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
============

Sarcomas are infrequent and heterogeneous tumours. They represent 1--2% of all adult malignant neoplasms and between 4% and 10% of head and neck cancers \[[@ref1]--[@ref4]\]. More than 50 histological varieties have been described with different biological behaviours \[[@ref5]\]. The natural history of head and neck sarcomas is similar to that of sarcomas of the limbs; however, the anatomical complexity of this area makes surgical management difficult, since extensive surgery, with significant functional and aesthetic sequelae, is required to obtain adequate margins. Factors such as the histological subtype, degree of differentiation, and extent of the disease influence the patient's survival and should be taken into consideration when preparing the treatment plan \[[@ref5]\].

The purpose of this research was to evaluate the clinical characteristics and factors influencing the survival of patients with soft-tissue sarcomas in the Social Security Institute's Hospital Oncology Service (SOH-IVSS) in the period between 1991 and 2016.

Materials and methods
=====================

Sixty-two patients with soft-tissue sarcomas of the head and neck were treated in the SOH-IVSS between 1991 and 2016. Patients with bone sarcomas, carcinosarcomas, and Kaposi's sarcoma, as well as patients of paediatric age, were excluded from the study.

Sarcomas were classified histologically according to the definitions set forth by the World Health Organisation (WHO), and the American Joint Committee on Cancer (AJCC) 7th edition (2010) classification was used to determine the stage of the patients' tumours \[[@ref7]\]. The tumour differentiation grade was established using the French FNCLCC (Fédération Nationale de Centres de Lutte Contre le Cancer \[National Federation of Cancer Research Centers\]) gradation system \[[@ref8]\]. A *R*0 resection was considered when the margins were negative, *R*1 when they were microscopically positive, and *R*2 in the case of macroscopic residual disease.

The research was retrospective, descriptive, and cross sectional. The following variables were evaluated: age, sex, location, symptoms, histological subtype, tumour size, differentiation grade, the presence of nodal disease and remote metastasis, treatment performed and surgical margins.

The mean and standard deviation of the continuous variables were calculated, as well as the frequency and percentages of the nominal variables. Overall survival (OS) was analysed for the different evaluated factors. The calculation of overall survival was based on Kaplan--Meier's non-parametric model. Survival curves were compared with the log-rank procedure and were considered to be statistically significant if *p* \< 0.05. The multivariable analysis was performed using Cox regression.

Results
=======

The mean age of patients with soft-tissue sarcomas of the head and neck was 45 years with a standard deviation of 19 years; the time from onset of disease to the first evaluation in our hospital was 6 months: (interval 1--360); the mean tumour size was 7.1 cm with a standard deviation of 4.0 cm. There were more males than females (54.8% vs. 45.2%). The most frequent symptom was the presence of a tumour in 92%; other symptoms were dysphonia (4.8%) and nasal obstruction and/or epistaxis (3.2%). Regarding location, 25.9% originated in the soft tissue of the neck; 22.6% in the maxillary antrum; 14.5% in the oral cavity; 14.5% on the scalp; 12.9% on facial skin, among others ([Table 1](#table1){ref-type="table"}).

Based on the Tumour, Node, Metastasis (TNM) categorisation of tumours according to the AJCC classification, 49.9% were classified as T2b tumours, corresponding to tumours larger than 5 cm located in a deep plane. With respect to lymph node status, the most frequent category was N0 in 96.8% of cases. There was an absence of remote metastasis at the time of diagnosis in 95.2% of cases.

Regarding the clinical stage, the majority were stage III (40.2%); followed by stage Ia and Ib, with 19.4% each ([Table 2](#table2){ref-type="table"}).

Regarding the nuclear grade, most tumours were considered to be poorly differentiated (grade 3) at 61.3%; well-differentiated tumours (grade 1) occurred in 30.6% of cases and moderately differentiated tumours (grade 2) in 7.9% ([Table 2](#table2){ref-type="table"}). Undifferentiated pleomorphic sarcoma was the most frequently observed histological type (24.2%), followed by malignant peripheral nerve sheath tumours ([Table 3](#table3){ref-type="table"}).

