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| <h1>Early Diagnosis</h1> | | <h1>Early Diagnosis</h1> |
− | | + | <p>Author Bozitaozhong</p> |
| <h2> | | <h2> |
| <a id="section1"> | | <a id="section1"> |
| <span class="place_holder"></span> | | <span class="place_holder"></span> |
− | Section1
| + | INTRODUCTION |
| </a> | | </a> |
| </h2> | | </h2> |
− | <p><strong>Instructions: you have the change not only the main text, but also have to modify the text in the navgation bar on the left side. Now put your content here and do the same for the following sections. </strong>xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx Note template is here --- | + | <p>Each year, more than <strong>14 million</strong> people are diagnosed with cancer, the majority of whom live in low- and middle-income countries (LMICs). The number of deaths due to cancer in LMICs exceeds those due to HIV/AIDS, tuberculosis and malaria combined.<br> |
− | <span class="footnote_link">OD
| + | <br> |
− | <span class="footnote">
| + | Approximately <strong>two thirds</strong> of global cancer deaths are in less developed countries, where case fatality rates are higher due to late-stage presentation and less accessible treatment. The consequences of delays in care and advanced cancer are dire, as the likelihood of death and disability from cancer increases significantly as cancer progresses. It is therefore critical to develop programs to provide access to timely diagnosis and treatment.<br> |
− | <span class="footnote_header">OD</span>
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− | <span class="footnote_txt">Optical density</span>
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− | </span>
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− | </span>
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| <a id="section2"> | | <a id="section2"> |
| <span class="place_holder"></span> | | <span class="place_holder"></span> |
− | Section2 | + | UNDERSTANDING EARLY DIAGNOSIS AND SCREENING |
| </a> | | </a> |
| </h2> | | </h2> |
− | <p>xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxxxxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxxxxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx | + | <p>Early diagnosis is defined as <strong>the early identification of cancer in patients who have symptoms of the disease</strong>. This contrasts with cancer screening that seeks to identify unrecognized (pre-clinical) cancer or pre-cancerous lesions in an apparently healthy target population. Cancer early diagnosis and screening are both important components of comprehensive cancer control, but are fundamentally different in resource and infrastructure requirements, impact and cost.<br> |
| + | <br> |
| + | When done promptly, cancer may be detected at a potentially curable stage, improving survival and quality of life. There are three steps to early diagnosis:<br> |
| + | • Step 1: awareness of cancer <strong>symptoms</strong> and accessing care;<br> |
| + | • Step 2: clinical <strong>evaluation</strong>, diagnosis and staging; and<br> |
| + | • Step 3: access to <strong>treatment</strong>, including pain relief.<br> |
| + | <br> |
| + | In contrast, <strong>screening</strong> aims to identify unrecognized cancer or its precursor lesions in an apparently healthy, asymptomatic population by means of tests (e.g. HPV assay), examinations (e.g. VIA visual inspection with acetic acid), imaging (e.g. mammography) or other procedures that can be applied rapidly and accessed widely by the target population.<br> |
| + | <br> |
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| </p> | | </p> |
| + | <!--******************************Fig 1****************************--> |
| + | <div class="img_in_text zoom_out_able"> |
| + | <img src="https://static.igem.org/mediawiki/2018/6/64/T--SJTU-BioX-Shanghai--interlab_Fig1.jpg"/> |
| + | </div> |
| + | |
| + | <!--****************************************************************--> |
| + | <p>Barriers to early diagnosis are generally analogous to those in the cancer screening process and include limited access to diagnostic tests and pathology; poor follow-up and coordination; inaccessible high-quality, timely treatment; and financial obstacles. Policies and programmes to overcome these barriers should focus on improving early diagnosis, prior to implementing cancer screening when possible.<br> |
| + | <br> |
