A Challenging Differential Diagnosis Between Brain Radionecrosis and Recurrent Metastatic Disease, with Temporary Clinical/Radiological Response to Bevacizumab and Later Imaging Suspicious for Oligoprogression

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

I think it´s important for the reader that you explain the diffences between fractionated whole brain RT an focal stereotactic RT.

You propose 2-3 monthly MR follow up for patients could you cite the recommondation you cited. According to my view 3-4 monthly is  sufficient. Such FU regimens are used for patients after focal RT of brainmets, not for Patients after whoile brain irradtation.

Case presentation

The patient received 3 courses of RT  to the same spot with in 4 years.

It would be helpful if you ad MR pictures of the treated brain metastases progression.

What makes you shure it was progress in this situation and not RT induces changes ( "radionecrosis")?

It would be helpful if you also could RT plans of this region.

What was cumulative BED in the region were the Radionecrosis occured?

Discussion

There are some very informative metaanalyses on this topic published perhaps you coul include some of them in your disussion.

Ther are national and international guidelines for the treat ment aof BRN published you should add this to your discussion. Bev is standard of care in the treatment of BRN

 

Comments on the Quality of English Language

Please correct some typos .. line 33, line 65..

Author Response

Open Review

(x) I would not like to sign my review report
( ) I would like to sign my review report

 

Quality of English Language

(x) The English could be improved to more clearly express the research.
( ) The English is fine and does not require any improvement.

 

	Yes	Can be improved	Must be improved	Not applicable
Does the introduction provide sufficient background and include all relevant references?	(x)	( )	( )	( )
Is the research design appropriate?	( )	(x)	( )	( )
Are the methods adequately described?	( )	(x)	( )	( )
Are the results clearly presented?	( )	(x)	( )	( )
Are the conclusions supported by the results?	( )	(x)	( )	( )
Are all figures and tables clear and well-presented?	( )	(x)	( )	( )

 

Comments and Suggestions for Authors

I think it´s important for the reader that you explain the diffences between fractionated whole brain RT an focal stereotactic RT.

Response: Whole Brain Radiotherapy (WBRT) treats the entire brain over multiple sessions, often causing cognitive side effects but covering microscopic disease. Stereotactic Radiosurgery/Radiotherapy (SRS/SRT) delivers high-dose, precise radiation only to tumors in 1–5 sessions, sparing healthy tissue and preserving cognitive function. SRS and SRT are preferred for limited metastases, while WBRT handles extensive disease.

You propose 2-3 monthly MR follow up for patients could you cite the recommondation you cited. According to my view 3-4 monthly is sufficient. Such FU regimens are used for patients after focal RT of brainmets, not for Patients after whoile brain irradtation.

Response: We agree with you, we modified in the text: Regarding follow-up imaging regimens patients with brain metastases require MRI monitoring every 2-3-4 months for the first 2 years after the initial treatment. Thank you for your advice!

Case presentation

The patient received 3 courses of RT  to the same spot with in 4 years.

It would be helpful if you ad MR pictures of the treated brain metastases progression.

Response We don’t have the MRI picture because the patient performed the treatment in other Radiotherapy Center

What makes you sure it was progress in this situation and not RT induces changes ( "radionecrosis")?

Response: We are not sure! We mentioned in the section Conclusions: The case we presented is a clinically plausible mixed or evolving scenario in which radionecrosis and tumor progression may have coexisted. Thank you for your recommendation!

 

It would be helpful if you also could RT plans of this region.

Response

 

The images are from radiotherapy treatment, in SRT technique, performed in November 2024, total dose 25 Gy/5 fractions for progressive right parietal disease.

What was cumulative BED in the region were the Radionecrosis occured?

Response:

Cumulative biological effective dose (BED) for right parietal lesions was 170 Gy. The cumulative Biologically Effective Dose (BED) ranges between 120 and 200 Gy assuming an alfa/beta report of 3 Gy for late-reacting normal brain tissues, for symptomatic brain radionecrosis.

Discussion

There are some very informative metaanalyses on this topic published perhaps you coul include some of them in your disussion.

Response: We presented at the end of the discussions two studies, regarding Bevacizumab.