Regarding the involvement of the tumour in neighbouring structures ([Table 4](#table4){ref-type="table"}), in 62.9% of cases, there was no evidence of involvement of the bone or neurovascular structures, whereas 30.6% had bone involvement and 6.5% involvement of blood vessels and/or nerves.

Regarding the treatment received, 43.5% were treated with surgery alone; 35.5% with surgery followed by external beam radiation therapy, and 14.3% were not able to be treated surgically. Of the patients operated on, the majority (69.8%) had wide and negative resection margins, 30.2% had microscopically positive margins and none had macroscopically positive margins.

Until the end of follow-up, 51.5% did not present with relapses, while 37.2% had some type of relapse during their treatment. It was also observed that 11.3% progressed under treatment.

[Table 5](#table5){ref-type="table"} presents the final indicators; the disease-free interval (DFI) had a median of 19 months (mean 43 months); the follow-up had a median of 20 months (mean 44 months). At the end of the follow-up, 50% of the patients were alive without disease and 35.5% dead with disease. Age, tumour size, and the presence of negative margins were not associated with survival. T2a and T2b tumours (*p* = 0.014), the presence of lymph node metastasis (*p* = 0.001), advanced stages (*p* = 0.003), and invasion of bone, blood vessels and/or nerves (*p* = 0.008) are associated with decreased survival ([Figures 1](#figure1){ref-type="fig"}--[4](#figure4){ref-type="fig"}).

T2a and T2b tumours (*p* = 0.002), stages III and IV (*p* = 0.019) and the involvement of blood vessels, nerves and/or bone were associated with decreased survival in the multivariable analysis ([Table 6](#table6){ref-type="table"}).

Discussion
==========

Head and neck sarcomas are infrequent and heterogeneous tumours. Studies of this entity are limited by the small number of patients and the different biological behaviour of the distinct histological subtypes \[[@ref9]\].

In this research, the mean age was 45 years, the male sex was the most frequently affected (54.8%) and the mean tumour size was 7.1 cm. In general, the age of presentation is between 50 and 60 years when the paediatric population is not included \[[@ref2], [@ref9], [@ref10]\]. The younger mean age of diagnosis in our study cannot be explained by early diagnosis as 70.9% of the patients had tumours larger than 5 cm.

As in most of the reports, predominance of the male sex was observed \[[@ref5], [@ref9]--[@ref11]\]. The data on the stage of the disease at the time of diagnosis are varied, Barker *et al*. had only 11% of head and neck sarcomas diagnosed in stages III and IV \[[@ref10]\]; in our research, 45% presented in these stages.

Differences in the way of grouping the areas where the sarcomas originate makes it difficult to compare the series. Salcedo *et al*. report in their research that the two most frequent locations were the paranasal sinuses and the soft tissues of the neck, as in our study \[[@ref9]\]. Because of their proximity to vital structures, head and neck sarcomas present surgical difficulties and, depending on their location, may be managed with greater or lesser difficulty. Tumours located in the soft tissues of the neck or on the scalp tend to be more easily treated, but tumours located in the paranasal sinuses tend to be in the vicinity of the brain, which makes treatment more complex; this translates into a greater likelihood of positive margins after surgery.

A relevant factor in the classification of sarcomas is their histological grade; in our research, this was not associated with a decrease in survival, however, this link has been established in other research \[[@ref5], [@ref9]--[@ref11]\].

Whenever feasible, surgery is the central element in the treatment of soft-tissue sarcomas. In our series, as in most reports, surgical treatment was performed on the majority of patients. Given the anatomical complexity of the head and neck area, obtaining negative margins is not always possible. In our research, 30.2% of the cases had microscopically positive margins; this coincides with the data reported by Salcedo *et al*.; however, in our case, this factor had no adverse effects on survival \[[@ref9]\].

