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 {#Sec1}
============

Trans-oral laser microsurgery (TLM) is a well-known and widely used method in the treatment of early and moderately advanced glottic cancer. It is characterized by a high rate of local control, five-year survival and five-year disease-free survival^[@CR1],[@CR2]^. However, TLM is associated with a risk of both major postoperative complications such as bleeding or dyspnoea and minor complications such as granulomas, laryngeal webbing and scaring.

Laryngeal granulomas (LG) belong to late, minor, postoperative complications following TLM. LG and glottic web constitute 22% of all complications and affect more likely patients after TLM involving the anterior commissure (AC)^[@CR3]^. LG are mucosal lesions consisting of granulation tissue and arise as tissue's response to injury and irritation^[@CR4]^. Lee *et al*. proved that the frequency of aforementioned complications following TLM depends on surgeon's experience and the size of the tumor^[@CR2]^. Most often, LG occurs within 1 or 2 months after surgery^[@CR4]^. According to the literature, there is no dedicated treatment for LG. There are two approaches: (1) conservative therapy (antireflux therapy, voice therapy, botulin toxin, mitomicin C, steroids) and (2) surgery^[@CR5]^. Proton pump inhibitors (PPIs) are widely used to treat LG, as laryngopharyngeal reflux is present in up to 76% of affected patients^[@CR5]--[@CR7]^. Surgical methods, CO~2~ laser or cold instruments, are faster than conservative therapy, however, they involve a significant risk of local scarring and recurrence. Surgery is traditionally reserved for persisting cases^[@CR5]^. Although LG are purely benign lesions, there is always a concern of the cancer recurrence within LG or in the surrounding tissue.

In our study, we want to address a question, whether narrow-band imaging (NBI) is useful in the assessment of patients with granuloma-like lesion following TLM due to glottic cancer. NBI is a reliable blue light endoscopy, which is widely used in the detection of early head and neck cancers by assessing mucosal vascular pattern. Thereby, the aim of this study was to evaluate NBI in the differentiation between postoperative laryngeal granuloma and local tumor recurrence.

Material and Method {#Sec2}
===================

We enrolled 154 consecutive patients with confirmed diagnosis of laryngeal cancer, who underwent TLM cordectomy between April 2015 and November 2017 in two tertiary referral centres in Poland: Poznan 114/154 (74.03%) and Lodz (40/154 (26.97%) Medical University Department of Otolaryngology. Demographic and clinical characteristics of enrolled patients are presented in Table [1](#Tab1){ref-type="table"}.Table 1Demographic and clinical characteristics of enrolled patients.VariableAll patientsPatients with LGP valueN (%)N (%)Sex   Male138 (90)41 (87)0.522^a^   Female16 (10)6 (13)Smoking history   Current heavy smoker64 (42)23 (49)0.218^a^   Former or never smoker90 (58)24 (51)T-status   Tis22 (15)3 (7)0.191^a^   T1a44 (29)12 (26)   T1b24 (16)8 (17)   T261 (40)23 (50)Cordectomy type   I14 (9)2 (4)0.373^a^   II15 (10)3 (6)   III26 (17)6 (13)   IV22 (14)9 (19)   V43 (28)14 (30)   VI34 (22)13 (28)Treating Department   Poznan114 (74)36 (77)0.630^a^   Lodz40 (26)11 (23)Location of LG   AC22 (47)---   PG20 (43)   MG5 (10)^a^Chi2 test.

Following TLM, all patients were scoped once a month with trans-nasal flexible video-endoscope (Olympus Medical System Corporation, Tokyo, Japan) by means of white light, NBI and video-stroboscopic evaluation.

In 47/154 patients (31%) granuloma-like lesion (GLL) was found. In 22 cases (47%), it was localised in the anterior commissure, 20/47(43%) in posterior one third of the glottis and 5/47 (11%) in the middle part of the glottis (Table [1](#Tab1){ref-type="table"}).