Lee SH, Choi JW, Kong DS, Seol HJ, Nam DH, Lee JI. Effect of Bevacizumab Treatment in Cerebral Radiation Necrosis : Inves-tigation of Response Predictors in a Single-Center Experience. J Korean Neurosurg Soc. 2023 Sep;66(5):562-572. doi: 10.3340/jkns.2022.0229. Epub 2023 Jan 16.

Zhuang H, Zhuang H, Shi S, Wang Y. Ultra-Low-Dose Bevacizumab For Cerebral Radiation Necrosis: A Prospective Phase II Clinical Study. Oncotargets and Therapy. 2019 ;12:8447-8453. DOI: 10.2147/ott.s223258.

Thank you for your recommendation!

 

Ther are national and international guidelines for the treat ment aof BRN published you should add this to your discussion. Bev is standard of care in the treatment of BRN

Response: Done:

We included in the text: According to The International Stereotactic Radiosurgery Society, BRN management depending on the BRN grade.

The recommendations for the management of symptomatic BRN are included in the international guidelines for the treatment of BRN  published by The International Stereotactic Radiosurgery Society and ASCO-SNO-ASTRO.

1. .Balamurugan V, Lim-Fat M-J, Kotecha R, De Salles A, Fariselli L, Levivier M, Ma L, Paddick I, Bruce E. Pollock B E. et al. A Systematic Review Informing the Management of Symptomatic Brain Radiation Necrosis After Stereotactic Radiosurgery and International Stereotactic Radiosurgery Society Recommendations International Journal of Radiation Oncology, Biology, Physics, Volume 118, Issue 1, 14 – 28
2. Vogelbaum M A., Brown , Messersmith H, Brastianos PK, Burri S, Cahill D, Dunn IF, Gaspar LE, Gatson NTN, Gondi V et al. Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. J Clin Oncol 40, 492-516(2022). DOI:10.1200/JCO.21.02314

 

 

 

 

Comments on the Quality of English Language

Please correct some typos .. line 33, line 65..

Response: Done

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript addresses a clinically relevant problem, namely the differentiation between brain radiation necrosis and tumor progression after repeated brain irradiation in a patient with metastatic breast cancer. However, in its current form, the manuscript remains scientifically weak, insufficiently documented, and poorly presented. Substantial revision is required before the work can be considered further.

Major comments

1. The central diagnostic claim is overstated.
   The manuscript repeatedly implies that perfusion MRI “established” the differential diagnosis between brain radiation necrosis and tumor progression. This is not justified by the data presented. In your own case narrative, the later MRI showed hyperperfusion suggestive of evolving disease, and biopsy was proposed but refused. Therefore, the case is not a definitive demonstration of radionecrosis, but rather a clinically plausible mixed or evolving scenario in which radionecrosis and tumor progression may have coexisted. The manuscript must be rewritten in a much more cautious and scientifically defensible way.

2. The imaging methodology is inadequately described.
   Since the entire manuscript relies on perfusion MRI as the key diagnostic tool, the technical details are far too sparse. You do not adequately describe:

   • the perfusion technique used,

   • acquisition parameters,

   • post-processing approach,

   • whether DSC or DCE was used at each time point,

   • whether rCBV or other quantitative metrics were measured,

   • what thresholds or interpretive criteria supported radionecrosis rather than recurrence,

   • whether prior corticosteroid use could have influenced imaging appearance.
     Without these details, the reader cannot assess the validity of the radiological interpretation.

3. There is no robust diagnostic confirmation.
   Histopathology is correctly acknowledged as the gold standard, yet the manuscript uses language that goes beyond what the available evidence supports. Because biopsy was refused, the diagnosis remains presumptive. This limitation must be moved to the foreground and discussed explicitly as the major weakness of the report.

4. The therapeutic effect of bevacizumab is overinterpreted.
   Clinical and radiological improvement after bevacizumab is compatible with radionecrosis, but it does not prove the diagnosis. Anti-VEGF treatment may reduce edema and contrast enhancement without resolving the underlying diagnostic ambiguity. The manuscript should avoid implying causal certainty.

