reduction, sunitinib therapy was stopped because the size of liver metastases had significantly increased. After treating the patient with molecular targeted therapies, which showed low effectiveness, we introduced platinum-based chemotherapy as a third-line therapy, based on the consideration that the tumor was composed of poorly-differentiated cells. However, everolimus was eventually re-attempted. Unfortunately, the liver metastases increased in size and number at 3 months after the second administration of everolimus. Although the administration of irinotecan plus cisplatin was initially performed as a next step, the tumor progression led to the gradual deterioration of her general condition. Thus, chemotherapy was discontinued during the first course. She died just 13 months after the initial diagnosis of PNET. An autopsy was performed.

Macro-pathologically, a 5-cm multinodular tumor was located in the pancreatic tail and several serous cystic neoplasms were seen in the pancreas. In addition, multiple brown tumors and white nodules were found scattered in the liver and lungs, respectively. Micro-pathologically ([Fig. 2](#g002){ref-type="fig"}), the Ki-67 index of the primary tumor was 25% and the number of mitotic cells seen in the tumor was approximately 1 per 10 HPFs. The final diagnosis was NET-G3, because of the low nuclear grade and because the cell morphology of the primary neuroendocrine neoplasm differed from large or small cell carcinoma. Immunohistochemistry (IHC) revealed that the tumor was positive for synaptophysin, chromogranin A and CD56 and negative for gastrin, insulin, glucagon, somatostatin and vasoactive intestinal peptide (VIP). Additionally, IHC revealed Rb immunopositivity. In addition, the findings from the pathological examination of the liver and lung tumors were consistent with metastases of PNET. Furthermore, some necrosis and the disappearance of tumor cells was seen in the liver tumor, which might reflect the influence of molecular targeted therapy.

![A microscopic examination of the pancreatic tumor (Hematoxylin and Eosin staining) showed nests of small polygonal cells, separated by thin fibrous septae and typical salt and pepper chromatin in each cell (magnification. a: ×100, b: ×400). c: Immunohistochemistry showed that the Ki-67 labeling index of the pancreatic tumor was 25% (MIB-1 staining, magnification 100×). d: The retained expression of Rb in the pancreatic neuroendocrine tumor was indicated by immunohistochemistry (magnification 40×).](1349-7235-57-2007-g002){#g002}

Discussion
==========

VHL is hereditary cancer syndrome with an autosomal dominant feature due to a germline mutation of the *VHL* tumor suppressor gene residing in chromosome 3p25.5 ([@B1]). Patients with VHL frequently develop central nervous system (CNS) tumors including cerebellar, brainstem, nerve root, and supratentorial haemangioblastomas. In addition, renal cell carcinomas (RCC), phaeochromocytomas, pancreatic cysts and PNET may develop. Haemangioblastomas of CNS and RCC are considered to be common causes morbidity in VHL patients ([@B5], [@B6]). However, few patients die due to pancreatic involvement. The mortality rate of patients with pancreatic manifestations is reported to be only 0.5% (3/633) ([@B7]). Generally, in comparison to sporadic PNET, VHL-associated PNET is reported to have low-malignant potential ([@B8]-[@B10]), and it rarely results in death. In Japan, PNET with metastasis was found in only 7.5% of VHL patients and no PNET-related deaths were reported among patients with VHL-associated PNET ([@B3]). The fact that the majority of VHL-associated PNET cases involved G1 or G2 disease ([@B11]) may be one of the reasons for the better prognosis of patients with VHL-related PNET. However, in the present case, PNET led to death and the survival time was only 13 months. Blansfield et al. reported that a primary lesion of \>3 cm in size, a doubling time of \<500 days and exon 3 mutation of *VHL* are predictors of malignant potential in VHL-associated PNET ([@B7]). In the present case, the tumor was over 3 cm in size and the tumor doubling time was 208 days before treatment, which indicated aggressive behavior. However, the mutation site was in exon 2 (not exon 3), which did not correspond to the previous report.

A search of the Pubmed database using the search term, "Neuroendocrine carcinoma" and "von Hippel Lindau Disease (VHL)" or "Neuroendocrine neoplasm" and "WHO G3" and "VHL" revealed no reports. To the best of our knowledge, this is the first report on the treatment of advanced VHL-associated PNET G3.

Recently, the concept that PNET with a Ki-67 index of \>20% includes 2 categories-well-differentiated neuroendocrine carcinoma (WDNEC) and poorly-differentiated neuroendocrine carcinoma (PDNEC)-was established ([@B12], [@B13]). After the WHO 2010 classification, pancreatic NEC was divided into NET G3 and NEC G3 in the WHO 2017 classification ([@B14]). In contrast to NEC G3, platinum-based chemotherapy was shown to be ineffective for NET G3 ([@B15]). However, it is difficult to distinguish between NET G3 and NEC G3 in some cases (including the present case). Tang et al. ([@B12]) reported that IHC to detect Rb may help to distinguish between these two entities, because the rates of PDNEC and WDNEC in cases that were negative for the expression of Rb (as assessed by IHC) were 86% and 0%, respectively. It was also shown that platinum-based chemotherapy is less effective for Rb-positive PNET than it is for Rb-negative PNET ([@B16]). The present case was classified as NET G3 based on the cell morphology, and the Rb immunopositivity of the tumor cells. Thus, a poor response to platinum-based chemotherapy could be predicted in the present case.

Everolimus, a molecular targeted drug was used as a first-line therapy for this patient. The efficacy of everolimus for PNET G1 and G2 was shown in a clinical trial ([@B17]). Furthermore, the administration of everolimus was associated with good outcomes in WDNEC. The progression-free survival (PFS) and overall survival were 6 months and 28 months, respectively ([@B18]). In our case, first-line therapy with everolimus resulted in PFS for 6 months. Although this indicated that everolimus would be effective, the result was worse than the results observed in patients with NET G1 and G2.

Sunitinib, which was used as the second-line therapy for this case, is a multi-tyrosine kinase inhibitor targeting signals of vascular endothelial growth factor (VEGF) receptor 1,2 and platelet-derived growth factor (PDGF)-beta receptor, which is related to tumor vascularity, metastasis, and proliferation ([@B19]). The antitumor efficacy of sunitinib in the treatment of PNET G1/G2 was also shown in a clinical trial ([@B19]). According to a genetic analysis ([@B20]), tumor angiogenesis factors, including VEGFR1 and 2, are expressed at higher levels in patients with VHL-related PNET than in those with sporadic PNET. To support this, there is a report of a case in which sunitinib therapy resulted in a good prognosis in a patient with VHL-related PNET ([@B19]). However, in the present case, the response to sunitinib was ultimately unfavorable.

On the other hand, streptozocin, which was shown to be effective and safe for WDNEC (NET G3) ([@B21]), might have been an option in this case. However, it was not on the market in Japan at that time. Greater clinical experience is required to build a consensus on the efficacy of everolimus and sunitinib therapy in cases of VHL-associated NET G3.

We reported an advanced case of VHL-associated PNET, which followed an aggressive clinical course. Further cases of NET G3 with VHL should be accumulated.

**The authors state that they have no Conflict of Interest (COI).**

[^1]: Correspondence to Dr.　Ken Kawabe, <<PRESIDIO_ANONYMIZED_EMAIL_ADDRESS>>