| + | A situation analysis should be performed prior to planning or scaling-up early diagnosis or screening programmes. The assessment can include effectiveness and costs of current cancer control strategies, current population coverage of services, obstacles to care including delays, financial protection and quality of care.<br> |
| + | <br> |
| + | </p> |
| + | <!--******************************Fig 1****************************--> |
| + | <div class="img_in_text zoom_out_able"> |
| + | <img src="https://static.igem.org/mediawiki/2018/6/64/T--SJTU-BioX-Shanghai--interlab_Fig1.jpg"/> |
| + | </div> |
| + | |
| + | <!--****************************************************************--> |
| + | <p>The overall status of early diagnosis and screening programmes can be assessed in the distribution of cancer stage at diagnosis and trends overtime.<br></p> |
| | | |
| <h2> | | <h2> |
| <a id="section3"> | | <a id="section3"> |
| <span class="place_holder"></span> | | <span class="place_holder"></span> |
− | Section3
| + | IMPACT OF EARLY DIAGNOSIS |
| </a> | | </a> |
| </h2> | | </h2> |
− | <p>xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx. The text-link template is here.</p> | + | <p>There is consistent evidence that the early diagnosis of cancer, combined with accessible, affordable effective treatment, results in improvements in both the stage of cancer at presentation and mortality from cancer. <p style=”color:red; font-size: 1.3vw;”>Over 50% of the decrease in breast cancer mortality in women under age 65 was due to improved early diagnosis and the provision of effective treatment.</p><br> |
− | <a title="https://static.igem.org/mediawiki/2018/0/09/2018_InterLab_Plate_Reader_Protocol.pdf" href="https://static.igem.org/mediawiki/2018/0/09/2018_InterLab_Plate_Reader_Protocol.pdf">2018 Interlab Plate Reader Protocol</a> <br/>
| + | <br> |
− | <a title="http://parts.igem.org/Help:Protocols/Transformation" href="http://parts.igem.org/Help:Protocols/Transformation">Protocols/Transformation</a> | + | It is also well established that reducing delays in care can have a significant impact on improving outcomes. <p style=”color:red; font-size: 1.3vw;”>In one study, patients who experienced a short delay (<3 months) experienced an absolute 7% greater likelihood of survival from breast cancer compared with those who had moderate delays (3–6 months) in care.</p><br> |
| + | <br> |
| + | While improving early diagnosis generally improves outcomes, not all cancer types benefit equally. Cancers that are common, that can be diagnosed at early stages from signs and symptoms and for which early treatment is known to improve the outcome are generally those that benefit most from early diagnosis. Examples include breast, cervical, colorectal and oral cancers.<br> |
| + | </p> |
| + | <!--******************************Fig 1****************************--> |
| + | <div class="img_in_text zoom_out_able"> |
| + | <img src="https://static.igem.org/mediawiki/2018/6/64/T--SJTU-BioX-Shanghai--interlab_Fig1.jpg"/> |
| + | </div> |
| + | |
| + | <!--****************************************************************--> |
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| <h2> | | <h2> |
| <a id="section4"> | | <a id="section4"> |
| <span class="place_holder"></span> | | <span class="place_holder"></span> |
− | section4 | + | ACHIEVING EARLY DIAGNOSIS |
| </a> | | </a> |
| </h2> | | </h2> |
− | <p> xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx The figure template is here.</p> | + | <p> There are three key steps to cancer early diagnosis.<br></p> |
| + | <!--******************************Fig 1****************************--> |
| + | <div class="img_in_text zoom_out_able"> |
| + | <img src="https://static.igem.org/mediawiki/2018/6/64/T--SJTU-BioX-Shanghai--interlab_Fig1.jpg"/> |
| + | </div> |
| | | |
− |
| + | <!--****************************************************************--> |
− | <!--******************************Fig 1****************************-->
| + | <p>Step 1: Awareness and accessing care<br> |
| + | Symptom appraisal (period from detecting a bodily change to perceiving a reason to discuss the symptoms with a health-care practitioner); and health-seeking behavior (period from perceiving a need to discuss the symptoms with a health-care practitioner to reaching the health facility for an assessment).<br> |
| + | <br> |
| + | Step 2: Clinical evaluation, diagnosis and staging<br> |