5. The case timeline needs to be reorganized and clarified.
   The chronology is difficult to follow. The paper would benefit from a concise timeline table including:

   • primary breast cancer diagnosis and subtype,

   • surgery/systemic therapy,

   • dates and doses of WBRT and each SRT course,

   • date of symptom onset,

   • MRI dates and key findings,

   • bevacizumab dosing and number of cycles,

   • subsequent imaging and clinical status.
     At present, the reader has to reconstruct the sequence manually.

6. Discussion is too generic and insufficiently case-anchored.
   Much of the discussion reads like a broad narrative overview rather than an analysis of this specific case. The authors should focus more directly on:

   • cumulative radiation exposure and reirradiation context,

   • risk factors for radionecrosis in this patient,

   • why perfusion MRI was considered persuasive here,

   • what alternative explanations remained,

   • why surgery was not performed,

   • what the October 2025 MRI means for the interpretation of the previous response.

7. The manuscript should be presented explicitly as a diagnostic dilemma, not as a resolved diagnostic proof.
   In its present version, the manuscript would be stronger and more honest if framed as:
   “a challenging differential diagnosis between BRN and recurrent metastatic disease, with temporary clinical/radiological response to bevacizumab and later imaging suspicious for oligoprogression.”
   That framing is defendable. The current framing is not.

Minor comments

1. Replace “MRI with infusion protocol” with the correct radiological terminology throughout. The manuscript appears to mean perfusion MRI, not “infusion”.

2. “Karnovsky Index” should be corrected to Karnofsky Performance Status.

3. Several grammatical constructions are incorrect or non-standard and reduce scientific clarity.

4. Figure legends are too limited and do not explain what exact imaging feature supports the interpretation.

5. If possible, annotate the figures with arrows and specify the sequence shown.

6. Table 1 should explain why these comparator case reports were selected and what message the comparison is intended to support.

7. The conclusion should be shortened and made more conservative.

Comments on the Quality of English Language

The English requires substantial revision. The manuscript contains frequent grammatical errors, incorrect word choices, awkward phrasing, and repeated misuse of technical terminology. These problems are not merely stylistic; they interfere with scientific precision.

Examples include the repeated use of “infusion MRI” instead of “perfusion MRI”, incorrect or inconsistent medical phrasing, and multiple sentences with unclear syntax. The paper should undergo thorough editing by a fluent scientific English writer familiar with oncologic and neuroradiologic terminology.

Author Response

Open Review

(x) I would not like to sign my review report
( ) I would like to sign my review report

 

Quality of English Language

(x) The English could be improved to more clearly express the research.
( ) The English is fine and does not require any improvement.

 

	Yes	Can be improved	Must be improved	Not applicable
Does the introduction provide sufficient background and include all relevant references?	( )	(x)	( )	( )
Is the research design appropriate?	( )	(x)	( )	( )
Are the methods adequately described?	( )	( )	(x)	( )
Are the results clearly presented?	( )	(x)	( )	( )
Are the conclusions supported by the results?	( )	(x)	( )	( )
Are all figures and tables clear and well-presented?	( )	(x)	( )	( )

 

Comments and Suggestions for Authors

This manuscript addresses a clinically relevant problem, namely the differentiation between brain radiation necrosis and tumor progression after repeated brain irradiation in a patient with metastatic breast cancer. However, in its current form, the manuscript remains scientifically weak, insufficiently documented, and poorly presented. Substantial revision is required before the work can be considered further.

Major comments

1. The central diagnostic claim is overstated.
   The manuscript repeatedly implies that perfusion MRI “established” the differential diagnosis between brain radiation necrosis and tumor progression. This is not justified by the data presented. In your own case narrative, the later MRI showed hyperperfusion suggestive of evolving disease, and biopsy was proposed but refused. Therefore, the case is not a definitive demonstration of radionecrosis, but rather a clinically plausible mixed or evolving scenario in which radionecrosis and tumor progression may have coexisted. The manuscript must be rewritten in a much more cautious and scientifically defensible way.

Response: we mentioned:

 

-in the section The particularities of our case:  It is possible that corticosteroids have an impact on the interpretation of MRI scans, particularly for Bevacizumab emphasizing that corticosteroids can even decrease tumor enhancement on contrast-MRI.

- in the section Conclusions: The case we presented is a clinically plausible mixed or evolving scenario in which radionecrosis and tumor progression may have coexisted. Thank you for your recommendation!