Invasion of adjacent structures is an infrequent phenomenon in head and neck sarcomas. According to Le Vay *et al*., an independent prognostic factor which is considered to be highly significant in terms of local control and survival is tumoural involvement of the bone, neurovascular structures or the skin \[[@ref12]\]. In our study, invasion of adjacent structures was an important factor, occurring in 37.1% of cases. Invasion of neighbouring structures was a significant factor for decreased survival.

As in most series, advanced stages (III and IV), the presence of lymph node metastasis, tumour size greater than 5 cm and invasion of bone, blood vessels, and/or nerves adversely and significantly affected the survival of the patients \[[@ref5], [@ref9]--[@ref14]\].

Conclusions
===========

Soft-tissue sarcomas of the head and neck are heterogeneous tumours with different biological behaviour depending on their histological type and degree of differentiation. Our research evaluated 62 patients with a diagnosis of soft-tissue sarcoma of the head and neck treated over a 25-year period. Several factors were discovered, which are considered to be prognoses of survival. One of these was tumour size; tumours larger than 5 cm usually had a worse prognosis than those measuring less than 5 cm. Another prognostic factor was the stage; patients with stage III and IV tumours had lower survival than those with earlier stage tumours. Finally, the invasion of neighbouring structures, such as bone, nerves, and/or blood vessels, which is directly correlated with increased local aggressiveness of the tumour, also represented a significant prognostic factor.

Major prognostic factors should be taken into account to determine which lesions should be considered to be potentially recurrent and to choose the most effective treatment regime.

The management of these tumours continues to be a major challenge for the multidisciplinary cancer team due to the unusual presentation, the diversity of histological types and the complexity of treatment, taking into account the proximity of the vital structures of the head and neck to the tumour.

Due to the rarity and diversity of head and neck sarcomas, it is difficult for institutions to gain much experience. To obtain better results in the study of prognostic factors, it will be necessary to combine the experience of multiple institutions in order to add a greater number of patients and to determine with greater accuracy the factors that may influence prognosis.

Conflicts of interest.
======================

There are no conflicts of interest.

![Kaplan--Meier survival curve according to T classification.](can-11-740fig1){#figure1}

![Kaplan--Meier survival curve according to N classification.](can-11-740fig2){#figure2}

![Kaplan--Meier survival curve according to stage.](can-11-740fig3){#figure3}

![Kaplan--Meier survival curve according to involvement.](can-11-740fig4){#figure4}

###### Characteristics of the sample according to clinical and epidemiological indicators.

  Variables                                                            Statistics
  -------------------------------------------------------------------- ------------
  Number of patients                                                   62
  Age (years) [(\*)](#table1_fn1){ref-type="table-fn"}                 45 ± 19
  Evolution time (months) [(\*\*)](#table1_fn2){ref-type="table-fn"}   6 (1--360)
  Size (cm) [(\*)](#table1_fn1){ref-type="table-fn"}                   7.1 ± 4.0
  Sex                                                                  
  Male                                                                 34 (54.8%)
  Female                                                               28 (45.2%)
  Symptoms                                                             
  Tumour                                                               57 (92.0%)
  Dysphonia                                                            3 (4.8%)
  Nasal obstruction and/or epistaxis                                   2 (3.2%)
  Location                                                             
  Soft tissue of the neck                                              16 (25.9%)
  Maxillary antrum and/or nasal fossa                                  14 (22.6%)
  Oral cavity                                                          9 (14.5%)
  Scalp                                                                9 (14.5%)
  Facial skin                                                          8 (12.9%)
  Larynx                                                               3 (4.8%)
  Oropharynx                                                           1 (1.6%)
  Ethmoidal or sphenoidal sinus                                        1 (1.6%)
  Parotid                                                              1 (1.6%)

mean ± deviation

median (minimum--maximum)

###### Characteristics of the sample according to anatomopathological indicators.

  Variables          NP %
  ------------------ -----------
  T classification   
  T1a                6 (9.7)
  T1b                12 (19.4)
  T2a                13 (21.0)
  T2b                31 (49.9)
  N classification   
  N0                 60 (96.8)
  N1                 2 (3.2)
  M classification   
  M0                 59 (95.2)
  M1                 3 (4.8)
  Nuclear grade      
  Grade 1            19 (30.6)
  Grade 2            5 (8.1)
  Grade 3            38 (61.3)
  Stage              
  Ia                 6 (9.7)
  Ib                 12 (19.4)
  IIa                12 (19.4)
  IIb                4 (6.5)
  III                25 (40.2)
  IV                 3 (4.8)