First, each patient with GLL underwent trans-nasal flexible video-endoscope (Olympus Medical System Corporation, Tokyo, Japan) with the optical filter for NBI. By using blue light (NBI), we assessed the vascular pattern of glottis and in particular vascular pattern of granulation tissue and mucosa surrounding the lesion. The diagnostic criteria defining suspected character of the lesion in NBI endoscopy were as follows: symmetrical arranged brown dot-like loops with narrow-angled turning point, which correspond to perpendicular vascular changes according to European Laryngological Society (ELS) classification^[@CR8]^.

Detecting perpendicular vascular changes during NBI, in or surrounding granulation tissue, classified those patients to the "suspicious" group A. The remaining patients, presenting with longitudinal vascular pattern, which is considered normal, were qualified to the group B. Following NBI endoscopy, excisional biopsies with a cold instrument under general anaesthesia were performed in all patients. Eventually, the surgical specimens were sent to pathology. Moderate and severe dysplasia, carcinoma *in situ* and invasive cancer were defined as positive histology, laryngeal granuloma and other benign laryngeal lesions as negative histology and premalignant lesions as suspicious histology.

The main predictive variables were mucosa and submucosa vascular pattern in patients with GLL (according to ELS classification) and final histology. The additional variables were age, sex and number of days following TLM to GLL detection.

The primary outcome measure was the correlation between the observed vascular pattern of mucosa (according to ELS classification) surrounding GLL and the result of the final histology.

Ethical approval {#Sec3}
----------------

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol was approved by Bioethics Committee of Poznan University of Medical Sciences.

Informed consent {#Sec4}
----------------

Informed written consent was obtained from all individual participants included in the study.

Result {#Sec5}
======

Out of 47 patients, who presented with GLL, 13/47 (28%) (group A) had perpendicular vascular changes visualized in NBI on the mucosa surrounding granulation tissue (Fig. [1](#Fig1){ref-type="fig"}). The remaining 34/47 (72%) (group B) had longitudinal vascular changes on mucosa surrounding GLL (Fig. [2](#Fig2){ref-type="fig"}). In all patients, the microvascular pattern in NBI was compared with the final histology.Figure 1Granuloma-like lesion with the suspicious vascular pattern in NBI.Figure 2Granuloma-like lesion with the benign vascular pattern in NBI.

In group A, with suspicious, perpendicular vessels seen in NBI, the final histology results were: 13/13 (100%) samples were positive: 10/13(77%) severe dysplasia, 1/13(8%) cancer *in situ*, 2/13(15%) moderate dysplasia. (Graph 1.) In group B, with longitudinal vessels seen in NBI, the final histology results were: 3/34 (9%) samples were positive: 3/3: moderate dysplasia, 30/34 samples were negative, all samples were granulation tissue (Fig. [3](#Fig3){ref-type="fig"}).Figure 3The summary of results.

There was a significant correlation between the vascular pattern of the mucosa in NBI in area of the granuloma tissue and the final histological result: Chi2(1) = 34.82; p = 0.00001 (Table [2](#Tab2){ref-type="table"}). Sensitivity, specificity and accuracy of NBI were as follows: 81%, 100%, 94%.Table 2Chi-square analysis of the NBI vascular pattern vs histology result.Positive NBI vascular patternNegative NBI vascular patternPositive histology133Negative histology031Chi2(1) = 34.82; p = 0.00001

The local recurrence of laryngeal cancer after excisional biopsy was found in 1/47 (2%) patient during 10^th^ month of follow-up. In presented group, the mean number of days to detection of GLL was 164 days. The earliest detected GLL was visualized after 10 days and the latest after 577 days following TLM. There was no statistically significant correlation between presence of GLL and sex, smoking history, initial T-status, type of cordectomy or treating department (Table [1](#Tab1){ref-type="table"}).