We eliminated from the section The particularities of our case:  The cerebral MRI with perfusion protocol, established the differential diagnosis between BRN and TP, and that revealed the importance of this imaging setting.  

Thank you very much!

1. The imaging methodology is inadequately described.
   Since the entire manuscript relies on perfusion MRI as the key diagnostic tool, the technical details are far too sparse. You do not adequately describe:

• the perfusion technique used,
• acquisition parameters,
• post-processing approach,

Response: We added in the Discussion chapter: the perfusion technique used, acquisition parameters,post-processing approach

Thank you very much!

• whether DSC or DCE was used at each time point,
• whether rCBV or other quantitative metrics were measured,
• what thresholds or interpretive criteria supported radionecrosis rather than recurrence,

Response:  We don t have the data regarding our patient, but we mentioned in the paper that: Brain perfusion MRI in Romania, particularly for neuro-oncology, primarily utilizes Dy-namic Susceptibility Contrast (DSC-MRI). Specialized software is used for post-processing, (rCBV) being the primary parameter for differentiating tumor progression from radi-onecrosis.

whether prior corticosteroid use could have influenced imaging appearance.
Without these details, the reader cannot assess the validity of the radiological interpretation.

1. There is no robust diagnostic confirmation.
   Histopathology is correctly acknowledged as the gold standard, yet the manuscript uses language that goes beyond what the available evidence supports. Because biopsy was refused, the diagnosis remains presumptive. This limitation must be moved to the foreground and discussed explicitly as the major weakness of the report.

Response: We added the Limitations of the study: Although advanced imaging techniques provide valuable information, there was no his-topathological verification of the final diagnosis. Because biopsy was refused, the diagno-sis remains presumptive.

Thank you very much!

1. The therapeutic effect of bevacizumab is overinterpreted.
   Clinical and radiological improvement after bevacizumab is compatible with radionecrosis, but it does not prove the diagnosis. Anti-VEGF treatment may reduce edema and contrast enhancement without resolving the underlying diagnostic ambiguity. The manuscript should avoid implying causal certainty.

Response: We mentioned in the paper that Bevacizumab  is an effective therapy for symptomatic brain radionecrosis, reducing edema and improving neurological symptoms and at Limitations of the study: Although advanced imaging techniques provide valuable information, there was no histopathological verification of the final diagnosis. Because biopsy was refused, the diagnosis remains presumptive.

Thank you very much!

1. The case timeline needs to be reorganized and clarified.
   The chronology is difficult to follow. The paper would benefit from a concise timeline table including:

• primary breast cancer diagnosis and subtype,
• surgery/systemic therapy,
• dates and doses of WBRT and each SRT course,
• date of symptom onset,
• MRI dates and key findings,
• bevacizumab dosing and number of cycles,
• subsequent imaging and clinical status.
  At present, the reader has to reconstruct the sequence manually.

Response:

	Moment in time	Event
1.	2018	primary breast cancer diagnosis and subtype Stage cT2N1M0, Luminal B, , histopathologic result was yp T0N1(1+/4N) L0V0R0, IHC: RE95%, RP25%, HER2= 1+, ki67=45%; HT. After surgery, the histopathological exam identified lymph node metastases and the status HER 2 was negative.
2.	2018	surgery/systemic therapy, Neoadjuvant chemotherapy treatment, surgery-conservative treatment-left sectorectomy and sentinel lymph node
3.	2020	Brain CT revealed M1BRA – left and right frontal, left and right parietal and right temporal lesions. Whole brain adjuvant radiotherapy TD=30 Gy/10 fractions. Systemic therapy with CDK4/6 inhibitor plus Fulvestrant and ovarian suppression therapy.
4.	2023	February: Stereotactic radiotherapy (SRT) on left parietal brain metastases, 21Gy/3fractions.
5.	2024	October: brain MRI: slightly increase of right brain lesion November: Stereotactic radiotherapy (SRT) on right parietal brain metastases, 25Gy/5fractions.
6.	2025	May: neurologic hemiparesis clinical status 4/5 brachial, 3/5 crural; possible walking with unilateral support; Karnofsky Performance Status (KPS)=60-70% May-July: 4 cycles of Bevacizumab 400 mg/cycle, KPS = 80-90% July: brain perfusion MRI showed improving intra-axial post-therapeutic changes, but pachymeningeal thickening is maintained October: PET-CT showed no metabolic activity. The patient refused injectable systemic oncological treatment and continued and continued with Fulvestrant and ovarian suppression therapy.