| + | Accurate clinical diagnosis; diagnostic testing and staging; and referral for treatment. This step is also known as the diagnostic interval.<br> |
| + | <br> |
| + | Step 3: Access to treatment<br> |
| + | The patient with cancer needs to be able to access high-quality, affordable treatment in a timely manner.<br> |
| + | |
| + | </p> |
| + | <!--******************************Fig 1****************************--> |
| <div class="img_in_text zoom_out_able"> | | <div class="img_in_text zoom_out_able"> |
| <img src="https://static.igem.org/mediawiki/2018/6/64/T--SJTU-BioX-Shanghai--interlab_Fig1.jpg"/> | | <img src="https://static.igem.org/mediawiki/2018/6/64/T--SJTU-BioX-Shanghai--interlab_Fig1.jpg"/> |
− | <p class="fig_illustration">Fig 1. The particle standard curve obtained form the 2nd calibration experiment.</p>
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| </div> | | </div> |
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− | <!--****************************************************************-->
| + | <!--****************************************************************--> |
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− | <p> xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx xxx.</p>
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− | <p>The table template is here.</p>
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| + | <p> <strong>Delays and barriers</strong><br> |
| + | <br> |
| + | Poor health literacy:<br> |
| + | Lack of awareness about cancer symptoms is common and can result in a prolonged symptom appraisal interval and significant delays in seeking care.<br> |
| + | <br> |
| + | Cancer stigma:<br> |
| + | Cancer stigma is a sense of devaluation by individuals or communities related to cancer patients. Patients may be embarrassed about the symptoms or fear the financial or personal impact of receiving care for cancer.<br> |
| + | <br> |
| + | Limited access to primary care<br> |
| + | Access to primary care is critical for early diagnosis by enabling a timely diagnosis. Barriers to seeking primary care may be related to financial constraints, geographic/transportation obstacles, time-poverty and inflexible working conditions, non-availability of services, sociocultural or gender-related factors, compounded by generally lower health literacy and higher levels of cancer stigma.<br> |
| + | </p> |
| + | |
| + | <!--******************************Fig 1****************************--> |
| + | <div class="img_in_text zoom_out_able"> |
| + | <img src="https://static.igem.org/mediawiki/2018/6/64/T--SJTU-BioX-Shanghai--interlab_Fig1.jpg"/> |
| + | </div> |
| | | |
− | <!--*****************************Table 1****************************-->
| + | <!--****************************************************************--> |
− | <div class="table_in_text">
| + | <p> |
− | <p class="table_illustration">Table 1. Colony forming units per 0.1 OD<sub>600</sub></p>
| + | Inaccurate clinical assessment and delays in clinical diagnosis:<br> |
− | <table style="border-collapse: collapse; ">
| + | Patient encounters with health-care providers can result in delays in care when they lack diagnostic capacity or are isolated from the health system.<br> |
− | <tr style="border-top:2px solid #000;">
| + | Cancer signs and symptoms can be vague, non-specific or difficult to detect. <br> |
− | <th rowspan="2">samples</th>
| + | A larger percentage of countries do not have programmes or guidelines to strengthen the early identification of common cancers at the primary care level.<br> |
− | <th colspan="3">dilution factor</th>
| + | <br> |
− | <th rowspan="2">CFU/mL</th>
| + | Inaccessible diagnostic testing, pathology and staging:<br> |
− | </tr>
| + | Barriers to or harms from diagnostic tests and pathology can range from inaccessible or unavailable services to overusing tests, depending on resource availability.<br> |
− |
| + | <br> |
− | <tr>
| + | <br> |
− | <td>8×10<sup>4</sup></td>
| + | Poor coordination and loss to follow-up:<br> |
− | <td>8×10<sup>5</sup></td>
| + | The facility where a clinical diagnosis is made may be different from where the biopsy is obtained, pathology reviewed and/or staging performed. Delays in cancer diagnosis may arise due to poor follow-up, lack of referral pathways and fragmented health services. Less than 50% of low- and middle-income countries currently have clearly defined referral systems for suspected cancer from primary care to secondary and tertiary care.<br> |