Discussion {#Sec6}
==========

Narrow band imaging has been in use in laryngology for 10 years now. In our previous papers, we proved that the NBI sensitivity, specificity and accuracy in detection of premalignant and malignant head and neck tumors is higher compared with classical endoscopy with white light only^[@CR9],[@CR10]^. At first, NBI positive findings were identified as well-demarcated areas with scattered brownish spots^[@CR11],[@CR12]^. In 2011, Ni *et al*. introduced the NBI classification for premalignant and malignant lesions in larynx. This classification consists of five types of different vascular patterns; additionally type 5 is divided into three subtypes. Types 1--3 are identified as vascular pattern characteristic for benign lesions, whereas types 4--5 are common in premalignant and malignant lesions^[@CR13]^. However, the aforementioned classification is difficult to implement in everyday practice. Therefore, European Laryngeal Society (ELS) in 2016 proposed simpler classification for glottic lesions^[@CR8],[@CR14]^. Authors distinguished only two types of vascular patterns. The first type is characterized by longitudinal vessels in two dimensions (length and width) and represents benign lesions. The second type, which are perpendicular vessels in third dimension towards the surface of the epithelium, represents premalignant and malignant lesions^[@CR8]^.

In our study, the new classification introduced by ELS (2016) was used to assess vascular pattern surrounding granuloma-like lesions following TLM. Lesions characterized by perpendicular vascular pattern or intraepithelial papillary capillary loops, were identified as NBI positive, others as NBI negative.

Granulomas can be divided according to their etiology into two main subtypes: spontaneous granulomas, also known as contact granulomas, and iatrogenic granulomas^[@CR15]^. In this study, we assessed only patients with iatrogenic granulomas, sequel of CO~2~ laser cordectomies. The inflammation process that is associated with infection of the perichondrium is a trigger in granuloma formation process. According to many authors, the common histological features of granulomas are identified as nonspecific reparative granulation tissue covered by hyperplastic squamous epithelium with acanthotic thickening^[@CR16],[@CR17]^. In this study, the definite confirmation of the benign character of granuloma-like lesion was the granulation tissue without atypical cells in the final histology examination.

Shoffel-Havakuk *et al*.^[@CR15]^ claimed that smoking is a significant risk factor in patients with iatrogenic granuloma. In our group, a significant proportion of patients 23/47(49%), who developed GLL were in fact heavy smokers. Schoffel-Havakuk *et al*.^[@CR15]^ considered a pedunculated character of lesion as a common feature of iatrogenic granulomas; we confirmed this finding in our study in majority of patients (40/47).

The main feature of all granulomas is their typical location: the posterior third of the glottis. The primary laryngeal cancer in this location is very rare. If present in this site, usually is a result of cancer extension from the anterior glottic lesion^[@CR18]^. Among our patients, 22/47 had granuloma in the anterior commissure, 20/47 in the posterior third of the glottis and 5/47 in middle part of the glottis. NBI positive lesions (13/47), which were confirmed in histology, were localized respectively: 8 in anterior commissure, 3 in middle part of the glottis and 2 in the posterior part of the glottis. According to these results, localization not always is a good prognostic factor to predict benign character of granuloma following TLM. Therefore, NBI can be very helpful in determination of the potential local recurrence or benign granuloma.

Iatrogenic granulomas have shorter recovery time and lower recurrence rate in comparison to spontaneous granulomas. Therefore, based on our findings, we recommend for patients after TLM with typical features for contact granulomas and without pathological vessels in NBI, conservative treatment (antireflux therapy) and close observation. According to our experience, the need for biopsy among patients after TLM should be based on clinical assessment by white light and NBI endoscopy and initial response to antireflux medication.

Conclusions {#Sec7}
===========

Based on our results, NBI can reliably differentiate between postoperative laryngeal granuloma and local tumor recurrence. We recommend that in cases of typical granuloma without pathological vessels in NBI, conservative antireflux therapy should be implemented. However, these patients should remain under close and regular tumor follow-up.

**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

H.K. and J.J. performed examination of patients, all authors actively participated in data analysis and in writing this manuscript.

H.K. literature search, figures, study design, data collection, data analysis, data interpretation, writing. W.P. figures and study design, data collection, data analysis, data interpretation, writing. J.J. literature search, figures, study design, data collection, data analysis, data interpretation, writing. K.P. literature search, figures, study design, data analysis, data interpretation, writing. M.W. study design, data analysis, data interpretation, literature search, merit supervision.

The authors declare no competing interests.