NP = number of patients

###### Characteristics of the sample according to the histological diagnosis.

  Histological diagnosis                     NP %
  ------------------------------------------ ----------
  Undifferentiated pleomorphic sarcoma       15(24.2)
  Fibrosarcoma                               10(16.1)
  Leiomyosarcoma                             9 (14.5)
  Dermatofibrosarcoma                        6 (9.7)
  Malignant peripheral nerve sheath tumour   5 (8.0)
  Pleomorphic rhabdomyosarcoma               4 (6.5)
  Angiosarcoma                               4 (6.5)
  Liposarcoma                                4 (6.5)
  Synovial sarcoma                           2 (3.2)
  Lone fibrous tumour                        2 (3.2)
  Myxofibrosarcoma                           1 (1.6)

NP = number of patients

###### Characteristics of the sample according to clinical--surgical indicators.

  Variables                                                       NP %
  --------------------------------------------------------------- -----------
  Involvement                                                     
  No involvement                                                  39 (62.9)
  Bone                                                            19 (30.6)
  Blood vessels and/or nerves                                     4 (6.5)
  Treatments                                                      
  Just surgery                                                    27 (43.5)
  Surgery + POEBRT[\*](#table2_fn1){ref-type="table-fn"}          22 (35.5)
  Surgery + POEBRT + CT[\*\*](#table2_fn2){ref-type="table-fn"}   4 (6.5)
  Just CT                                                         1 (1.6)
  Just EBRT[\*\*\*](#table2_fn3){ref-type="table-fn"}             2 (3.2)
  CT + EBRT                                                       6 (9.7)
  Margins                                                         
  *R*0                                                            37 (69.8)
  *R*1                                                            16 (30.2)
  *R*2                                                            0
  Relapse                                                         
  No relapse                                                      32 (51.5)
  Local relapse                                                   12 (19.4)
  Remote relapse                                                  6 (9.7)
  Local and remote relapse                                        5 (8.1)
  Progression and/or persistence under treatment                  7 (11.3)

NP = number of patients

Postoperative external beam radiation therapy.

Chemotherapy.

External beam radiation therapy.

###### Characteristics of the sample according to final events.

  Variables                                                                                                         Statistics
  ----------------------------------------------------------------------------------------------------------------- ----------------
  Disease-free interval (months)([\*](#table5_fn2){ref-type="table-fn"}/[\*\*](#table5_fn1){ref-type="table-fn"})   19/43 (1--211)
  Follow-up (months)([\*](#table5_fn2){ref-type="table-fn"}/[\*\*](#table5_fn1){ref-type="table-fn"})               20/44 (1--211)
  Final results                                                                                                     
  Alive without disease                                                                                             31 (50.0%)
  Alive with disease                                                                                                3 (4.8%)
  Dead with disease                                                                                                 22 (35.5%)
  Dead without disease                                                                                              5 (8.1%)
  Losses                                                                                                            1 (1.6)

median

mean (minimum--maximum)

###### Cox regression.

  Variables                           RR         95% CI     p           
  ----------------------------------- ---------- ---------- ----------- -----------
  Age ( \> 45 years)                  1.09       0,37       3.25        0.265
  **T classification (T2a or T2b)**   **5.19**   **1.57**   **17.16**   **0.002**
  N classification (N1)               1.30       0.99       2.16        0.547
  M classification (M1)               1.02       0.90       2.09        0.485
  Nuclear grade (G3)                  0.55       0.14       1.12        0.591
  **Stage (III or IV)**               **3.64**   **1.13**   **5.14**    **0.019**
  **Involvement (yes)**               **2.71**   **1.06**   **6.92**    **0.037**
  Margins (positive)                  2.35       0.72       7.68        0.159