− | <td>8×10<sup>6</sup></td>
| + | <br> |
− | </tr>
| + | <br> |
− |
| + | Financial, geographic and logistical barriers<br> |
− | <tr style="border-top:2px solid #000;">
| + | In a significant number of countries, basic treatment services are unavailable.<br> |
− | <td>1.1</td> <td>TNTC</td> <td>48</td> <td>11</td> <td>3.84E+07</td>
| + | Fear of financial catastrophe is also a major cause of non-attendance for diagnosis, delay and abandonment of treatment among patients with early cancer symptoms.<br> |
− | </tr>
| + | Patients may have to travel long distances to access a facility capable of providing cancer treatment, and longer travel distance has been associated with late presentation.<br> |
− | <tr>
| + | |
− | <td>1.2</td> <td>248</td> <td>41</td> <td>10</td> <td>3.28E+07</td>
| + | |
− | </tr>
| + | |
− | <tr>
| + | |
− | <td>1.3</td> <td>172</td> <td>54</td> <td>5</td> <td>4.32E+07</td>
| + | |
− | </tr>
| + | |
− | <tr>
| + | |
− | <td>2.1</td> <td>TNTC</td> <td>143</td> <td>20</td> <td>1.14E+08</td>
| + | |
− | </tr>
| + | |
− | <tr>
| + | |
− | <td>2.2</td> <td>TNTC</td> <td>153</td> <td>25</td> <td>1.22E+08</td>
| + | |
− | </tr>
| + | |
− | <tr>
| + | |
− | <td>2.3</td> <td>TNTC</td> <td>151</td> <td>18</td> <td>1.21E+08</td>
| + | |
− | </tr>
| + | |
− | <tr>
| + | |
− | <td>3.1</td> <td>TNTC</td> <td>119</td> <td>16</td> <td>9.52E+07</td>
| + | |
− | </tr>
| + | |
− | <tr>
| + | |
− | <td>3.2</td> <td>TNTC</td> <td>125</td> <td>19</td> <td>1.00E+08</td>
| + | |
− | </tr>
| + | |
− | <tr>
| + | |
− | <td>3.3</td> <td>TNTC</td> <td>89</td> <td>18</td> <td>7.12E+07</td>
| + | |
− | </tr>
| + | |
− | <tr>
| + | |
− | <td>4.1</td> <td>TNTC</td> <td>209</td> <td>16</td> <td>1.67E+08</td>
| + | |
− | </tr>
| + | |
− | <tr>
| + | |
− | <td>4.2</td> <td>TNTC</td> <td>130</td> <td>17</td> <td>1.04E+08</td>
| + | |
− | </tr>
| + | |
− | <tr style="border-bottom:2px solid #000;">
| + | |
− | <td>4.3</td> <td>TNTC</td> <td>164</td> <td>10</td> <td>1.31E+08</td>
| + | |
− | </tr>
| + | |
| | | |
− | </table> | + | </p> |
| + | <!--******************************Fig 1****************************--> |
| + | <div class="img_in_text zoom_out_able"> |
| + | <img src="https://static.igem.org/mediawiki/2018/6/64/T--SJTU-BioX-Shanghai--interlab_Fig1.jpg"/> |
| </div> | | </div> |
| | | |
| + | <!--****************************************************************--> |
| + | <p> |
| + | Sociocultural barriers:<br> |
| + | Patients may inaccurately believe cancer is incurable or associate cancer treatment with death or pain, resulting in delays in or not pursuing care.<br> |
| + | </p> |
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− |
| + | |
| <h2> | | <h2> |
| <a id="section5"> | | <a id="section5"> |
| <span class="place_holder"></span> | | <span class="place_holder"></span> |
− | Section5 | + | CONCLUSION |
| </a> | | </a> |
| </h2> | | </h2> |
− | <p>XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX </p> | + | <p>Delayed diagnosis and inability to access treatment contribute significantly to cancer morbidity and mortality globally. Solutions must be oriented around a comprehensive health system response and service integration, prioritizing high-impact and cost-sensitive interventions.<br> |
| + | Early diagnosis improves cancer outcomes by providing the greatest likelihood of successful treatment, at lower cost and with less complex interventions. The principles to achieve early diagnosis are relevant at all resource levels and include increasing cancer awareness and health participation; promoting accurate clinical evaluation, pathologic diagnosis and staging; and improving access to care. These programmatic investments are particularly important where disparities are the most profound and to provide access to cancer care for all.<br> |
| + | A cancer death is a tragedy to a family and community with enormous repercussions. By developing effective strategies to identify cancer early, lives can be saved and the personal, societal and economic costs of cancer care can be reduced.<br> |
| + | <p style=”color:red; font-size: 1.3vw;”>(Add one statement to strengthen the importance of cutting down the cost of early diagnosis)<br></p> |
| + | </p> |
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| </div> | | </div> |