 

1. Discussion is too generic and insufficiently case-anchored.
   Much of the discussion reads like a broad narrative overview rather than an analysis of this specific case. The authors should focus more directly on:

• cumulative radiation exposure and reirradiation context,
• risk factors for radionecrosis in this patient,
• why perfusion MRI was considered persuasive here,
• what alternative explanations remained,
• why surgery was not performed,
• what the October 2025 MRI means for the interpretation of the previous response. (dr laura sa raspunda)

Response: We mentioned in the text:

The risk factor for our case is: re-irradiation (WBRT in 2020 followed by SRT in 2023, 2024).

The patient refused the biopsy.

Otherwise, our patient refused the biopsy and the injectable systemic oncological treatment and for these reasons it remains a diagnostic dilemma; Brain perfusion MRI from october 2025 was considered persuasive due to the dimensional augmentation of the right fronto-parietal pahimeningeal lesion, with right frontal nodular area.

 

1. The manuscript should be presented explicitly as a diagnostic dilemma, not as a resolved diagnostic proof.
   In its present version, the manuscript would be stronger and more honest if framed as:
   “a challenging differential diagnosis between BRN and recurrent metastatic disease, with temporary clinical/radiological response to bevacizumab and later imaging suspicious for oligoprogression.”
   That framing is defendable. The current framing is not.

Response: We changed the title, thank you very much for your suggestion!

Also, we mentioned in the text that this case is a diagnostic dilemma.

Minor comments

1. Replace “MRI with infusion protocol” with the correct radiological terminology throughout. The manuscript appears to mean perfusion MRI, not “infusion”.

Response: Done, thank you so much!

1. “Karnovsky Index” should be corrected to Karnofsky Performance Status.

Response: Done

1. Several grammatical constructions are incorrect or non-standard and reduce scientific clarity.
2. Figure legends are too limited and do not explain what exact imaging feature supports the interpretation.
3. If possible, annotate the figures with arrows and specify the sequence shown.

Response:

 

1. Table 1 should explain why these comparator case reports were selected and what message the comparison is intended to support.

Response: We chose these case reports because we wanted to highlight that BRN occurs in different locations of cancer, being a challenge for clinicians, both in terms of diagnosis and therapeutic management.

Also, we added in the text 2 meta-analyses:

Lee SH, Choi JW, Kong DS, Seol HJ, Nam DH, Lee JI. Effect of Bevacizumab Treatment in Cerebral Radiation Necrosis : Inves-tigation of Response Predictors in a Single-Center Experience. J Korean Neurosurg Soc. 2023 Sep;66(5):562-572. doi: 10.3340/jkns.2022.0229. Epub 2023 Jan 16.

Zhuang H, Zhuang H, Shi S, Wang Y. Ultra-Low-Dose Bevacizumab For Cerebral Radiation Necrosis: A Prospective Phase II Clinical Study. Oncotargets and Therapy. 2019 ;12:8447-8453. DOI: 10.2147/ott.s223258.

 

1. The conclusion should be shortened and made more conservative.

Response: Done

 

Comments on the Quality of English Language

The English requires substantial revision. The manuscript contains frequent grammatical errors, incorrect word choices, awkward phrasing, and repeated misuse of technical terminology. These problems are not merely stylistic; they interfere with scientific precision.

Examples include the repeated use of “infusion MRI” instead of “perfusion MRI”, incorrect or inconsistent medical phrasing, and multiple sentences with unclear syntax. The paper should undergo thorough editing by a fluent scientific English writer familiar with oncologic and neuroradiologic terminology.

Response:  Done (MDPI author service)

 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The paper presents a clinical case addressing the diagnostic challenge of distinguishing brain radiation necrosis from tumor recurrence in a patient with breast cancer brain metastases, highlighting the role of advanced imaging techniques and the potential therapeutic benefit of bevacizumab. Addressing the following concerns can improve the paper:

-Authors need to improve the methodological clarity of the diagnostic process by explicitly describing the imaging criteria used to differentiate brain radiation necrosis from tumor progression, including quantitative perfusion metrics, imaging thresholds, or standardized diagnostic frameworks. This would strengthen the scientific rigor of diagnostic interpretation.

-I suggest the authors expand the discussion of differential diagnosis by more systematically comparing MRI perfusion, MR spectroscopy, PET imaging, and radiomics approaches, including their reported sensitivities and limitations in distinguishing radionecrosis from recurrent tumors. This would better contextualize the presented case within the broader neuro-oncology literature.

-Authors can provide a clearer therapeutic rationale for the use of bevacizumab, including dosing strategy, duration of therapy, and evidence from clinical trials or meta-analyses supporting its use in radiation necrosis, rather than relying primarily on individual case reports.

-They need to strengthen the scientific contribution of the manuscript by clarifying the novelty of the presented case relative to existing literature and by discussing the limitations of the study, particularly the absence of histopathological confirmation due to the refusal of a brain biopsy.

Author Response

Open Review

(x) I would not like to sign my review report
( ) I would like to sign my review report

 

Quality of English Language

(x) The English could be improved to more clearly express the research.
( ) The English is fine and does not require any improvement.

 

	Yes	Can be improved	Must be improved	Not applicable
Does the introduction provide sufficient background and include all relevant references?	( )	(x)	( )	( )
Is the research design appropriate?	( )	(x)	( )	( )
Are the methods adequately described?	( )	(x)	( )	( )
Are the results clearly presented?	( )	(x)	( )	( )
Are the conclusions supported by the results?	( )	(x)	( )	( )
Are all figures and tables clear and well-presented?	( )	(x)	( )	( )

 

Comments and Suggestions for Authors

The paper presents a clinical case addressing the diagnostic challenge of distinguishing brain radiation necrosis from tumor recurrence in a patient with breast cancer brain metastases, highlighting the role of advanced imaging techniques and the potential therapeutic benefit of bevacizumab. Addressing the following concerns can improve the paper:

-Authors need to improve the methodological clarity of the diagnostic process by explicitly describing the imaging criteria used to differentiate brain radiation necrosis from tumor progression, including quantitative perfusion metrics, imaging thresholds, or standardized diagnostic frameworks. This would strengthen the scientific rigor of diagnostic interpretation.

Response: Thank you for the suggestion! We have included in the text, during the discussions, all the details related to the differential diagnosis between brain radiation necrosis and tumor progression.

-I suggest the authors expand the discussion of differential diagnosis by more systematically comparing MRI perfusion, MR spectroscopy, PET imaging, and radiomics approaches, including their reported sensitivities and limitations in distinguishing radionecrosis from recurrent tumors. This would better contextualize the presented case within the broader neuro-oncology literature.

Response:Done, thank you very much!

-Authors can provide a clearer therapeutic rationale for the use of bevacizumab, including dosing strategy, duration of therapy, and evidence from clinical trials or meta-analyses supporting its use in radiation necrosis, rather than relying primarily on individual case reports.

Response: We presented at the end of the discussions two studies:

Lee SH, Choi JW, Kong DS, Seol HJ, Nam DH, Lee JI. Effect of Bevacizumab Treatment in Cerebral Radiation Necrosis : Inves-tigation of Response Predictors in a Single-Center Experience. J Korean Neurosurg Soc. 2023 Sep;66(5):562-572. doi: 10.3340/jkns.2022.0229. Epub 2023 Jan 16.

Zhuang H, Zhuang H, Shi S, Wang Y. Ultra-Low-Dose Bevacizumab For Cerebral Radiation Necrosis: A Prospective Phase II Clinical Study. Oncotargets and Therapy. 2019 ;12:8447-8453. DOI: 10.2147/ott.s223258.

Thank you for your recommendation!

-They need to strengthen the scientific contribution of the manuscript by clarifying the novelty of the presented case relative to existing literature and by discussing the limitations of the study, particularly the absence of histopathological confirmation due to the refusal of a brain biopsy.

Response: Done (at limitations of the study)

Limitations of the study: Although advanced imaging techniques provide valuable information, there was no histopathological verification of the final diagnosis. Because biopsy was refused, the diagnosis remains presumptive.

Thank you!

 

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The paper was improved and is ready to be published.